From: Subject: Ivermectin (PIM 292) Date: Fri, 24 Sep 2004 22:08:54 -0700 MIME-Version: 1.0 Content-Type: multipart/related; boundary="----=_NextPart_000_0040_01C4A283.150B15C0"; type="text/html" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2800.1441 This is a multi-part message in MIME format. ------=_NextPart_000_0040_01C4A283.150B15C0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.inchem.org/documents/pims/pharm/ivermect.htm Ivermectin (PIM 292)

Ivermectin

1.=20 NAME

1.1=20 Substance

1.2=20 Group

1.3=20 Synonyms

1.4=20 Identification numbers

1.4.1=20 CAS number

1.4.2=20 Other numbers

1.5=20 Brand names, Trade names

1.6=20 Manufacturers, Importers

2.=20 SUMMARY

2.1=20 Main risks and target organs

2.2=20 Summary of clinical effects

2.3=20 Diagnosis

2.4=20 First aid measures and management principles

3.=20 PHYSICO-CHEMICAL PROPERTIES

3.1=20 Origin of the substance

3.2=20 Chemical structure

3.3=20 Physical properties

3.3.1=20 Properties of the substance

3.3.2=20 Properties of the locally available formulation

3.4=20 Other characteristics

3.4.1=20 Shelf-life of the substance

3.4.2=20 Shelf-life of the locally available formulation

3.4.3=20 Storage conditions

3.4.4=20 Bioavailability

3.4.5=20 Specific properties and composition

4.=20 USES

4.1=20 Indications

4.2=20 Therapeutic dosage

4.2.1=20 Adults

4.2.2=20 Children

4.3=20 Contraindications

5.=20 ROUTES OF ENTRY

5.1=20 Oral

5.2=20 Inhalation

5.3=20 Dermal

5.4=20 Eye

5.5=20 Parenteral

5.6=20 Other

6.=20 KINETICS

6.1=20 Absorption by route of exposure

6.2=20 Distribution by route of exposure

6.3=20 Biological half-life by route of exposure

6.4=20 Metabolism

6.5=20 Elimination by route of exposure

7.=20 PHARMACOLOGY AND TOXICOLOGY

7.1=20 Mode of action

7.1.1=20 Toxicodynamics

7.1.2=20 Pharmacodynamics

7.2=20 Toxicity

7.2.1=20 Human data

7.2.1.1=20 Adults

7.2.1.2=20 Children

7.2.2=20 Relevant animal data

7.2.3=20 Relevant in vitro data

7.3=20 Carcinogenicity

7.4=20 Teratogenicity

7.5=20 Mutagenicity

7.6=20 Interactions

7.7=20 Main adverse effects

8.=20 TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

8.1=20 Material sampling plan

8.1.1=20 Sampling and specimen collection

8.1.1.1=20 Toxicological analyses

8.1.1.2=20 Biomedical analyses

8.1.1.3=20 Arterial blood gas analysis

8.1.1.4=20 Haematological analyses

8.1.1.5=20 Other (unspecified) analyses

8.1.2=20 Storage of laboratory samples and specimens

8.1.2.1=20 Toxicological analyses

8.1.2.2=20 Biomedical analyses

8.1.2.3=20 Arterial blood gas analysis

8.1.2.4=20 Haematological analyses

8.1.2.5=20 Other (unspecified) analyses

8.1.3=20 Transport of laboratory samples and specimens

8.1.3.1=20 Toxicological analyses

8.1.3.2=20 Biomedical analyses

8.1.3.3=20 Arterial blood gas analysis

8.1.3.4=20 Haematological analyses

8.1.3.5=20 Other (unspecified) analyses

8.2=20 Toxicological Analyses and Their Interpretation

8.2.1=20 Tests on toxic ingredient(s) of material

8.2.1.1=20 Simple Qualitative Test(s)

8.2.1.2=20 Advanced Qualitative Confirmation Test(s)

8.2.1.3=20 Simple Quantitative Method(s)

8.2.1.4=20 Advanced Quantitative Method(s)

8.2.2=20 Tests for biological specimens

8.2.2.1=20 Simple Qualitative Test(s)

8.2.2.2=20 Advanced Qualitative Confirmation Test(s)

8.2.2.3=20 Simple Quantitative Method(s)

8.2.2.4=20 Advanced Quantitative Method(s)

8.2.2.5=20 Other Dedicated Method(s)

