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
ðg/kg.
4.2 Therapeutic dosage
4.2.1 Adults
Oral: 3 to 12 mg as a single dose per os (about 150 to
200 ðg/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 ðg/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 ðg/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 ðg/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 ðg/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 ðg/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, 35°C 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 ðg/kg orally and
greater, but not at the recommended dose of the
commercial product (6 ðg/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 ðg/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 ðg/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 ðg/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 ðg/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 ðg/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 ðg/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, 35°C 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 ðg/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