A. Toxicity Tests
Toxicity tests determining the human food safety of IVOMEC® (ivermectin) Injection for cattle are included in the Freedom of
Information summary for this NADA (approval date, February 13, 1984). A
detailed summary of these studies has been published (Ivermectin and
Abamectin, Campbell, W.C. (ed.) Springer-Verlag, New York, 1989).
Additional toxicity information provided in this supplemental NADA is
summarized below:
1. Studies Conducted in Healthy Volunteers.
Four pre-clinical studies were performed with ivermectin to determine the
therapeutic dose, bioavailability, metabolism and pharmacokinetics in humans.
These studies, while designed to obtain specific information listed in the study objective, also provided useful human safety observations which were summarized under the heading "Safety Report". These subjects were closely monitored in a hospital throughout the studies for signs and symptoms of adverse experiences. Physical examinations were conducted pre- and post-treatment. Vital signs, including blood pressure, pulse and respiratory rate were measured before and at frequent intervals post-dosing.
Hematological evaluation included: hemoglobin, hematocrit, total white blood
count, differential white blood count and platelet count. Blood chemistry
included: SGOT, SGPT, alkaline phosphatase, total bilirubin, LDH creatinine,
BUN, blood sugar, total protein, albumin and globulin.
Urinalysis included: protein, sugar, red blood cells, white blood cells and
epithelial cells. There were no adverse clinical experiences reported and
laboratory values were all within normal ranges.
2. A Multiclinic, Double Blind Study of Ivermectin (MK-933) and Placebo in
Patients with Onchocerciasis.
Study # 5003 Protocol # 519-00
Investigators:
Dr. B. Green, M.D. Dr. K. Awadzi
Case Western Reserve Tamale Hospital
and the Uniroyal Rubber Plantation Ghana
Liberia
Professor M. Lariviere, M.D. Dr. P. Vingtain, M.D.
University of Paris and Odienne Hospital Institut D'Ophtalmologie
Ivory Coast Tropical D'Ophtalmologie
Bamako, Mali
Drs. Schulz-Key, Ph.D. and G. Helling, M.D. Dr. G. Zea-Flores, M.D.
Institute of Tropical Medicine Roosevelt Hospital
Tuebingen, W. Germany and Sokode, Togo Guatemala City, Guatemala
Objective:
To document, in onchocerciasis patients, the safety and efficacy of treatment
with ivermectin.
Study Design: A multicenter,
double-blind, randomized, placebo controlled study comparing three doses
of ivermectin (100, 150 and 200 µg/kg). Enrollment criteria specified
hospitalized male and female patients, 12 to 60 years of age with moderate
or severe infections with Onchocerca volvulus but otherwise in
good health. Patients were monitored, in hospital, for adverse signs.
Safety endpoints included ophthalmologic examinations, physical examinations,
hematology, blood chemistry and urinalysis. A total of 1278 patients were
treated as follows: ivermectin at 100 µg/kg (319), 150 µg/kg
(322), 200 µg/kg (322), placebo (315).
Safety Report: All
doses of ivermectin were well tolerated. As expected, adverse reactions
related to microfilarial death were common. Overall, 47.6 to 52.8% of
persons in the treatment groups, and 29.8% of persons in the placebo group
showed clinical adverse experiences. None of these were considered serious,
and no persons were discontinued from the study. There was an episode
of transient hypotension in a person taking anti-hypertensive therapy
and choloroquine, not thought to be drug-related, and an isolated episode
of possible hypoglycemia.
3. An open study of the
Tolerability, Safety and Efficacy of Single Oral 150 µg/kg doses
of ivermectin (MK-933) in children 5 to 12 years of age with onchocerciasis.
Study # 5544, Protocol
# 545-00
Investigator: Professor M.
Lariviere, M.D., University of Paris.
Site: Odienne Hospital,
Ivory Coast
Objective: To investigate,
in children 5 to 12 years of age and infected with O. volvulus, the
tolerability, laboratory and clinical safety, and efficacy of a single
oral dose (150 mg/kg) of ivermectin.
Study Design: An open
study in male (n=71) and female (n=32) children with onchocerciasis and
otherwise in good health. All patients were hospitalized for at least
seven days following administration of ivermectin and monitored for adverse
signs. Safety endpoints included ophthalmologic examination, physical
examination, hematology, blood chemistry and urinalysis.
Safety Report: Ivermectin
was well tolerated. The most common clinical experience was headache and
myalgia. No clinical adverse reactions were considered serious and no
laboratory adverse experiences were reported.
4. Signs of ivermectin
toxicosis in man.
Results of accidental overdosing
with ivermectin - containing veterinary products suggest that the acute
signs and symptoms of ivermectin intoxication in man are similar to those
observed in laboratory animals, however, the doses required to elicit
these signs are higher in man.
Ivermectin Adverse Reactions
Database
Clinical Summaries Case Report
# 00014493.
A two-year old male ingested
a quantity of IVOMEC® injectable formulation for cattle (10 mg/ml
of ivermectin) and received an estimated ivermectin dosage of approximately
6-8 mg/kg. The patient exhibited drowsiness, ataxia, vomiting, mydriasis,
right bundle branch block, ventricular ectopy and weakness. The child
recovered with no apparent after affects.