8.2.3=20 Interpretation of toxicological analyses

8.3=20 Biomedical investigations and their interpretation

8.3.1=20 Biochemical analysis

8.3.1.1=20 Blood, plasma or serum

8.3.1.2=20 Urine

8.3.1.3=20 Other fluids

8.3.2=20 Arterial blood gas analyses

8.3.3=20 Haematological analyses

8.3.4=20 Interpretation of biomedical investigations

8.4=20 Other biomedical (diagnostic) investigations and their=20 interpretation

8.5=20 Overall Interpretation of all toxicological analyses and = toxicological=20 investigations

8.6=20 References

9.=20 CLINICAL EFFECTS

9.1=20 Acute poisoning

9.1.1=20 Ingestion

9.1.2=20 Inhalation

9.1.3=20 Skin exposure

9.1.4=20 Eye contact

9.1.5=20 Parenteral exposure

9.1.6=20 Other

9.2=20 Chronic poisoning

9.2.1=20 Ingestion

9.2.2=20 Inhalation

9.2.3=20 Skin exposure

9.2.4=20 Eye contact

9.2.5=20 Parenteral exposure

9.2.6=20 Other

9.3=20 Course, prognosis, cause of death

9.4=20 Systematic description of clinical effects

9.4.1=20 Cardiovascular

9.4.2=20 Respiratory

9.4.3=20 Neurological

9.4.3.1=20 CNS

9.4.3.2=20 Peripheral nervous system

9.4.3.3=20 Autonomic nervous system

9.4.3.4=20 Skeletal and smooth muscle

9.4.4=20 Gastrointestinal

9.4.5=20 Hepatic

9.4.6=20 Urinary

9.4.6.1=20 Renal

9.4.6.2=20 Other

9.4.7=20 Endocrine and reproductive systems

9.4.8=20 Dermatological

9.4.9=20 Eye, ear, nose, throat: local effects

9.4.10=20 Haematological

9.4.11=20 Immunological

9.4.12=20 Metabolic

9.4.12.1=20 Acid-base disturbances

9.4.12.2=20 Fluid and electrolyte disturbances

9.4.12.3=20 Others

9.4.13=20 Allergic reactions

9.4.14=20 Other clinical effects

9.4.15=20 Special risks

9.5=20 Other

9.6=20 Summary

10.=20 MANAGEMENT

10.1=20 General principles

10.2=20 Relevant laboratory analyses

10.2.1=20 Sample collection

10.2.2=20 Biomedical analysis

10.2.3=20 Toxicological analysis

10.2.4=20 Other investigations

10.3=20 Life supportive procedures and symptomatic/specific = treatment

10.4=20 Decontamination

10.5=20 Elimination

10.6=20 Antidote treatment

10.6.1=20 Adults

10.6.2=20 Children

10.7=20 Management discussion

11.=20 ILLUSTRATIVE CASES

11.1=20 Case reports from literature

11.2=20 Internally extracted data on cases

11.3=20 Internal cases

12.=20 Additional information

12.1=20 Availability of antidotes

12.2=20 Specific preventive measures

12.3=20 Other

13.=20 REFERENCES

14.=20 AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE=20 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 =
B_1a)
             70209-81 (component B_1b)
     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=20
       non-infected humans.  Only side effects have been reported:=20
       itching, swollen lymph glands, dizziness, hypotension, fever,=20
       headache and myalgia.  Side effects are more frequent and=20
       severe in patients with high microfilaria counts.
       
       Other persons at risk include veterinarians and farm workers=20
       involved in treating animals for worms and ectoparasites. =20
       Most cases reported involve accidental self-injection and some=20
       ingestions of injectable solutions.  No human deaths have been=20
       reported.
     2.2 Summary of clinical effects
       In human poisoning exposures reported, the signs and =
symptoms=20
       reported are: vomiting, tachycardia, mydriasis, somnolence and=20
       blood pressure fluctuation.  The effects of small quantities=20
       of accidentally injected veterinary formulations appear=20
       negligible.  The adverse reactions encountered in patients=20
       being treated for filariasis are: fever, headaches, weakness,=20
       cough, swollen lymph glands, arthralgia, myalgia and=20
       gastrointestinal symptoms.
     2.3 =
Diagnosis
       The diagnosis is based on history of administration and=20
       occurrence of adverse effects or toxic effects.
       
       No specific laboratory tests are necessary unless clinically=20
       indicated.  Although a sensitive assay exists for ivermectin,=20
       it is unlikely to be useful in the clinical management of=20
       poisoning.

