A. Dose Establishment
The dose was selected based on efficacy against adult
A. tubaeforme which proved to be the dose-limiting parasite. In
all efficacy trials, the percent efficacy was calculated for each treatment
group as the Control Geometric Mean minus the Treated Geometric Mean divided by
the Control Geometric Mean X100.
1. Hookworm Dose Determination Study: ASR 13872
a. Investigators: Dr. K. Todd and Dr. A. Paul, Univ. of
Illinois, Urbana, Illinois
b. Study design:
1) Purpose: To determine the effective dose of ivermectin chewables against
adult hookworms
2) Test animals: 32 cats (17 male, 15 female), 10 weeks to 7 months of age, 8
per group
3) Control: Vehicle chewables comprised of formulation excipients without
active ingredient
4) Diagnosis: Cats were experimentally infected with infective larvae of
Ancylostoma tubaeforme 22 days before treatment so that the infection
was in the adult stage at the time of treatment.
5) Dosage form: Chewables
6) Route of administration: Oral
7 Dosages: 0, 12, 24, and 36 mcg/kg, tailored to body weight
8) Duration of study: Cats were necropsied on Day 7
9) Pertinent parameters measured: Worm counts at necropsy
c. Results: Efficacy of ivermectin against adult
A. tubaeforme was 83.8%, 99.3% and 99.6% at 12, 24, and 36 mcg/kg,
respectively. The dose plateaus at 24 mcg/kg.
d. Conclusion: 24 mcg/kg was selected as the dose of ivermectin providing
>99% control of adult hookworms in cats
e. Adverse reactions: No adverse reactions were observed.
2. Heartworm Dose Determination Study: ASR 13660
a. Investigator: Dr. J. McCall, TRS Laboratories Inc., Athens,
Georgia
b. Study design:
1) Purpose: To determine the effective dose of ivermectin chewables for
preventing the development of heartworms (Dirofilaria immitis)
2) Test animals: 40 cats (20 male, 20 female), 8 to 8.5 months of age, 8 per
group
3) Control: Vehicle chewables comprised of formulation excipients without
active ingredient
4) Diagnosis: Cats were experimentally infected with infective larvae of
D. immitis 30 days before treatment (cats in one group were
infected 45 days before treatment)
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosages: 0, 12, 24, and 36 mcg/kg, tailored to body weight; administered 30
days after infection; and 12 mcg/kg, administered 45 days after infection (one
group)
8) Duration of study: Cats were necropsied on Day 150
9) Pertinent parameters measured: Worm counts at necropsy
c. Results: Ivermectin was 100% effective at all dose levels in
preventing the development of D. immitis.
d. Conclusion: Ivermectin administered at 12, 24, and 36 mcg/kg body weight
prevents the development of D. immitis.
e. Adverse reactions: No adverse reactions were observed.
B. Dose Confirmation
1. Heartworm Dose Confirmation Studies: ASR 14324 and ASR 14328
a. Investigators: Dr. J. McCall, TRS Laboratories Inc., Athens,
Georgia (ASR 14324); and Dr. L. Cruthers, Professional Laboratory and
Research Services Inc., Corapeake, North Carolina (ASR 14328)
b. Study design:
1) Purpose: To confirm the efficacy of ivermectin chewables at 24 mcg/kg in
preventing the development of Dirofilaria immitis
2) Test animals: ASR 14324: 20 cats (10 male, 10 female), 6.2 to 7.5 months of
age, 10 cats per group; ASR 14328: 20 cats (10 males, 10 females),
approximately 8 months of age, 10 cats per group
3) Control: Vehicle chewables comprised of formulation excipients without
active ingredient
4) Diagnosis: Cats were experimentally infected with infective larvae of
D. immitis 30 days before treatment
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: 24 mcg/kg, tailored to body weight
8) Duration of study: Cats were necropsied on Day 151
9) Pertinent parameters measured: Worm counts at necropsy
c. Results: Ivermectin was 100% effective in preventing the
development of D. immitis.
d. Conclusion: Ivermectin administered at the minimum recommended dose of
24 mcg/kg prevents the development of D. immitis
e. Adverse reactions: No adverse reactions were observed.
