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© 2006 Betterchem.com
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Approval Date:
September 23, 1993
Freedom of
Information Summary
NADA 140-974
I. GENERAL INFORMATION:
| NADA |
140-974 |
| Sponsor: |
Merck Sharp & Dohme
Research Laboratories
Division of Merck & Co., Inc.
P.O. Box 2000
Rahway, New Jersey 07065-0914 |
| Generic Name: |
Ivermectin |
| Trade Name: |
IVOMEC® Premix for
Swine |
| Marketing Status: |
OTC |
II. INDICATIONS FOR USE
For the treatment and control of
gastrointestinal roundworms (Ascaris suum , adults and fourth-stage
larvae; Ascarops strongylina , adults; Hyostrongylus rubidus ,
adults and fourth-stage larvae; Oesophagostomum spp. adults and
fourth-stage larvae), kidneyworms (Stephanurus dentatus, adults and
fourth-stage larvae), lungworms ( Metastrongylus spp., adults), lice
( Haematopinus suis ) and mange mites ( Sarcoptes scabiei var.
suis ) when incorporated into complete swine feeds at the level
listed in the table below. Follow mixing directions when preparing complete
feeds.
III. DOSAGE FORM, ROUTE OF ADMINISTRATION, AND RECOMMENDED DOSAGE
Add IVOMEC Premix to starter, grower and finisher feeds at 300 g per ton to
supply 1.8 g ivermectin per ton (2 ppm) of feed. Use this Type C Medicated Feed
as the only feed for 7 consecutive days. This provides approximately 100 mcg
of ivermectin per kg of bodyweight per day.
300g
Required amount of
IVOMEC Premix (Type A) Medicated Article 0.6 % to medicate one ton of
complete (Type C) Medicated Feed
1.8g
Required level of ivermectin per
ton of complete (Type C) Medicated Feed.
IVOMEC Premix should be thoroughly and evenly mixed in the feed in accordance
with good manufacturing practices for medicated feeds. Dispersion of ivermectin
in the feed is enhanced by diluting 1 part ivermectin Type A Medicated Article
with 14 parts of finely ground feed ingredients to provide an intermediate
premix. Ten lb of this intermediate premix is used to provide 1.8 g ivermectin
in one ton of complete Type C Medicated Feed.
IV. EFFECTIVENESS
Several formulations of ivermectin, including an injectable formulation
for swine, are currently marketed by Merck & Co., Inc. as effective
antiparasitic agents for various animal species. Data collected from a
development program that included 26 clinical studies conducted in diverse
areas of the United States as well as a number of international sites
demonstrate that ivermectin as a 0.6% w/w Type A medicated article added to
the ration at a rate to provide 2 ppm ivermectin (equivalent to approximately
100 mcg/kg/day) and fed to pigs for seven consecutive days effectively controls
a wide range of economically important endo- and ectoparasites of growing
swine. All of the studies involving efficacy evaluations against parasites were
conducted as controlled studies. Both ecto-and endoparasite counts of treated
swine were compared with those of untreated controls. The pigs were either
experimentally or naturally infected with one or more species of ectoparasites
(lice and mites) or endoparasites (nematodes). Each claim for a parasite
species was supported by at least two controlled studies. Efficacy was
expressed as percentage (%) reduction of parasites as compared to controls. The
% reduction was calculated as follows:
(Arithmetic mean number of parasites in control swine -
Percentage Arithmetic mean number of parasites in treated swine)
Reduction of = ---------------------------------------------------------- X 100
Parasites Arithmetic mean number of parasites in control swine
The efficacy of ivermectin was at least 93% for each endoparasite claim except
for the fourth-stage larvae of Oesophagostomum spp. (90%) while
ectoparasite populations were reduced following treatment. Data from United
States and international studies supports the claim that ivermectin
administered in the ration of growing swine at 2 ppm for seven consecutive days
is effective against adult and larval stages of the important nematode and
arthropod parasites that affect swine.
A. Dose Titration
Dose titration studies were conducted to determine the amount of
ivermectin that would be required in a seven-day treatment regimen to control
swine endo- and ectoparasites. One ectoparasite study, and two endoparasite
studies, each including eight controls and 24 medicated swine were conducted.
