Gastrointestinal Roundworms(adults
and 4th stage larvae):
Ostertagia ostertagi (including inhibited O. ostertagi)
O. lyrata
Haemonchus placei
Trichostrongylus axei
T. colubriformis
Cooperia oncophora
C. punctata
C. pectinata
Oesophagostomum radiatum
Bunostomum phlebotomum
Nematodirus helvetianus (adults only)
N. spathiger (adults only)
Lungworms (adults and fourth-stage
larvae):
Dictyocaulus viviparus
Liver Flukes
Fasciola hepatica (adults only)
Cattle Grubs (parasitic
stages):
Hypoderma bovis
H. lineatum
Sucking Lice:
Linognathus vituli
Haematopinus eurysternus
Solenopotes capillatus
Mites (Scabies):
Psoroptes ovis (syn. P. communis var. bovis)
Sarcoptes scabiei var. bovis
Additional indications contained
in this supplemental NADA are for control of infections of Dictyocaulus viviparus
and Ostertagia ostertagi for 21 days after treatment, and Oesophagostomum
radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia
punctata, and Cooperia oncophora for 14 days after treatment.
IVOMEC Injection for Cattle is
identical to IVOMEC PLUS except that it does not contain clorsulon. Because
clorsulon is not active against nematodes, the two products would be expected
to show similar efficacy. Data demonstrating the effectiveness of IVOMEC PLUS
Injection for Cattle for previously registered therapeutic indications are discussed
in the parent NADA 140-833 FOI Summary (approval date September 17, 1990). In
this original approval, demonstration of equivalence of IVOMEC and IVOMEC PLUS
was considered sufficient for the therapeutic claims. For the persistence claims
for IVOMEC PLUS, only one study in a representative parasite species was necessary
to include all species that were granted a persistence claim under NADA 128-409.
The effectiveness of IVOMEC Injection for Cattle for the persistent efficacy
indications listed above was demonstrated by data discussed in the supplemental
NADA 128-409 FOI Summary (approval date xxxxx).
Data from the following dose confirmation
trials demonstrate that IVOMEC PLUS Injection for Cattle given at the recommended
dosage is similar to IVOMEC Injection for Cattle with respect to control of
infections of Dictyocaulus viviparus and Ostertagia ostertagi
for 21 days after treatment, and Haemonchus placei, Trichostrongylus
axei, Cooperia punctata and Cooperia oncophora for 14 days
after treatment. The claim for Oesophagostomum radiatum is granted based
on the premise that at least one study was accomplished in a representative
species of parasite for IVOMEC PLUS. There were sufficient studies using IVOMEC
PLUS to show efficacy against 6 of the 7 parasites for which the additional
persistence claims are warranted for IVOMEC.
A. Dose Confirmation
Trial ASR 15065
1. Type of study: Dose confirmation
study in cattle with induced infections of gastrointestinal roundworms.
2. Investigator:
Bruce N. Kunkle, D.V.M.,
M.S., Ph.D.
Merck & Co., Inc.
Fulton, Missouri
3. General design:
a. Purpose: To determine the period
after treatment during which infections of gastrointestinal roundworms are controlled.
b. Animals: Thirty (30) Holstein
calves (10 per group). Animals were approximately 4 to 5 months old and weighed
157 to 234 kg at the start of the study. Animals were free of patent infections
at the time of treatment.
c. Controls: Negative controls
received the vehicle for IVOMEC Injection for Cattle subcutaneously at 1 mL/50
kg body weight.
d. Infection: Infective larvae
were given to each animal daily, starting on the day after treatment, according
to the following schedule: Ostertagia ostertagi (1000 per day for 21
days).
e. Dosage form: The dosage form
of IVOMEC PLUS was an injectable solution containing 10 mg ivermectin and 100
mg clorsulon per mL.
f. Route of administration: Subcutaneous
injection
g. Dose: Ten animals received IVOMEC
PLUS at 1 mL/50 kg body weight (200 mcg ivermectin and 2 mg clorsulon/kg body
weight) once and ten animals received IVOMEC at 1 mL/50 kg body weight (200
mcg ivermectin/kg body weight).
h. Test duration: 49 to 50 days
after treatment
i. Pertinent variables measured:
Worm counts were determined at necropsy which was 49 to 50 days after treatment
and 28 to 29 days after the last larvae were administered.