2. Hookworm Dose Confirmation Studies: ASR 14015 and ASR 14166
a. Investigators: Dr. E. Roberson, TRS Laboratories, Inc., Athens,
Georgia (ASR 14015); and Dr. A. Paul, University of Illinois, Urbana,
Illinois (ASR 14166)
b. Study design:
1) Purpose: To confirm the efficacy of ivermectin chewables at 24 mcg/kg
against immature (L4) hookworms
2) Test animals: ASR 14015: 14 cats (7 males, 7 females), 4.8 to 5 months of
age, 7 per group; ASR 14166: 14 cats (7 males, 7 females), 15 to 16 weeks of
age, 7 per group
3) Control: Vehicle chewables comprised of formulation excipients without
active ingredient
4) Diagnosis: Cats were experimentally infected with infective larvae of
Ancylostoma tubaeforme and A. braziliense eight days before
treatment so that the infections were in the fourth larval stage at the time of
treatment
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: 24 mcg/kg, tailored to body weight
8) Duration of study: Cats were necropsied on either Day 21 (ASR 14015 ) or
Day 14 (ASR 14166)
9) Pertinent parameters measured: Worm counts at necropsy
c. Results: The efficacy of ivermectin in ASR 14015 against L4
A. tubaeforme was 97.3%, and against L4 A. braziliense was
100%. The efficacy of ivermectin in ASR 14166 against L4
A. tubaeforme was 97.8%, and against L4 A. braziliense was
98.9%.
d. Conclusion: Ivermectin administered at the minimum recommended dose of
24 mcg/kg is effective against infections of immature (L4) A.
tubaeforme and A. braziliense
e. Adverse reactions: No adverse reactions were observed.
3. Hookworm Dose Confirmation Study: ASR 14612
a. Investigator: Dr. M. Drag, Merck Missouri Farm, Fulton,
Missouri
b. Study design:
1) Purpose: To confirm the efficacy of ivermectin chewables, in two different
batches, using different methods of administration, in removing and controlling
adult hookworm infections
2) Test animals: 48 cats (24 males, 24 females), 11 to 13 months of age, 8 per
group
3) Control: Vehicle chewables comprised of formulation excipients without the
active ingredient
4) Diagnosis: Cats were experimentally infected with infective larvae of
Ancylostoma tubaeforme and A. braziliense 33 or 34 days
before treatment, so that the hookworms were in the adult stage at the time of
treatment. Patency was confirmed by fecal egg counts.
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: 24 mcg/kg: the ivermectin groups were as follows:
Trt 2: Ivermectin Batch 014, tailored to 24 mcg/kg, quartered and manually
dosed
Trt 3: Ivermectin Batch 017, tailored to 24 mcg/kg, quartered and manually
dosed
Trt 4: Ivermectin Batch 014, tailored to 24 mcg/kg, quartered and manually
dosed, if not voluntarily consumed
Trt 5: Ivermectin Batch 014, tailored to 24 mcg/kg, crumbled and mixed with
canned food before administration
Trt 6: Ivermectin Batch 014, > or = 24 mcg/kg, quartered and manually dosed, if not
voluntarily consumed
8) Duration of study: Cats were necropsied on Day 7
9) Pertinent parameters measured: Worm counts at necropsy.
c. Results: Efficacy of ivermectin against adult A. tubaeforme
was 94.9%, 100%, 98.3%, 100% and 100%, respectively, in Treatment Groups 2, 3,
4, 5, and 6. Efficacy of ivermectin against A. braziliense was >99%
to 100% in all five treatment groups. Twenty-four of the 48 cats had remnants
of the chewables in their feces at 24 hours post-treatment and 4 cats passed
remnants in the feces at 48 hours post-treatment. No remnants were detected at
72 hours.
d. Conclusion: Ivermectin administered at the minimum dose of 24 mcg/kg,
in two different batches using different methods of administration, (quartered
and manually dosed, offered free choice, and quartered and then mixed with
food), is effective against infections of adult A. tubaeforme and
A. braziliense. The appearance of chewable remnants in the feces
within 48 hours of administration did not affect efficacy.
e. Adverse reactions: No adverse reactions were observed.
4. Hookworm Dose Confirmation Study: ASR 14340
a. Investigator: Dr. J. McCall, TRS Laboratories Inc., Athens,
Georgia
b. Study design:
1) Purpose: To confirm the efficacy of ivermectin chewables at 24 mcg/kg
against hookworms
2) Test animals: 14 cats (6 males, 8 females), 5 to 120 months of age, 7 per
group
3) Control: Vehicle chewables comprised of formulation excipients without
active ingredient
4) Diagnosis: All cats had natural hookworm infections as determined by fecal
egg counts on Day -1
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: > or = 24 mcg/kg, as per label
8) Duration of study: Cats were necropsied on Day 7
9) Pertinent parameters measured: Worm counts at necropsy
c. Results: Efficacy of ivermectin was 100%
d. Conclusion: Ivermectin administered at the minimum recommended dose of
24 mcg/kg is effective against natural infections of hookworms
e. Adverse reactions: No adverse reactions were observed.