     2.4 First aid measures and =
management principles
       Ingestion: clinical management is symptomatic and =
supportive.=20
       Dilute with water; induce emesis using syrup of ipecac; obtain=20
       medical advice.  The management of adverse reactions is purely=20
       symtomatic and responds to analgesics and antihistamines.
       
       Eye contact: remove any contact lenses, flush the contaminated=20
       eyes gently with water for 10 to 15 minutes holding the=20
       eyelids open, and obtain medical advice.
       
       Skin contact: flush the contaminated area gently with water=20
       for 10 to 15 minutes.  Obtain medical advice.
       
       Parenteral contact: although the effects on adults following=20
       accidental self-injections of small quantities (< 2 ml)=20
       appear to be negligible, appropriate measures should be=20
       considered in view of the risk of secondary infection from a=20
       contaminated syringe.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Ivermectin is a semi-synthetic derivative of one of the=20
       avermectins, a group of macrocyclic lactones produced by the=20
       soil bacterium Streptomyces avermitilis (Reynolds, =
1989).
  =
   3.2 Chemical structure
       A mixture of:
       
       80% ivermectin component B_1a (5-O-demethyl-22,23-
       dihydroavermectin A_1a)
       
       C₄₈H₇₄O₁₄
       
       MW =3D 875.1
       
       20% ivermectin component B_1b (5-O-demethyl-25-de(1-
       methylpropyl)-22, 23-dihydro-25-(1-methylethyl)avermectin =
A_1a)
       
       C₄₇H₇₂O₁₄
       
       MW =3D 861.1
       
       (Reynolds, 1989)
 =
    3.3 Physical properties
       =
3.3.1 Properties of the substance
             Ivermectin forms colourless crystals
             Water Solubility =3D 4 mg/L
             Soluble in polar organic solvents (e.g. butanol=20
             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=20
             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=20
       treatment of onchocerciasis in humans, and also for=20
       strongyloidiasis, ascariasis, trichuriasis and=20
       enterobiasis.  It is being used in mass treatment of=20
       programmes in endemic regions.
       
       Ivermectin is an antiparasitic agent with a broad=20
       spectrum of activity against nematode worms and=20
       ectoparasites in animals, and has been in use for nearly=20
       a decade.  Veterinary dosages range from 20 to 3000=20
       =F0g/kg.
  =
   4.2 Therapeutic dosage
       4.2.1 Adults
             Oral:  3 to 12 mg as a single dose per os (about =
150 to=20
             200 =F0g/kg bodyweight) for onchocerciasis and other=20
             parasitic infections.
       4.2.2 Children
             Ivermectin is not given to children weighing less =
than=20
             15 kg.  The dose is 150 =F0g/kg bodyweight (in children=20
             weighing more).
     4.3 =
Contraindications
       Ivermectin is contraindicated in persons with an =
immediate=20
       hypersensitivity to the drug.  It should not be given to=20
       mothers who are breast-feeding until the infant is at least=20
       three months old (Reynolds, 1993).
    5. ROUTES OF ENTRY
     5.1 =
Oral
       Ivermectin is moderately well absorbed following oral=20
       administration (Hayes & Laws, 1991).
     5.2 Inhalation
       Not applicable.
     5.3 =
Dermal
       Animal studies indicate that ivermectin can be absorbed=20
       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=20
       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=20
       approximately twice the systemic availability of ivermectin=20
       capsules or tablets.  In this study, peak serum concentrations=20
       of ivermectin were 81, 50 and 46 ng/ml following single 12 mg=20
       oral doses of the solution (40% v/v ethanol), capsules (6 mg=20

       each) and tablets (6 mg each), respectively, to healthy=20
       volunteers. Values of area under the concentration-time curve=20
       (AUC) were 1473, 1034, and 885 ng/hr/ml, respectively.  The=20
       greater availability of the alcoholic solution suggests that=20
       the extent of absorption of ivermectin is limited in part by=20
       its solubility (Edwards et al., 1988).
     6.2 Distribution by route of exposure
       The highest tissue concentrations occur in the liver and =
the=20
       fat (Reynolds, 1993).  Extremely low levels of ivermectin are=20
       found in the brain,  which probably accounts for the paucity=20
       of CNS side effects (Reynolds, 1993).
       