4. Results - The following parasites
had a minimum of six adequately infected control animals:
Arithmetic mean (percent reduction)
----------------------------------------
Parasite Control IVOMEC IVOMEC PLUS
-------------------- ------- ------ -----------
Ostertagia ostertagi 1258.0 82.0 (93.5%) 68.9 (94.5%)
5. Statistical methods:
Nematode percentage efficacies
were calculated for each medication using the following formula:
[Arithmetic mean number of nematodes
in non-medicated cattle) - (Arithmetic mean number of nematodes in each group
of medicated cattle)] ÷ (Arithmetic mean number of nematodes in non-medicated
cattle) x 100 = Percentage Efficacy
6. Conclusion:
Under the conditions of this study,
both IVOMEC PLUS and IVOMEC Injection for Cattle controlled infections of Ostertagia
ostertagi for 21 days after treatment.
7. Adverse reactions:
One animal died 22 days after treatment.
The apparent cause of death was an esophageal impaction, which was not believed
to be related to the experimental treatment.
Trial ASR 15071
1. Type of study: Dose confirmation
study in cattle with induced infections of gastrointestinal roundworms and lungworms.
2. Investigator:
Bruce N. Kunkle, D.V.M.,
M.S., Ph.D.
Merck & Co., Inc.
Fulton, Missouri
3. General design:
a. Purpose: To determine the period
after treatment during which infections of gastrointestinal roundworms and lungworms
are controlled.
b. Animals: Thirty (30) crossbred
calves (10 per group). Animals were approximately 8 to 9 months old and weighed
235 to 275 kg at the start of the study. Animals were free of patent infections
at the time of treatment.
c. Controls: Negative controls
received the vehicle for IVOMEC Injection for Cattle subcutaneously at 1 mL/50
kg body weight.
d. Infection: Infective larvae
were given to each animal daily, starting on the day after treatment, according
to the following schedule: Haemonchus placei (500 per day for 14 days);
Trichostrongylus axei (1000 per day for 14 days); and Cooperia punctata
(1000 per day for 14 days).
e. Dosage form: The dosage form
of IVOMEC PLUS was an injectable solution containing 10 mg ivermectin and 100
mg clorsulon per mL.
f. Route of administration: Subcutaneous
injection
g. Dose: Ten animals received IVOMEC
PLUS at 1 mL/50 kg body weight (200 mcg ivermectin and 2 mg clorsulon/kg body
weight) once and ten animals received IVOMEC 1 mL/50 kg body weight (200 mcg
ivermectin/kg body weight).
h. Test duration: 42 or 43 days
after treatment
i. Pertinent variables measured:
Worm counts were determined at necropsy which was 42 or 43 days after treatment
and 28 or 29 days after the last larvae were administered.
4. Results - The following parasites
had a minimum of six adequately infected control animals:
Arithmetic mean (percent reduction)
---------------------------------------
Parasite Control IVOMEC IVOMEC PLUS
--------------------- ------- ------ -----------
Haemonchus placei 1022.0 16.0 (98.4%) 2.0 (99.8%)
Trichostrongylus axei 1578.0 4.0 (99.7%) 4.0 (99.7%)
Cooperia punctata 1996.2 11.0 (99.4%) 0.0 (100%)
5. Statistical methods:
Nematode percentage efficacies
were calculated for each medication using the following formula:
[Arithmetic mean number of nematodes
in non-medicated cattle) - (Arithmetic mean number of nematodes in each group
of medicated cattle)] ÷ (Arithmetic mean number of nematodes in non-medicated
cattle) x 100 = Percentage Efficacy
6. Conclusion:
Under the conditions of this study,
both IVOMEC PLUS and IVOMEC Injection for Cattle controlled infections Haemonchus
placei, Trichostrongylus axei and Cooperia punctata for 14
days after treatment.
7. Adverse reactions:
One animal exhibited lameness of
the left rear leg during the trial. This event was not believed to be related
to the experimental treatments.
Trial ASR 15073
1. Type of study: Dose confirmation
study in cattle with induced infections of gastrointestinal roundworms and lungworms.
2. Investigator:
Edward G. Johnson, D.V.M.
Johnson Research
Parma, Idaho
3. General design:
a. Purpose: To determine the period
after treatment during which infections of gastrointestinal roundworms and lungworms
are controlled.
b. Animals: Thirty (30) crossbred
calves (10 per group). Animals were approximately 6 to 10 months old and weighed
215 to 283 kg at the start of the study. Animals were free of patent infections
at the time of treatment.
c. Controls: Negative controls
received the vehicle for IVOMEC Injection for Cattle subcutaneously at 1 mL/50
kg body weight.
d. Infection: Infective larvae
were given to each animal daily, starting on the day after treatment, according
to the following schedule: Haemonchus placei (500 per day for 14 days);
Trichostrongylus axei (1000 per day for 14 days); Cooperia punctata
(1000 per day for 14 days); Cooperia oncophora (1000 per day for 14 days);
and Dictyocaulus viviparus (50 per day for 21 days).