Ivermectin dosages of 0, 50, 100 or 200 mcg/kg/day for seven consecutive days
were evaluated. Local procedures were followed regarding animal husbandry
during the studies and standard procedures were used for allocating animals,
collecting samples, enumerating and identifying parasites and performing
necropsies. The endoparasite studies used induced infections but naturally
infested animals were used in the ectoparasite study. Based on the data
collected, the optimum dose was determined to be 100 mcg/kg/day for seven
days.
Ectoparasite Dose Titration
Study 12581 was conducted in the United States to establish the optimum
level of ivermectin effective against Sarcoptes scabiei var suis
. Thirty-two pigs with natural infestations were randomly allocated into four
groups and fed ivermectin in feed at 0, 50, 100 or 200 mcg/kg/day for seven
consecutive days, followed by nonmedicated ration until the study was
terminated. Mites in scrapings from specified areas of the skin were counted.
Mite infestation was markedly reduced in all ivermectin-treated pigs at seven
days after the termination of treatment and these animals were free of
infestation on Day 42 of the study. The medicated rations were readily
consumed. No adverse reactions were observed during the course of the study.
Data from the controls and pigs treated with ivermectin are listed below.
(Eds. note: The following table consists of 2 columns.)
Sarcoptes scabiei
Dose Level % Efficacy (Range Day 14-42)
50 mcg/kg 99 - 100
100 mcg/kg 99 - 100
200 mcg/kg 100 - 100
Investigator:
Dr. J.E. Holste
Merck Research Farm
Route 2, Box 136
Fulton,
Missouri 65251
Endoparasite Dose Titration
Study 12583 was conducted in the United States to establish the optimum
level of ivermectin in feed against nematodes. Thirty-two pigs were
artificially infected and randomly allocated to four groups of equal size. When
the nematodes were in the fourth larval stage (L4), the groups were given
ivermectin in feed at 0, 50, 100 or 200 mcg/kg/day for seven days followed by
nonmedicated ration until the study was terminated. Necropsies were performed
16 to 17 days after the termination of treatment and the reductions in
nematode counts are summarized below. The medicated rations were readily
consumed. No adverse reactions were observed during the course of the
study.
(Eds. note: The following table consists of 4 columns.)
Percent Reduction Relative to Controls
Ivermectin (mcg/kg/day)
Nematode (L4) 50 100 200
Ascaris suum 100 100 100
Hyostrongylus rubidus 99 100 100
Oesophagostomum spp. 94 96 92
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2, Box
136
Fulton, Missouri 65251
Study 12443 was conducted in West Germany to establish the optimum level of
ivermectin in feed against immature Hyostrongylus rubidus . Thirty-two
pigs with induced infections were randomly allocated to four groups of equal
size. When the nematodes were in the fourth larval stage (L4), the groups were
given ivermectin in feed at 0, 50, 100 or 200
mcg/kg/day for seven days, followed by nonmedicated ration until the study was
terminated. Necropsies were performed 35-37 days after the termination of
treatment and the findings listed below recorded. The medicated ration was
readily consumed. No adverse reactions were observed during the course of the
study.
(Eds. note: The following table consists of 4 columns.)
Percent Reduction Relative to Controls
Ivermectin (mcg/kg/day)
Nematode (L4) 50 100 200
Hyostrongylus rubidus 93 99 99
Investigator:
Dr. E.M. Heinze-Mutz
Merck Sharp & Dohme
Kathrinenhof
Walchenseestrasse 8-12
D-8201
Lauterbach, West Germany
Justification of Dose Selection
Results from the above dose titration studies showed that 100 mcg/kg/day
for seven days was adequate to control Sarcoptes scabiei var suis
as well as L4 nematodes. Dose responses observed against L4 nematodes
in two separate studies support the selection of 100 mcg/kg/day.
B. Dose Confirmation
Eight dose confirmation studies were conducted with ectoparasites
(mange mites and swine lice). The studies included 105 ivermectin-treated pigs
and 105 controls. The infestations were naturally acquired in five studies and
induced in three. The parasite numbers were recorded from selected sample
sites. The reductions of Sarcoptes scabiei var suis and
Haematopinus suis are summarized in Table 1.