       Radioactive residues and metabolic studies have been conducted=20
       in a variety of animal species, including rats, cattle, sheep=20
       and swine.  The animals were given radio-labelled ivermectin=20
       in single doses of 300 to 400 =F0g/kg bodyweight subcutaneously=20
       or orally.  Liver and fat contained the highest residues in=20
       all species, with very little residue in the muscle and kidney=20
       (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=20
       following half-lives have been calculated (MSD, 1988).
       
       SPECIES         ROUTE        T_1/2
       
       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=20
       faeces.  Ivermectin is little metabolised by mammals; 90% of=20
       the administered dose is excreted in the faeces and tissue=20
       residues are of the parent compound (Campbell, 1985)
     6.5 Elimination by route of exposure
       Ivermectin is excreted mainly in the faeces (unchanged), =
less=20
       than 1% appearing in the urine and less than 2% in breast milk=20
       (Reynolds, 1993).  In animal studies, regardless of whether=20
       ivermectin is administered parenterally or orally, only 0.5 to=20
       2% of the dose is excreted in urine; the remainder (about 90%)=20
       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=20
             neural and neuromuscular transmission but since mammals=20
             have only central GABA-ergic synapses which are to a=20
             large extent protected by the blood-brain barrier they=20
             are relatively resistant to ivermectin.  Some=20
             penetration of the blood-brain barrier does occur at=20
             relatively high doses, with brain levels peaking between=20
             two and five hours after administration.  Symptoms seen=20
             in a range of mammalian species are CNS depression, and=20

             consequent ataxia, as might be expected from=20
             potentiation of inhibitory GABA-ergic synapses (Hayes & =

             Laws, 1991).
       7.1.2 Pharmacodynamics
             Ivermectin inactivates parasitic nematodes, =
arachnids,=20
             and insects.  Its action on the nematodes is by=20
             inhibiting signal transmission from the ventral cord=20
             interneurons to the inhibitory transmitter GABA from pre-
             synaptic nerve terminals, as well as by potentiating=20
             GABA binding to the post-synaptic receptors.  The target=20
             species become paralysed and die.
             
             At recommended doses, ivermectin does not readily=20
             penetrate the CNS of mammals, where GABA functions as a=20
             neurotransmitter.  The principal peripheral=20
             neurotransmitter, acetylcholine, is unaffected by=20
             ivermectin (MSD, 1988).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Amounts approaching the therapeutic =
doses in=20
                     animals (100 to 200 =F0g/kg bodyweight) are not=20
                     hazardous to humans.  Ingestions of large=20
                     quantities (10 to 100 times the animal=20
                     therapeutic dosage) may produce symptoms=20
                     resembling those observed in animal toxicology=20
                     studies at high toxic levels.
                     
                     An adult female accidentally self-injected a=20
                     small quantity (approximately 200 =F0g/kg)=20
                     subcutaneously.  Twelve hours later she=20
                     experienced colicky pain with nausea but=20
                     recovered within 12 hours (MSD, 1988).
                     
                     Clinical studies of oral ivermectin given in=20
                     doses from 2 to 200 =F0g/kg (maximum 12 mg) have=20
                     shown a pattern of adverse experiences that=20
                     included only one serious event (transient=20
                     stupor).  The remaining adverse experiences were=20
                     considered not serious and were chiefly of the=20
                     type expected based on the characteristics of=20
                     the underlying disease and the responses seen=20
                     after treatment with other microfilaricidal=20
                     drugs, except for reports of "depression" (not=20
                     psychiatrically tested) in four patients in open=20
                     studies (MSD, 1988).
             7.2.1.2 =
Children
                     A 16-month-old boy weighing 15 kg =
ingested=20
                     approximately 100 to 130 mg of ivermectin (as an=20
                     injectable solution).  Ten hours post-ingestion=20
                     he had mydriasis in one pupil, with frequent=20
                     vomiting, pallor, 35=B0C temperature, tachycardia,=20
                     somnolence and variable blood pressure.  He=20
                     developed urticaria the following day, and had=20
                     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 -=20
             52.8
             
             Dermal
             
             Rat:  660
             
             At relatively high doses in animal toxicity studies, CNS=20
             effects and visual disturbances have been observed. =20
             Higher doses cause death due to respiratory depression.
             
             Ivermectin, given to rats IV at a dose of 4 mg/kg,=20
             produced moderate incoordination; 6 mg/kg induced a=20
             state resembling anaesthesia which began one minute=20
             after injection and lasted for four to five hours. =20
             Higher doses caused death due to respiratory depression=20
             (Hayes & Laws, 1991).
             