5. Other Confirmation Studies
Five trials (ASR 12914, 13204, 13210, 13221, and 14560) were conducted in cats
with experimental or natural infections of adult A. tubaeforme to
confirm the efficacy of ivermectin at 24 mcg/kg. Three of these trials
also included infections of adult A. braziliense. Thirty-three cats were
treated with ivermectin chewables and 33 with vehicle. The percent efficacy
achieved in each study is shown below.
Parasite Trial Number Percent Efficacy
Ancylostoma tubaeforme 12914 99.6
(induced infections, adult
worms)
13210 100
13204 90.7
14560 71.9
(natural infections) 13221 100
Ancylostoma braziliense 13204 92.8
(induced infections, adult
worms)
13221 99.8
14560 52.2
Combined efficacy for these five trials is 94.4% against A.
tubaeforme and 94.9% against A. braziliense.
C. Field Investigations
A waiver of criteria for an adequate and well-controlled field investigation
specified in 21 CFR 514.111(a)(5)(ii) was granted by CVM. Specifically, the
criteria in paragraph (a)(5)(ii)(a)(4) for a comparison of the
results of the treatment with a control was waived for the field investigations
with ivermectin for the prevention of heartworm disease in cats caused by
Dirofilaria immitis (see attachment 1).
1. Field Trials under Protocol 3784: Four trials (ASR 14007, 14009, 14010, and
14014) were conducted under this protocol.
a. Investigators:
Trial 14007 Dr. K. Acre Altamonte Veterinary Hospital
Altamonte Springs, Florida
Trial 14009 Dr. M. Dzimianski South Jackson Veterinary Services
Nicholson, Georgia
Trial 14010 Dr. T. Clekis Animal Hospital of St. Petersburg
St. Petersburg, Florida
Trial 14014 Dr. T. McArthur Altamaha Animal Clinic
Vidalia, Georgia
b.
Study design:
1) Purpose: To confirm the safety, efficacy and acceptability of ivermectin
chewables at use level for the removal and control of hookworms under field
conditions.
2) Test animals: Cats ranged in age from 10 weeks to 12 years.
Males Females Total
Trial 14007 4 6 10
Trial 14009 11 13 24
Trial 14010 20 21 41
Trial 14014 7 14 21
Total 42 54 96
3)
Control: Vehicle chewables comprised of formulation excipients without active
ingredient.
4) Diagnosis: Natural infections of hookworms confirmed by fecal egg counts.
Before being placed on trial, cats over 4 months old were tested for adult
heartworm antigen and found negative.
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: Recommended dose of > or = 24 mcg/kg, as per label, monthly for 3
months
8) Pertinent parameters measured: Fecal samples were examined for intestinal
nematode eggs approximately 7 to 14 days after each of three monthly
treatments. Study reports were compiled from owners' and investigators'
records.
c. Results: Of 96 cats enrolled, 66 had hookworm infections and had at
least one follow-up examination. Numbers of cats positive at each examination
were:
Pre-Test 7 to 14 days 37 to 44 days 52 to 74 days
Ivermectin 48/48 4/48 1/45 0/44
Control 18/18 9/18 11/18 11/17
A variety of medications were administered to cats during the study,
including vaccines, flea treatments, antimicrobials, sedatives, anesthetics and
steroid preparations. Owners or veterinarians successfully administered 99.6%
of the ivermectin chewables (free choice, in food, or manually).
d. Conclusion: Ivermectin, administered in this chewable dosage form, is
acceptable to cats and is safe and effective in removing and controlling
hookworm infections under field conditions when administered monthly at the
recommended dose of > or = 24 mcg/kg.
e. Clinical Observations: See page 13
2. Field Trials under Protocol 2876: Seven trials (ASR 13138, 13211, 13212,
13213, 13217, 13218, and 13339) were conducted under this protocol.
a. Investigators:
Trial 13138 Dr. R. Blakely Central Hospital for Animals
Carterville, Illinois
Trial 13211 Dr. R. Lange Lange Animal Hospital
Knoxville, Tennessee
Trial 13212 Dr. M. Coleman Suburban Animal Hospital
Gainesville, Florida
Trial 13213 Dr. R. Brady Westbury Animal Hospital
Houston, Texas
Trial 13217 Dr. T. Greene Greene Veterinary Clinic
Livonia, Louisiana
Trial 13218 Dr. K. Acre Howell Branch Animal Hospital
Winter Park, Florida
Trial 13339 Dr. T. Clekis Animal Hospital of North Charleston
Charleston, South Carolina
b. Study design:
1) Purpose: To confirm the safety, efficacy and acceptability of ivermectin
chewables at use level for the removal and control of hookworms and the
prevention of heartworm disease under field conditions.