Confirmation of the dose selected for endoparasites (gastrointestinal,
pulmonary and kidney nematodes) was affirmed in 15 controlled studies. The
dose-confirmation data were obtained using 181 ivermectin-treated pigs and 181
controls. Infections were acquired naturally in eight of the studies and were
induced in seven. All pigs were killed 14 to 180 days after treatment for
parasite recoveries. Table 2 contains a summary of the reductions obtained.
(Eds. note: The following table consists of 3 columns.)
Table 1
Reductions of Ectoparasites on Swine Given Ivermectin In Feed at
2 ppm for Seven Days Compared to Controls
Range of
Parasite/ No. of %
Days after treatment Trials Reduction
Sarcoptes scabiei var suis 3 (total no.)
14 days 3 100
21 days 1 100
28 days 2 100
Haematopinus suis 5 (total no.)
14 days 5 95 - 100
21 days 1 92 - 95
28 days 3 95 - 100
(Eds. note: The following table consists of 3 columns.)
Table 2
Reductions of Endoparasites in Swine Given Ivermectin In Feed
at 2 ppm for Seven Days Compared to Controls
No. of %
Parasite Trials Reduction
Oesophagostomum spp. adults 5 98.2
Oesophagostomum spp. L4 2 90.3
Ascaris suum adults 7 100.0
Ascaris suum L4 1 100.0
Hyostrongylus rubidus adults 3 96.9
Hyostrongylus rubidus L4 2 95.0
Ascarops strongylina adults 5 96.4
Metastrongylus spp. adults 4 100.0
Stephanurus dentatus adults 2 100.0
Stephanurus dentatus L4 2 100.0
Ectoparasite Dose-Confirmation Studies
- Study 12751 was conducted in the United States to confirm the efficacy of
ivermectin in feed against Sarcoptes scabiei var suis .
Fifty-six pigs with
natural infestations were allocated to two groups and housed four animals
per pen. One group was the nonmedicated control and received the basal
ration, the other group was given ivermectin in feed at 2 ppm for seven
days followed by nonmedicated feed until the study terminated. Mites
from preselected locations were counted biweekly until study termination
on Day 42. No living mites were found on any of the ivermectin-treated
pigs after Day 0. The medicated feed was readily consumed. No adverse
reactions were observed during the study.
(Eds. note: The following table consists of 4 columns.)
% Efficacy on Day
Parasite 14 28 42
S. scabiei 100 100 100
Investigator:
Dr. J.E. Holste
Merck Research Farm
Route 2, Box 136
Fulton, Missouri 65251
- Study 12760 was conducted in the United States to confirm the efficacy of
ivermectin in feed against Sarcoptes scabiei var suis . Twenty
pigs with naturally acquired infestations were randomly allocated to two
groups of equal size. One group was not treated and the other received
ivermectin in feed at 2 ppm for seven days. Mites from preselected
locations were counted on Days -2, 14, 28 and 42 of the study. No live
mites were found on the ivermectin-treated pigs during any of the last
three examinations. The medicated feed was readily consumed. No adverse
reactions were observed. The data from this study are summarized below.
(Eds. note: The following table consists of 4 columns.)
% Efficacy on Day
Parasite 14 28 42
S. scabiei 100 100 100
Investigator:
Dr. D.P. Bane
College of Veterinary Medicine
University of Illinois
Urbana, Illinois 61801
- Study 12772 was conducted in the United States to confirm the efficacy
of ivermectin in feed against Sarcoptes scabiei var suis . Twenty
pigs with natural infestations were allocated to two groups of equal size. One
group was not treated and the other received ivermectin in feed at 2 ppm for
seven days. Mites from preselected locations were counted on Days -1, 7 and 21
of the study. No live mites were found on the ivermectin-treated pigs on
either Day 7 or 21. The medicated feed was readily consumed. No adverse
reactions were observed. The data are summarized below.
(Eds. note: The following table consists of 3 columns.)