             In a 14-week oral toxicity study in dogs, no treatment-
             related effects were observed in animals given 0.5=20
             mg/kg/day.  Dogs given 1 and 2 mg/kg/day development=20
             mydriasis and lost a small amount of weight.  Four of=20
             eight dogs given 2 mg/kg/day developed tremors, ataxia,=20
             anorexia and became dehydrated (MSD, 1988).
             
             Dogs given oral doses of ivermectin at 10 mg/kg produced=20
             ataxia with tremor; at 40 mg/kg, death occurred due to=20
             respiratory depression (Campbell & Benz, 1984).
             
             Collie dogs have been shown to be more sensitive than=20
             other dogs to the  toxic effects of ivermectin. =20
             Depression, tremors, mydriasis, ataxia, coma and death=20
             have been seen in Collie dogs at 100 =F0g/kg orally and=20
             greater, but not at the recommended dose of the=20
             commercial product (6 =F0g/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=20
       treated mothers.  In a Liberian community-based ivermectin=20
       therapy programme, the incidence of major congenital=20
       malformations in children born both to ivermectin-treated and=20
       untreated mothers was about 2.5%, a figure comparable with=20
       rates previously reported in the population at large in Africa=20
       (WHO, 1990b).
       

       No adverse effects were reported when pregnant mares were=20
       given six oral doses of ivermectin 0.6 mg/kg paste at two-week=20
       intervals during organogenesis and early pregnancy, and six=20
       intramuscular injections of ivermectin at 0.6 mg/kg at two-
       month intervals during the last two trimesters.  The foals=20
       born were also unaffected (Campbell & Benz, 1984).
       
       Ivermectin is teratogenic in rats, rabbit and mice at or near=20
       materno-toxic dose levels.  The abnormalities are limited=20
       mainly to cleft palate.  Mice are the most sensitive species=20
       to the effect of ivermectin with maternotoxicity at a dose of=20
       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=20
       unscheduled DNA synthesis in a human fibroblast cell culture,=20
       suggesting that it does not damage DNA (MSD,  1988).
     =
7.6 Interactions
       Preliminary in vivo studies demonstrate that ivermectin =
can=20
       enhance some of the pharmacological actions of diazepam (MSD,=20
       1988).
     7.7 Main adverse effects
       Following the therapeutic use of ivermectin for =
onchocerciasis,
        adverse effects reported include hypersensitivity, transient=20
       headache, dizziness, insomnia and elevated body temperature,=20
       and occasional joint and muscle pain (Ali & Bashir, =
1990).
       
       The clinical picture on onchocerciasis therapy is often=20
       complicated by antigens released by micro filariae.  Therefore,
        the types of signs and symptoms encountered worldwide in=20
       accidental exposures to ivermectin may differ from the types=20
       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=20
       interpretation
     8.5 Overall =
Interpretation of all toxicological analyses and=20
       toxicological investigations
     8.6 =
References
    9. CLINICAL EFFECTS
  =
   9.1 Acute poisoning
       9.1.1 Ingestion
             Most human clinical effects have been reported =
following=20
             therapeutic clinical trial with ivermectin.  However,=20
             the clinical picture in onchocerciasis therapy is often=20
             complicated by antigens released by microfilariae. =20
             Therefore, the types of signs and symptoms encountered=20
             worldwide in accidental exposures to ivermectin may=20
             differ from the types of adverse experiences seen in=20
             onchocerciasis patients.
             
             Of the various human poisoning exposures reported, only=20
             one report mentioned some findings resembling those=20
             observed in animal toxicology studies at high toxic=20
             levels: vomiting, tachycardia, mydriasis, somnolence and=20
             blood pressure fluctuation (see Section 7.2.1.2).
             
             At relatively high doses in animal toxicity studies, CNS=20
             effects and mydriasis have been observed.  Higher doses=20
             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=20
             (MSD, 1988).
       9.1.5 Parenteral exposure
             The effects of small quantities of accidentally =
injected=20
             veterinary formulations appear negligible (see Section=20
             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=20
             dose of 150 =F0g/kg in community-based trials undertaken=20
             in Africa and Central America demonstrate an incidence=20
             of 9% reporting adverse effects.  The large majority of=20
             these were of the Mazzotti-type (oedema, pruritis and=20
             rash), and dizziness, lymphadenitis, transient=20
             hypotension, arthralgia, myalgia, headache, and ocular=20
             irritation resulting from the sudden death of massive=20
             numbers of microfilariae, but in only 0.25% of patients=20
             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,=20
       blood pressure fluctuation, CNS effects (somnolence, ataxia)=20
       and visual disturbances (mydriasis) have been observed. =20
       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=20
             patients receiving single doses of 150 or 200 =F0g/kg of=20
             ivermectin.  These ECG changes were not associated with=20
             symptoms or any clinical findings.  Transient changes in=20
             supine or standing blood pressure, and tachycardia, have=20
             been reported (Awadzi et al., 1985).
             