e. Dosage form: The dosage form
of IVOMEC PLUS was an injectable solution containing 10 mg ivermectin and 100
mg clorsulon per mL.
f. Route of administration: Subcutaneous
injection
g. Dose: Ten animals received IVOMEC
PLUS at 1 mL/50 kg body weight (200 mcg ivermectin and 2 mg clorsulon/kg body
weight) once and ten animals received IVOMEC at 1 mL/50 kg body weight (200
mcg ivermectin/kg body weight).
h. Test duration: 42 or 43 days
after treatment
i. Pertinent variables measured:
Worm counts were determined at necropsy which was 42 or 43 days after treatment,
28 or 29 days after the last Haemonchus placei, Trichostrongylus axei,
Cooperia punctata, and Cooperia oncophora larvae were administered,
and 21 or 22 days after the last Dictyocaulus viviparus larvae were administered.
4. Results - The following parasites
had a minimum of six adequately infected control animals:
Arithmetic mean (percent reduction)
----------------------------------------
Parasite Control IVOMEC IVOMEC PLUS
---------------------- ------- ------ -----------
Haemonchus placei 1353.5 10.0 (99.3%) 136.0 (90.0%)
Trichostrongylus axei 1202.0 0.0 (100%) 8.0 (99.3%)
Cooperia punctata 3067.8 0.7 (>99.9%) 0.0 (100%)
Cooperia oncophora 696.0 0.7 (>99.9%) 6.0 (99.1%)
Dictyocaulus viviparus 32.4 0.0 (100%) 0.0 (100%)
5. Statistical methods:
Nematode percentage efficacies
were calculated for each medicated group using the following formula:
[Arithmetic mean number of nematodes
in non-medicated cattle) - (Arithmetic mean number of nematodes in each group
of medicated cattle)] ÷ (Arithmetic mean number of nematodes in non-medicated
cattle) x 100 = Percentage Efficacy
6. Conclusion:
Under the conditions of this study,
both IVOMEC PLUS and IVOMEC Injection for Cattle controlled infections of Dictyocaulus
viviparus for 21 days after treatment, and Haemonchus placei, Trichostrongylus
axei, Cooperia punctata and Cooperia oncophora for 14 days
after treatment.
7. Adverse reactions:
Signs of respiratory disease, arthritis
and bloat were seen in two animals during the trial. These health problems were
not believed to be related to the experimental treatments.
The data submitted in support of
this supplemental NADA comply with the requirements of section 512 of the Act
and demonstrate that ivermectin and clorsulon injection, when used under the
proposed conditions of use, is safe and effective for the control of infections
of Dictyocaulus viviparus and Ostertagia ostertagi for 21 days
after treatment, and Oesophagostomum radiatum, Haemonchus placei,
Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora
for 14 days after treatment.
For cattle the tolerance of residues
are specified in 21 CFR 556.344 and 21 CFR 556.163. A tolerance for the marker
residue (22, 23-dihydro-avermectin B1a) of ivermectin is 100 ppb in the liver
(target tissue) and the tolerance for clorsulon (marker residue) in kidney (target
tissue) is 1.0 ppm. The withdrawal time is 49 days following one subcutaneous
injection of IVOMEC PLUS as specified in 21 CFR 522.1193.
The original approval of ivermectin
and clorsulon injection was as an over-the-counter drug. Adequate directions
for use have been written for the layman, and the conditions for use prescribed
on the labeling are likely to be followed in practice. Therefore, the Center
for Veterinary Medicine (CVM) has concluded that this product shall retain over-the-counter
marketing status.
Under the Center's supplemental
approval policy 21 CFR 514.106(b)(2)(v), this is a Category II change. The approval
of this change did not require a reevaluation of the safety or effectiveness
data in the parent application.
Under section 512(c)(2)(F)(iii)
of the FFDCA, this approval for food producing animals qualifies for THREE years
of marketing exclusivity beginning on the date of approval because the supplemental
application contains substantial evidence of the effectiveness of the drug involved,
any studies of animal safety, or, in the case of food producing animals, human
food safety studies (other than bioequivalence or residue studies) required
for the approval of the application and conducted or sponsored by the applicant.
The three years of marketing exclusivity applies only to the new claim for the
control of Dictyocaulus viviparus and Ostertagia ostertagi for
21 days after treatment and Oesophagostomum radiatum, Haemonchus placei,
Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora
for 14 days after treatment for which the supplemental application was approved.