2) Test animals: Cats ranged in age from 6 weeks to 17 years.
Males Females Total
Trial 13138 38 32 70
Trial 13211 32 30 62
Trial 13212 26 44 70
Trial 13213 37 35 72
Trial 13217 47 23 70
Trial 13218 31 36 67
Trial 13339 34 28 62
Total 245 228 473
3)
Control: None (waiver granted, see attachment 1)
4) Diagnosis: Fifty-one cats had natural infections of hookworms, confirmed by
fecal egg counts. Before being placed on trial, all cats 4 months old were
tested for circulating microfilariae and adult heartworm antigen and found
negative.
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: Recommended dose of > or = 24 mcg/kg, as per label, monthly for 5
months
8) Pertinent parameters measured: Fecal samples were examined for intestinal
nematode eggs before the first treatment and after the first, third and fifth
doses. Blood for evaluation of microfilariae and adult heartworm antigen was
obtained 6 months after the last treatment. Clinical study reports were
compiled from owners' and investigators' records.
c. Results: Of 51 cats with hookworms, 46 had at least one follow-up
fecal exam. Numbers of cats positive at each examination were:
Pre-Test Month 1 Month 3 Month 5
Ivermectin 46/46 2/46 1/39 1/38
Results from the 373 cats that completed the study and were available for
final heartworm tests confirmed the efficacy of ivermectin. One cat tested
heartworm antigen positive at month 11 of the study; however, because the
available antigen tests were not highly reliable in detecting natural heartworm
infections in cats, it is not clear exactly when this cat became infected. A
variety of medications were administered to cats during the study, including
vaccines, flea treatments, antimicrobials, sedatives, anesthetics and steroid
preparations. Owners or veterinarians successfully administered 98% of the
ivermectin chewables (free choice, in food, or manually).
d. Conclusion: Ivermectin, administered in this chewable dosage form, is
acceptable to cats and is safe and effective in removing and controlling
hookworm infections under field conditions and in preventing heartworm disease
when administered monthly at the recommended dose of > or = 24 mcg/kg.
e. Clinical Observations: See page 13
3. Field Trials under Protocol 2999: Three trials (ASR 13224, 13225 and 13468)
were conducted in kittens under this protocol.
a. Investigators:
Trial 13224 Dr. T. Clekis Animal Hospital of North Charleston
Charleston, South Carolina
Trial 13225 Dr. M. Coleman Suburban Animal Hospital
Gainesville, Florida
Trial 13468 Dr. R. Hawe Alexandria Animal Hospital
Alexandria, Virginia
b. Study design:
1) Purpose: To confirm the safety, efficacy and acceptability against hookworms
of ivermectin chewables at use level in kittens from 5 to 24 weeks old under
field conditions.
2) Test animals:
Males Females Total
Trial 13224 15 17 32
Trial 13225 9 7 16
Trial 13468 19 5 24
Total 43 29 72
3) Control: Vehicle chewables were comprised of formulation excipients without
active ingredient
4) Diagnosis: Two kittens in the ivermectin group had natural infections of
hookworms prior to treatment, confirmed by fecal egg counts.
5) Dosage form: Chewables
6) Route of administration: Oral
7) Dosage: Recommended dose of > or = 24 mcg/kg, monthly for 3 months
8) Pertinent parameters measured: Fecal samples were examined for intestinal
nematode eggs before the first treatment and approximately 7 to 14 days after
the third (last) monthly dose. Study reports were compiled from owners' and
investigators' records.
c. Results: Only two of the ivermectin-treated kittens had hookworms
at the start of the trial and both were negative at the final fecal
examination; the rest of the kittens from both the ivermectin and control
groups were hookworm negative at study initiation and remained hookworm-free
throughout the trial. A variety of medications were administered to kittens
during the study, including vaccines, flea treatments, antimicrobials,
sedatives, anesthetics and steroid preparations. Owners or veterinarians
successfully administered 97% of the ivermectin chewables (free choice, in
food, or manually).
d. Conclusion: Ivermectin, administered in this chewable dosage form, is
acceptable to kittens and is safe when administered at the recommended dose of
24 mcg/kg.
e. Clinical Observations: See Page 13
4. Field Trials under Protocols 2875 and 2878: Five trials were conducted in
the USA under protocol 2875 (ASR 13170, 13172, 13186, 13188 and 13190) and one
in Canada under protocol 2878 (ASR 13203).
a. Investigators:
Trial 13170 Dr. K. Blaicher Animal Medical Group
Plainfield, New Jersey
Trial 13172 Dr. B. Levine Toms River Veterinary Hospital
Toms River, New Jersey
Trial 13186 Dr. S. McDonough Cat Hospital of Philadelphia
Philadelphia, Pennsylvania
Trial 13188 Dr. A. Ellis River Cove Animal Hospital
Williston, Vermont
Trial 13190 Dr. D. Lukof Harleysville Veterinary Hospital
Harleysville, Pennsylvania
Trial 13203 Dr. C. MacKay MacKay Animal Clinic Whitby,
Ontario, Canada
b.