             Tachycardia and variable blood pressure featured in a=20
             case involving a 16-month-old boy ingesting=20
             approximately 100 to 130 mg of ivermectin (as an=20
             injectable solution) (see Section 7.1.2.2).
       9.4.2 Respiratory
             Coughing has been reported as a side effect of =
treatment=20
             with ivermectin.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Headache, dizziness and insomnia have =
been=20
                     reported in clinical trials.
                     
                     Four of eight dogs given ivermectin 2 mg/kg/day=20
                     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=20
                     occasionally reported with ivermectin use=20
                     (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 =
=F0g/kg=20
             of ivermectin, a temporary mild to moderate elevation of=20
             alanine amino transferase activity occurred in some=20
             patients, but no consistent pattern emerged (Ali &=20
             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=20
             observed following single intramuscular administration=20
             of ivermectin 0.6 mg/kg (MSD, 1988).
       9.4.8 =
Dermatological
             A Mazzotti-type reaction (oedema, pruritis and =
rash) can=20
             follow administration of ivermectin to treat=20
             onchocerciasis (WHO, 1990a) (see Section =
9.2.1).
       9.4.9 Eye, ear, nose, =
throat: local effects
             Mild transient conjunctivitis and blurred vision =
have=20
             been reported with the therapeutic use of ivermectin; =20
             symptoms resolved within four days (Coulad et al.,=20
             1984).
             
             At high doses in humans and animals visual disturbances=20
             (mydriasis) have been observed.
       9.4.10 =
Haematological
              Haematological changes occurred in patients =
receiving=20
              single doses of 150 or 200 =F0g/kg of ivermectin.  There=20
              was an increase in total leucocyte count eight days=20
              after treatment.  No change in platelet counts or=20
              erythrocyte sedimentation rate occurred (Ali & Bashir, =

              1990).
              
              A single oral dose of ivermectin (150 =F0g/kg) in 28=20
              patients resulted in haematoma in two patients and=20
              prolongation of prothrombin time in all patients.  This=20
              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 =F0g/kg=20
              of ivermectin a slight fall in eosinophil counts=20
              occurred followed by a steady rise; by day 28 the level=20
              was more than twice the initial level.  There was also=20
              a slight fall in lymphocyte counts and a rise in=20
              neutrophil counts (Ali & Bashir, 1990).
              
              Hypersensitivity reactions have been reported (MSD,=20
              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=20
                       following vomiting.
         =
     9.4.12.3 Others
                       Both hyperthermia and hypothermia =
have been=20
                       reported (Awadzi et al., 1985;  MSD, =
1988).
       9.4.13 Allergic reactions
              Hypersensitivity reactions have been reported =
(MSD,=20
              1988).
       9.4.14 =
Other clinical effects
              No data available.
       9.4.15 Special =
risks
              In 203 children exposed to ivermectin before =
birth, no=20
              significant increase in the incidence of major=20
              congenital malformations was observed (see Section 7.4)=20
              (WHO, 1990b).
              
              Ivermectin is present in the milk of lactating animals=20
              and humans.  A sensitive HPLC assay is available (see=20
              Section 8.2).
              
              Preliminary in vivo studies demonstrate that ivermectin=20
              can enhance some of the pharmacological actions of=20
              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=20
         overdose.  Adverse effects are transient, but analgesics and=20
         antihistamines may be required.  Since ivermectin is=20
         believed to enhance GABA activity in animals, it is probably=20
         wise to avoid drugs that enhance GABA activity=20
         (benzodiazepines, barbiturates, valproate, valproic acid) in=20
         patients with potentially toxic ivermectin exposure (MSD,=20
         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=20
                is unlikely to be useful in the clinical management=20
                of poisoning.
         10.2.4 =
Other investigations
                Not applicable.
      10.3 =
Life supportive procedures and symptomatic/specific=20
         treatment
         Supportive measures are indicated in case of life-
         threatening poisoning (which is rare).  Analgesics and=20
         antihistamines are indicated for the treatment of adverse=20
         effects.