% Efficacy on Day
Parasite 7 14
S. scabiei 100 100
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2, Box 136
Fulton, Missouri 65251
- Study 12461 was conducted in West Germany to confirm the efficacy of
ivermectin in feed against Haernatopinus suis. Sixteen pigs with
induced infestations were allocated to two groups of equal number. Pigs in
one group were not treated and those of the other group received
ivermectin in feed at 2 ppm for seven days. The lice on each pig were
counted weekly and the results are summarized below. The medicated feed was
readily consumed. No adverse reactions were observed. The lice that
appeared on the ivermectin-treated pigs on Days 14-28 of the study
originated from eggs that hatched during the posttreatment period.
(Eds. note: The following table consists of 5 columns.)
------------% Efficacy on Day-------------
Parasite 7 14 21 28
H. suis 100 95 92 95
Investigator:
Dr. E.M. Heinze-Mutz
Merck Sharp & Dohme
Kathrinenhof
Walchenseestrasse 8-12
D-8201
Lauterbach, West Germany
- Study 12593 was conducted in the United States to confirm the efficacy
of
ivermectin against swine lice. Twenty pigs with natural infestations of
Haernatopinus suis were allocated to two groups of equal number. Pigs
in one group were not treated and those of the other group received
ivermectin in feed at 2 ppm for seven days. The lice on each pig were
counted on Days -2, 7, 14 and 28, and the results are summarized below. The
medicated feed was readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 4 columns.)
% Efficacy on Day
Parasite 7 14 28
H. suis 100 100 100
Investigator:
Dr. H.N. Becker
Becker Veterinary Clinic
P.O. Box 990
Melrose, Florida 32666
- Study 12763 was conducted in the United States to confirm the efficacy
of ivermectin in feed against swine lice. Twenty pigs with induced
infestations of H. suis were allocated to two groups of equal size. Pigs
in one group received ivermectin in feed at 2 ppm for seven days and those
of the other group were not treated. The lice on each pig were counted
on Days -1, 7, 14 and 28 and the results are summarized below. The
medicated feed was readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 4 columns.)
% Efficacy on Day
Parasite 7 14 28
H. suis 100 100 100
Investigator:
Dr. R.E. Williams
Department of Entomology
Purdue University
West Lafayette, Indiana 47906
- Study 13038 was conducted in the United States to confirm that ivermectin in
feed is effective against swine lice. Twenty pigs with natural infestations of
Haematopinus suis were allocated to two groups of equal number.
One group was not treated and the other group received ivermectin in feed at 2
ppm for seven days. The lice on each pig were counted on Days 0, 7, 14 and 28 and
the results are listed below. The lice that appeared on the ivermectin-treated
pigs on Day 28 originated from eggs that hatched during the posttreatment
period. The medicated feed was readily consumed. No adverse reactions were
observed.
(Eds. note: The following table consists of 3 columns.)
% Efficacy on Day
Parasite 7 14
H. suis 100 100
Investigator:
Dr. J.E. Holste
Ghrist Veterinary Clinic
1111 E. Washington
Pittsfield, Illinois 62363
- Study 13039 was conducted in the United States to confirm the efficacy of
ivermectin in feed against natural infestations of Haematopinus suis,
the swine louse. Eighteen pigs with naturally acquired infestations
were randomly allocated to two groups of equal number. One group was not
treated and the other group received ivermectin in feed at 2 ppm for seven days.
The lice on each pig were counted weekly and the results are listed below. The
lice that appeared on the ivermectin-treated pigs on Days 21-28 originated from
eggs that hatched during the posttreatment period. The medicated feed was
readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 5 columns.)
------------% Efficacy on Day-------------
Parasite 7 14 21 28
H. suis 100 100 99 97
Investigator:
Dr. J.E. Holste
Merck Research Farm
Route 2, Box
136
Fulton, Missouri 65251
Endoparasite Dose Confirmation Studies
- Study 12461 was conducted in West Germany to confirm that ivermectin in
feed is effective against nematodes. Sixteen pigs with induced infections were
randomly allocated to two groups of equal number. When the nematodes became
adults, one group was not treated and the other group received ivermectin in
feed at 2 ppm for seven days. Necropsies were performed 21-23 days after
termination of treatment and the reductions in counts of adult nematodes are
summarized below. The medicated feed was readily consumed. No adverse reactions
were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Hyostrongylus rubidus 98
Oesophagostomum spp. 98
Metastrongylus spp. 100
Investigator:
Dr.E.M. Heinze-Mutz
Merck Sharp & Dohme
Kathrinenhof
Walchenseestrasse 8-12
D-8201
Lauterbach, West
Germany
- Study 12593 was conducted in the United States to confirm that ivermectin in
feed is effective against nematodes. Twenty pigs with natural infections were
randomly allocated to two groups of equal number. One group was not treated
and the other group received ivermectin in feed at 2 ppm for seven days.