Study design:
1) Purpose: To confirm the safety and acceptability of ivermectin chewables at
use level under field conditions.
2) Test animals: 377 cats (194 males and 183 females) were included in the
trials: 302 cats in the USA, 75 cats in Canada. The cats ranged in age from 8
weeks to 17 years.
3) Control: Vehicle chewables were comprised of formulation excipients without
active ingredient
4) Dosage form: Chewables
5) Route of administration: Oral
6) Dosage: Recommended dose of > or = 24 mcg/kg, monthly for 5 months
c. Results: A variety of medications were administered to cats during
the study; these included vaccines, flea treatments, antimicrobials, sedatives,
anesthetics and steroid preparations. In the USA, owners or veterinarians
successfully administered 96% of the ivermectin chewables, and in Canada, 97.5%
(free choice, in food, or manually).
d. Conclusion: Ivermectin, administered in this chewable dosage form, is
acceptable to cats and is safe when administered at the recommended dose of > or = 24
mcg/kg.
e. Clinical Observations: See below.
Clinical Observations from all 4 Field Investigations: In all clinical
trials, observations reported within 24 hours of treatment included vomition in
0.3% and diarrhea in < or = 0.2% of the doses administered. There were no statistical
differences between Heartgard for Cats and the product vehicle (control) for
these observations.
Clinical Vehicle-Treated Cats Ivermectin-Treated Cats
Observation (990 doses) (3,252 doses)
Vomiting 0.30% 0.28%
Diarrhea 0.20% 0.09%
D. Other Studies
Trials 14282 and 14430 showed that feeding of cats and breaking of
chewables reduced the variability in absorption of ivermectin and reduced the
incidence of remnants of chewables in the feces.
Trial 14282: Twelve cats were used in this crossover design study. Six cats
received a crumbled chewable on day 0 and a whole chewable on day 14 while the
remaining 6 cats received the whole chewable on day 0 and the crumbled chewable
on day 14. Blood was collected after each treatment for evaluation of
ivermectin levels. Cats given the crumbled chewable had a higher absorption of
ivermectin than those given the chewable administered whole.
Trial 14430: Twenty-four cats were divided into 4 groups and received whole
and crumbled ivermectin chewables while fasted and while fed ad libitum,
as follows:
Group Feeding Schedule How Fed
1 Day 0 -- Fed Ad libitum Whole
Day 6 -- Fasted
2 Day 0 -- Fasted Whole
Day 6 -- Fed Ad libitum
3 Day 0 -- Fed Ad libitum Crumbled
Day 6 -- Fasted
4 Day 0 -- Fasted Crumbled
Day 6 -- Fed Ad libitum
All feces produced for 72 hours after treatment were collected and
visually inspected for evidence of lack of disintegration of the chewable. Six
of the 24 cats had chewable fragments in the feces when fed ad libitum
compared to 21 of the 24 cats when fasted. Of the six cats that had chewable
fragments when fed ad libitum, 4 were with the whole chewable and 2 were
with the crumbled chewable.
Seven controlled studies were conducted in cats to address the
tolerance and safety of ivermectin chewables. Studies were specifically
designed to evaluate safety of ivermectin administered at exaggerated doses in
breeding queens and toms, in adult cats, in kittens, and at the recommended
dose in cats with heartworm microfilariae.
A. Pivotal Studies
1. Six-month Tolerance Study in Kittens: ASR 14034
a. Investigator: Dr. E. Schwartz, White Eagle Toxicology
Laboratories, Inc., Doylestown, Pennsylvania
b. Study design:
1) Purpose: To demonstrate tolerance of growing kittens to ivermectin
chewables at 1X, 3X, or 5X the label dose at 28-day intervals for 8 doses
2) Test animals: 28 6-week-old kittens (13 males, 15 females), 7 kittens per
group
3) Dosage form: Chewables
4) Dosages: Each kitten was treated 8 times at 28-day intervals. Kittens
received vehicle, or ivermectin at 1X (> or = 24 mcg/kg), at 3X (> or = 72 mcg/kg),
or at 5X (> or = 120 mcg/kg) the recommended dose.