      10.4 =
Decontamination
         In case of ingestion of significant amounts of =
ivermectin,=20
         induce emesis using syrup of ipecac.  Gastric lavage may be=20
         undertaken.
         
         Eye contact:  Remove any contact lenses then flush the=20
         contaminated eyes gently with water for 10 to 15 minutes=20
         holding eyelids open.
         
         Skin contact:  Flush the contaminated area gently with water=20
         for 10 to 15 minutes.
         
         Parenteral contact:  Although the effects on adults=20
         following accidental self-injections of small quantities (<=20
         2 ml) appear to be negligible, appropriate measures should=20
         be considered in view of the risk of secondary infection=20
         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=20
         choice in the treatment of human filariasis its=20
         pharmacokinetics and metabolism need to be extensively=20
         studied in humans. Currently there are no published reports=20
         about these aspects of the drug, although in animals several=20
         such studies have been conducted (Ali & Bashir, 1990).
         
         The efficacy of activated charcoal in gut decontamination=20
         following ingestion of ivermectin has not been documented=20
         and warrants investigation.
         
         A clinical trial of ivermectin as a single oral dose=20
         produced haematomata in two patients and prolongation of=20
         prothrombin time in all patients (see Section 9.4.10).  It=20
         was suggested that this was due to possible ivermectin-
         induced deficiency in Vitamin K, and it would be of interest=20
         in future trials to measure the plasma concentration of=20
         Vitamin K in ivermectin-treated patients, and/or determine=20
         if administration of Vitamin K in these patients would=20
         affect the status of Vitamin K and other coagulation factors=20
         (Homeida et al., 1988).
         
         Some authors have suggested the use of picrotoxin and=20
         physostigmine as antidotal therapies.  However, animal=20
         studies with these agents employing these agents as=20
         antidotes in ivermectin toxicity have been unsatisfactory=20
         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=20
         ivermectin veterinary paste formulation and remained=20

         asymptomatic (Hall et al., 1985).
         
         Case 2 - A 16-month-old Brazilian boy weighing about 15 kg=20
         accidentally drank an estimated 10 to 13 ml of Ivomec  (1%=20
         ivermectin) injectable solution.  Mydriasis was noted in one=20
         pupil along with frequent vomiting, pallor, 35=B0C temperature,
          tachycardia, somnolence, and variable blood pressure (40 to=20
         100 mm Hg) ten hours later.  The next morning urticaria=20
         occurred.  After three days, the boy was normal.  Therapy in=20
         hospital included calcium gluconate, caffeine, and an=20
         antihistamine.  The clinical indications for the calcium=20
         gluconate therapy were unclear (MSD,1988).
         
         Case 3 - An adult was reported to have accidentally self-
         injected a small quantity of Ivomec  (1% ivermectin)=20
         (estimated 200 =F0g/kg).  Twelve hours later she experienced=20
         colicky pain, with nausea, but recovered within 12 hours=20
         (MSD, 1988).
         
         Case 4 - A veterinarian, eight months pregnant, sprayed=20
         Eqvalan  (2% ivermectin) into her eye.  The eye was rinsed. =20
         Stinging at the contact site was the only adverse effect=20
         described (MSD, 1988).
      11.2 Internally extracted data on cases
         Case 1 - An adult accidentally injected an ivermectin =
animal=20
         formulation into the back of his left hand.  The needle=20
         stuck the base of his first metacarpal posteriorly, and=20
         about 2 ml were administered.  Gross swelling occurred, but=20
         no systemic effects were noted.  He was given an=20
         antihistamine and recovered uneventfully.
         
         Case 2 - A child was admitted to hospital after ingesting an=20
         unknown quantity of Ivomec  Cattle Drench (0.4% ivermectin)=20
         and appeared drowsy and hypotonic.  Both pupils were normal.=20
          He exhibited tachycardia and vomiting, and his ECG pattern=20
         was abnormal.  Treatment was symptomatic and supportive, and=20
         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=20
         reach of children.
         
         Ivermectin is contraindicated in patients who have a history=20
         of immediate hypersensitivity to the drug.
         
         Rapid in-vivo killing of large numbers of microfilariae may=20
         induce a systemic or ocular response.  This reaction may=20
         include optic neuritis, choreoretinitis, proteinuria,=20
         pruritus, rash and oedema.
         