Clinical Summaries Case Report
# 00052048.
A 16-year old male was reported
to have ingested 11.5 ml of the IVOMEC® Injectable formulation for
cattle. Symptoms included mydriasis, vomiting, pallor, tachycardia, somnolence,
variable blood pressure and urticaria. On follow-up, the patient was noted
to have recovered from all symptoms with the possible exception of urticaria.
Exposure was estimated at 115 mg total dose or 10X the therapeutic human
dose of ivermectin.
B. Safe Concentration Of
Residues
The safe concentration for
drug residues represents the amount of drug, parent and metabolites, which
can be consumed daily throughout a lifetime.
Allowable Daily Intake
These human studies support
the findings of the laboratory animal toxicity studies with ivermectin
that indicate that the primary human food safety concern for ivermectin
is related to its neurotoxic effects. The human clinical database on ivermectin
also indicated that the mouse teratology study, which was used to establish
the safe concentration in the original approval, is not the most appropriate
model for this calculation. Considering the results of the standard battery
of toxicology studies conducted with ivermectin, and the information obtained
in the human studies, the 90-day dog study with a NOEL of 0.5 mg/kg/day
for neurotoxicity is a more appropriate study for establishing the safe
concentration for ivermectin.
The subchronic and chronic
effects of ivermectin were quantitatively similar. Therefore, the 1000-fold
safety factor, which is generally applied to the 90-day studies to extrapolate
to chronic exposure, is inappropriate. Rather, a 500-fold safety factor
is assigned to the NOEL of 0.5 mg/kg/day obtained in the 90-day dog study.
The new ADI for ivermectin is 0.5 mg/kg/day divided by 500 or 1 µg/kg/day.
Safe Concentration
A safe concentration in muscle
of cattle is calculated from the acceptable daily intake; assuming the
average weight of man to be 60 kg and the daily human intake of muscle
to be 500 grams.
(60 kg) (1 µg/kg/day)
Safe concentration in muscle= ---------------------- = 120 ppb
500 g/day
The safe concentration of residues
in liver, kidney and fat are derived from this number using appropriate
food consumption values (food factors) for these tissues:
Liver: 120 ppb X 2 (food
factor) = 240 ppb
Kidney: 120 ppb X 3 (food
factor) = 360 ppb
Fat: 120 ppb X 4 (food factor)
= 480 ppb
Injection Site
Ingestion of an entire injection
site from an IVOMEC-treated animal is considered an unlikely event. The
human food safety assessment of injection site exposures is based on acute
toxicity of ivermectin. Clinical studies conducted in healthy non-parasitized
volunteers demonstrate that a 15 mg oral dose of ivermectin is well tolerated.
Applying a ten-fold safety factor to this 15 mg oral dose and a consumption
value of 500 grams results in a safe concentration of 3 ppm at injection
sites.
C. Metabolism And Total
Residue Depletion Studies
Section 6.C. of the Freedom
of Information Summary issued at the time of approval (February 13, 1984)
of IVOMEC® (ivermectin) Injection for cattle describes metabolism
of 3H labeled MK-933 in cattle, comparative metabolism in rats and total
residue depletion from edible tissues. No additional total residue depletion
or metabolism studies were provided in this supplement. Residue data generated
in radiolabeled study RN-190 was used to recalculate the tolerance (See
Below).
D. Recalculation Of The
Tolerance
The residue data generated
in RN-190 was used to calculate the tolerance for residues of ivermectin
H2B1a (marker substance) in cattle liver (marker tissue) based upon a
safe concentration of 240 ppb for total residues of ivermectin. Based
upon results of that study, ivermectin Bla represents approximately 42
percent of the total ivermectin residues in liver when residues are at
the safe concentration of 240 ppb. The tolerance for the marker residue
derived from that relationship is 100 ppb (42 percent of 240 ppb = 100.8
ppb).
E. Studies Demonstrating
A Withdrawal Period
A tissue residue depletion
study (ASR 13527) was conducted to determine the marker residue (H2Bla)
concentrations in edible tissues of cattle at times following treatment
with IVOMEC® injection for cattle injected subcutaneously at the recommended
use level. Crossbred, beef type cattle, aged 12-14 months and weighing
between 287 and 401 kg were used. Six male castrates and six females were
slaughtered on each of days 21, 28, 35, 42, 49 and 56. Six untreated cattle
(3 male castrates, 3 females) served as controls. Marker residue assays
were conducted on liver tissue and injection site samples using the high
performance liquid chromatography fluorescence determinative assay method.
Average marker residue concentrations in samples were:
-----------ppb Found-----------
Days Withdrawal Liver Injection Site
21 46 ± 37 NA
28 27 ± 16 1280 ± 2979
35 10 ± 10 576 ± 817
42 3 ± 3 570 ± 1037
49 3 ± 4 231 ± 724
56 NA NA
NA: Not assayed
Statistical analysis of the
residue depletion data generated in ASR 13527, using the tolerance of 100
ppb in liver, yields a withdrawal period of 34 days. However, the official
withdrawal period is set at 35 days as the 35-day sacrifice group
in study 13527 was the first group in which all injection site residues
were below the safe concentration (3 ppm) assigned for residues of ivermectin
at the injection site.