5) Route of administration: Oral
6) Test duration: 203 days
7) Pertinent parameters measured: A detailed physical examination was
conducted on each kitten before Day 0 and on Day 202. Kittens were weighed
before each treatment day and on Day 202. On each of the eight treatment
administration days, each kitten was observed hourly for 6 hours and
approximately 24 hours after treatment for any signs of reactions. On the
treatment days, detailed clinical evaluations were performed at 3 and 6 hours
after treatment and daily thereafter for 7 days. Hematology and blood
chemistry were assessed before Day 0 and on Days 61, 120, and 203.
Histopathology: Kittens were necropsied on Day 203.
c. Results: There were no statistically significant effects of
treatment on heart rate, respiration, temperature, and final weight gain;
though cats in the high dose group had statistically significantly less weigh
gain to Day 83. One cat in the high dose group vomited and a second cat showed
diarrhea within 24 hours of the first dose.
d. Conclusions: Ivermectin, administered in this chewable dosage form, is safe
when administered to kittens at the label dose of > or = 24 mcg/kg body
weight.
2. Reproduction Study in Male Cats: ASR 13234
a. Investigator: Dr. J. Laveglia, Food and Drug Research
Laboratories, Waverly, New York
b. Study design:
1) Purpose: To demonstrate the safety of ivermectin chewables to breeding male
cats at 4X the frequency and at 3X the label dose of > or = 24 mcg/kg.
2) Test animals: 14 adult male cats, 7 per group, and 28 adult female cats, 14
per group. Cats had sired or queened at least two litters each.
3) Dosage form: Chewables
4) Dosages: Male cats in the control group were offered three vehicle
chewables daily throughout the study while males in the ivermectin group
received at least 3X the minimum recommended dose of 24 mcg/kg once per week.
Three vehicle chewables were offered to the cats on non-treatment days.
Chewables were administered to each male cat in the ivermectin group 11 times
at 7-day intervals before being bred to each of two female cats. Female cats
were not treated. Weekly treatment of the males continued until the
parturition of the females to which they were mated or until termination of the
study.
5) Route of administration: Oral
6) Test duration: 18 months
7) Pertinent parameters measured: Males received a physical examination before
the start of the study and at the end of the study; they were observed daily
and weighed weekly. Within 48 hours of parturition, each kitten was examined
and weighed. Kittens were examined and weighed again at weaning.
c. Results: Six of the seven control males and all seven
ivermectin-treated males mated. No adverse effects were noted in any treated
male cats during the study. There were no statistically significant effects of
treatment on birth weight or weaning weight of kittens, on numbers of litters
with mortalities or abnormalities, on total litter size, percent born alive and
percent weaned, or on weight gains of male cats.
Test Group Litter Percent Live Mean Birth Weaning
Size(1) Birth Weight (grams) Index(2)
Control 3.9 90% 109.3 91%
Ivermectin 3.25 74% 111.0 76%
Statistical N.S. N.S. N.S. N.S.
Significance(3)
(1)Litter size was calculated as the total number of kittens divided by the
number of pregnant queens.
(2)Weaning Index was calculated as the number of kittens weaned divided
by the number born alive X100.
(3) No statistically significant differences between treated and control groups.
d. Conclusion: Ivermectin, administered in this chewable dosage form, is safe
when administered to breeding toms at the label dose of 24 mcg/kg body
weight.
3. Reproduction Study in Female Cats: ASR 13235
a. Investigator: Dr. J. Laveglia, Food and Drug Research
Laboratories, Waverly, New York
b. Study design:
1) Purpose: To demonstrate safety to breeding female cats given ivermectin
chewables at least at 4X the frequency and at 3X the label dose of > or =
24 mcg/kg
2) Test animals: 36 adult female cats, 6 per group; and 6 adult male cats, 1
per group. Cats had queened or sired at least two litters each.
3) Dosage form and route of administration: Chewables, administered orally
4) Dosages: Each ivermectin-treated cat received at least 3X the minimum
recommended dose of 24 mcg/kg at each administration. These cats were treated
through all stages of organogenesis and lactation. Chewables were administered
to each female cat in the ivermectin groups at least 5 times at 7-day intervals
before being bred to the male cat assigned to its replicate. Male cats were
not treated. During gestation, female cats of the four ivermectin treatment
groups were treated at least at 3X the label dose every fourth day from Day 1,
2, 3, or 4 of gestation to Day 33, 34, 31, or 32 of gestation, respectively.
Weekly treatment of the females resumed for the second half of gestation and
continued through parturition and lactation until their kittens were weaned.
5) Test duration: 13 months
6) Pertinent parameters measured: Females received a physical examination at
the start and end of the study; they were observed daily and weighed weekly.