         Ivermectin should not be administered to pregnant or=20
         lactating women, or to young children, unless it is=20
         considered that the benefits of therapy outweigh the=20

         potential risks from the drug.  At therapeutic doses,=20
         clinical evidence to date indicates no increase in=20
         congenital abnormalities in humans.  However, in animal=20
         studies at high maternotoxic doses foetal abnormalities have=20
         occurred.  ivermectin is excreted in breast milk.
         
         Preliminary in vivo studies demonstrate that ivermectin can=20
         enhance some of the pharmacological actions of =
diazepam.
      12.3 =
Other
    13. =
REFERENCES
    Ali BH, Bashir AA (1990)  Ivermectin in human filariasis: a =
mini=20
    review.  Vet Hum Toxicol, 32: 110-113.
    
    Awadzi K, Dadzie KY, Shulz-Key H, Haddock DRW, Gilles HM, Aziz MA=20
    (1985)  The chemotherapy of onchocerciasis X.  An assessment of=20
    four single dose regimes of MK-933 (ivermectin) in human=20
    oncorciasis.  Ann Trop Med Parasitol, 79: 63-78.
    
    Campbell WC, Fisher MH, Stapley EO et al. (1983)  Ivermectin: a=20
    potent new antiparasitic agent. Science, 221: 823-828.
    
    Campbell WC & Benz GW (1984)  Ivermectin: a review of efficacy=20
    and safety.  J Vet Pharmacol Ther, 7: 1-16.
    
    Campbell WC (1985)  Ivermectin: an update.  Parasitol  Today, 1:=20
    10-11.
    
    Chiou R, Stubbs RJ & Bayne WF (1987)  Detection of ivermectin in =

    human plasma and milk by high-performance liquid chromatography=20
    with fluorescence detection.  J Chromatogr, 416(1): 196-202.
    
    Coulad JP, Laraviere M, Aziz MA, Gervais MC, Gaxotte P, Delud AM,=20
    Cenac J (1984)  Ivermectin in onchocerciasis.  Lancet, 2: 526-
    527.
    
    Diallo S, Aziz MA, Nadir O, Badiane S, Bah IB, Gaye O (1987) =20
    Dose ranging study of ivermectin in treatment of filariasis due=20
    to wuchereria bancrofti (letter)  Lancet,  1: 1030.
    
    Edwards G, Dingsdale A, Helsby N et al. (1988)  The relative=20
    stability of ivermectin after administration as capsule, table=20
    and oral solution.  Eur J Clin Pharmacol, 35: 681-684.
    
    Hall AH, Spoerke DG, Bronstein AC, Kulig KW, Rumack BH (1985) =20
    Human ivermectin exposure. J Emerg Med, 3(3): 217-220.
    
    Hayes WJ & Laws ER (Eds) (1991)  Handbook of pesticide=20
    toxicology.  Volume 2.  Classes of pesticides.  Academic Press=20
    Inc, San Diego, California, 1576 pp.
    
    Homeida MM, Bagi IS, Ghalib HW, Sheikh H, Ismail A, Yousif MM,=20
    Suliman S, Ali HM, Bennet JL, William J (1988)  Prolongation of=20
    prothrombin time with ivermectin.  Lancet, 1: 1346-1347.
    
    Iliff-Sizemore SA, Partlow MR, Kelley ST (1990)  Ivermectin=20
    toxicology in a Rhesus Macaque.  Vet Hum Toxicol, 23(6): =
530-532.

    
    MSD (Merck Sharp & Dohme) (1988)  Poison Control Monograph. =20
    ivermectin.  Division of Merck & Co Ltd, West Point, =
Pennsylvania,
     18 pp.
    
    Reynolds JEF (Ed) (1993)  Martindale.  The extra pharmacopoeia. =20
    29th Edition.  Pharmaceutical Press, London.
    
    Reynolds JEF (Ed) (1993)  Martindale.  The extra pharmacopoeia. =20
    30th Edition.  Pharmaceutical Press, London.
    
    WHO (World Health Organization) (1990a)  Drug Information, Vol=20
    4(2): 48-49.
    
    WHO (World Health Organization) (1990b)  Drug Information, Vol=20
    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,=20
                    R. Fernando, W. Temple)
    
    Review:  IPCS, May 1994

    See Also:
       Toxic=
ological Abbreviations
       Iverme=
ctin (WHO Food Additives Series 27)
       Iverme=
ctin (WHO Food Additives Series 31)
       IVERM=
ECTIN (JECFA Evaluation)

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