Within 48 hours of parturition, each kitten was examined and weighed. Kittens
were observed daily; they were examined and weighed again at weaning.
c. Results: Three females (1 control, 2 ivermectin-treated) failed to
conceive. There were no statistically significant effects of treatment on
birth weight or weaning weight of kittens, on proportions of litters with
mortalities or abnormalities, on total litter size, percent born alive and
percent weaned, or on weight of female cats.
Test Group Litter Percent Live Mean Birth Weaning
Size(1) Birth Weight (Grams) Index(2)
Control 4.2 93.5% 123.3 95.3%
Ivermectin 3.5 89.5% 128.2 88.2%
Statistical N.S. N.S. N.S. N.S.
Significance(3)
(1)Litter size was calculated as the total number of kittens divided by the
number of pregnant queens.
(2)Weaning Index was calculated as the number of kittens weaned divided
by the number born alive X100.
(3)No statistically significant differences between treated and control groups.
d. Conclusion: Ivermectin, administered in this chewable dosage form, is safe
when administered to breeding queens at the label dose of 24 mcg/kg body
weight.
4. Reproduction Study in Male Cats: ASR 13952
a. Investigator: Dr. M. Gilman, Liberty Research, Inc., Waverly, New
York
b. Study design:
1) Purpose: To demonstrate safety to breeding male cats given ivermectin
chewables at 4X the frequency and at 3X the label dose of > or = 24 mcg/kg.
2) Test animals: 20 adult male cats, 10 per group, and 40 adult female cats,
20 per group. Cats had sired or queened at least two litters each.
3) Dosage form and route of administration: Chewables, administered orally
4) Dosages: Male cats were given three whole vehicle or ivermectin chewables
once per week. Each ivermectin-treated cat received at least 3X the minimum
recommended dose of 24 mcg/kg at each administration. Each male cat was
treated 10 times at 7-day intervals before being bred to each of two female
cats. Female cats were not treated. Weekly treatment of the males continued
until the parturition of the females to which they were mated or until
termination of the study.
5) Test duration: 10 months
6) Pertinent: Males received a physical examination before the start of the
study and at the end of the study; they were observed daily and weighed weekly.
Within 48 hours of parturition, each kitten was examined for malformations and
abnormalities. Kittens were weighed within 72 to 102 hours after birth and at
weaning, as part of an overall physical examination.
c. Results: All males in both groups mated. No adverse effects were
noted in any treated male cats during the study. There were no statistically
significant effects of treatment on average birth weight or weaning weight of
litters, on numbers of litters with mortalities or abnormalities, on total
litter size and percent born alive, or on male weights. The percentage of
kittens weaned was significantly (p<0.05) higher in the ivermectin-treated
group than in the control group.
Test Group Litter Percent Live Mean Birth Weaning
Size(1) Birth Weight (grams) Index(2)
Control 4.8 94% 157.6 86%
Ivermectin 3.9 89% 174.2 92%
Statistical N.S. N.S. N.S. N.S.
Significance(3)
(1)Litter size was calculated as the total number of kittens divided by the
number of pregnant queens.
(2)Weaning Index was calculated as the number of kittens weaned divided
by the number born alive X100.
(3)No statistically significant differences between treated and control groups.
d. Conclusion: Ivermectin, administered in this chewable dosage form, is safe
when administered to breeding toms at the label dose of > or = 24 mcg/kg body
weight
5. Reproduction Study in Female Cats: ASR 13951
a. Investigator: Dr. M. Gilman, Liberty Research, Inc., Waverly, New
York
b. Study design:
1) Purpose: To demonstrate safety to breeding female cats given ivermectin
chewables at 4X the frequency and at 3X the label dose of > or = 24 mcg/kg.
2) Test animals: 72 adult female cats, 6 per group, and 6 adult male cats, 1
per group. Cats had queened or sired at least two litters each.
3) Dosage form and route of administration: Chewables, administered orally
4) Dosages: Each female cat received three vehicle chewables (8 groups) or
three ivermectin chewables (4 groups) once a week for four weeks before
breeding began. Each ivermectin-treated cat received at least 3X the minimum
recommended dose of 24 mcg/kg at each administration. These cats were treated
through all stages of organogenesis and lactation. After breeding to the male
cat assigned to its replicate, the female cats were treated at least at 3X
every fourth day from Day 1, 2, 3, or 4 of gestation to Day 33, 34, 35, or 36
of gestation, respectively. Male cats were not treated. Weekly treatment of
the females resumed for the second half of gestation and continued through
parturition and lactation until their kittens were weaned.
5) Test duration: 121/2 months
6) Pertinent parameters measured: Females received a physical examination
before the start of the study and at the end of the study; they were observed
daily and weighed weekly. If any abnormalities were observed during the daily
observation then a physical examination was conducted. Within 48 hours of
parturition, each kitten was examined for malformations and abnormalities.
Kittens were weighed within 72 to 102 hours after birth and at weaning, as part
of an overall physical examination.
c. Results: Thirteen females (10 controls and 3 ivermectin-treated)
failed to conceive. There were no statistically significant effects of
treatment on birth weight of kittens, on proportions of litters with
mortalities or abnormalities, on total litter size, percent born alive and
percent weaned, or on weight of female cats.
Test Group Litter Percent Live Mean Birth Weaning
Size(1) Birth Weight (grams) Index(2)
Control 3.7 96% 175.5 95%
Ivermectin 3.9 96% 159.2 88%
Statistical N.S. N.S. N.S. N.S.
Significance(3)
(1)Litter size was calculated as the total number of kittens divided by the
number of pregnant queens.
(2)Weaning Index was calculated as the number of kittens weaned divided
by the number born alive X100.
(3)No statistically significant differences between treated and control groups.
Mean weight at weaning was 591.4 and 544.3 g, respectively, for the control
and ivermectin-treated kittens (p<0.05), but these means are within expected
ranges for normal weaning weights for kittens. The mean weights at weaning in
the four reproductive safety studies were similar:
Study Mean weaning weight (g) Mean weaning weight (g)
No. of control kittens of ivermectin-treated
kittens
13234 503.5 579.6
13235 531.5 580.3
13952 511.5 570.0
13951 591.4 544.3
d. Conclusion: Ivermectin, administered in this chewable dosage form, is safe
when administered to breeding queens at the label dose of > or = 24 mcg/kg body
weight.
6. Safety Study in Microfilariae-Positive Cats: ASR 12671
a. Investigator: Dr. J. McCall, TRS Laboratories, Inc., Athens,
Georgia
b. Study design:
1) Purpose: To demonstrate safety of ivermectin chewables given to cats with
patent infections of adult Dirofilaria immitis
2) Test animals: 12 cats (7 male and 5 female), 7 to 12 months of age, 6 per
group
3) Dosage and route of administration: Cats were treated orally with
ivermectin chewables to provide ivermectin at > or = 24 mcg/kg, or with vehicle
chewables
4) Infection: Each cat was infected on Day -13 with 4 female and 1 to 4 male
adult D. immitis via jugular venotomy
5) Duration: 14 days
6) Pertinent parameters measured: Clinical observations, hematology and
clinical chemistry were recorded throughout the trial. Heartworms were
recovered at necropsy on Day 14, and organ and tissue samples were examined
histopathologically.
c. Results: Live adult heartworms were recovered from all cats at
necropsy. Circulating microfilariae were seen in both treatment groups from
Day 0 through Day 9. However, on Days 11 and 14 there were no
microfilariae in the ivermectin-treated cats, whereas 5 of 6 cats in the
control cats were microfilaremic on Day 11 and 2 of 6 were microfilaremic on
Day 14. No adverse effects of treatment were observed.
d. Conclusion: Ivermectin, administered in this chewable dosage form, is safe
when administered to cats with patent infections of D. immitis at the
label dose of > or = 24 mcg/kg body weight.
7. Drug Tolerance Study: ASR 12996
a. Investigator: Dr. M. Gilman, Hazleton-LRE, Kalamazoo, MI
b. Study design:
1) Purpose: To evaluate toxicity of ivermectin in cats
2) Test animals: 24 cats (12 male and 12 female), 7 months of age, 6 per
group
3) Dosage and route of administration: Cats were given ivermectin tablets
orally, to provide ivermectin at 750, 1000, or 4800 mcg/kg, or they were given
vehicle tablets
4) Duration: 13 days
5) Pertinent parameters measured: Clinical observations were made before
treatment and at 4.5 and 7.5 hours after treatment and on Days 1, 2, 3, 4, 5,
6, 9, and 12; all cats were observed daily. Hematology, clinical chemistry,
and fecal examinations were performed before treatment and on Days 2, 8, and
12. At necropsy, gross and histopathological examinations were conducted.
c. Results: Typical signs of toxicosis consisted of exaggerated
startle response, absence of pupillary light response, unsteady gait,
incoordination, tremors, and recumbency. The no-effect-level for a single dose
of ivermectin was established at 750 mcg/kg (30X the recommended minimum dose
of 24 mcg/kg).
d. Conclusion: The toxic syndrome was established in these studies.
B. Corroborative Studies
The field trials conducted in support of this application are considered to be
corroborative target animal safety studies.