Necropsies were performed 21 days after the termination of treatment and the
reductions in nematode counts are summarized below. The medicated feed was
consumed readily. No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Oesoph. quadrispinulatum 99
Investigator:
Dr. H.N. Becker
Becker Veterinary Clinic
P.O. Box
990
Melrose, Florida 32666
- Study 12760 was conducted in the United States to confirm that ivermectin is
effective against nematodes. Twenty pigs with natural infections were randomly
allocated to two groups of equal size. One group was not treated and the other
group received ivermectin in feed at 2 ppm for seven days. Necropsies were
performed 35 days after the termination of treatment and the reductions in
nematode counts are summarized below. The medicated feed was readily consumed.
No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Ascarops strongylina 99
Investigator:
Dr. D.P. Bane
College of Veterinary Medicine
University of Illinois
Urbana, Illinois 61801
- Study 12761 was conducted in the United States to confirm that
ivermectin in feed is effective against nematodes. Twenty pigs with natural
infections were randomly allocated to two groups of equal size. One group
was not treated and the other group received ivermectin in feed at 2 ppm
for seven days. Necropsies were performed 14 days after the termination of
treatment and the reductions in counts of adult nematodes are summarized
below. The medicated feed was readily consumed. No adverse reactions were
observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Metastrongylus spp. 100
Ascarops strongylina 99
Investigator:
Dr. D.P. Bane
College of Veterinary Medicine
University of Illinois
Urbana, Illinois 61801
- Study 12764 was conducted in the United States to confirm that ivermectin in
feed is effective against nematodes. Twenty pigs with naturally acquired
infections were randomly allocated to two groups of equal size. One group was
given ivermectin in feed at 2 ppm for seven days and the other group was not
treated. Necropsies were performed 14-15 days after the termination of
treatment and the reduction in counts of adult Ascaris suum is
shown below. The medicated feed was readily consumed. No adverse reactions were
observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Investigator:
S.M. Gaafar
Department of Veterinary
Pathology
School of Veterinary Medicine,
Purdue University
West
Lafayette, Indiana 47907
- Study 12772 was conducted in the United States to confirm that ivermectin in
feed is effective against adult nematodes. Twenty pigs with natural infections
were randomly allocated to two groups of equal size. One group was not treated
and the other group received ivermectin in feed at 2 ppm for seven days.
Necropsies were performed 14-15 days after the termination of treatment and the
reductions in nematode counts are summarized below. The medicated feed was
readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Ascarops strongylina 99
Hyostrongylus rubidus 100
Metastrongylus spp. 100
Oesophagostomum spp. 100
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2,
P.O. Box 136
Fulton, Missouri 65251
- Study 12777 was conducted in the United States to confirm that ivermectin in
feed is effective against adult nematodes. Twenty pigs with natural infections
were randomly allocated to two groups of ten animals. One group received
ivermectin in feed at 2 ppm for seven days and the other group was not
treated. Necropsies were performed 14 days after termination of treatment and
the reductions in nematode counts are summarized below. The medicated feed was
readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Ascarops strongylina 93
Hyostrongylus rubidus 99
Metastrongylus spp. 100
Oesophagostomum spp. 100
Investigator:
Dr. T.B. Stewart
School of Veterinary Medicine
Louisiana State University
Baton Rouge, Louisiana 70803
- Study 13039 was conducted in the United States to confirm that ivermectin in
feed is effective against adult nematodes in swine. Eighteen pigs with natural
infections were randomly allocated to two groups of equal size. One group was
not treated and the other group received ivermectin in feed at 2 ppm for
seven days. Necropsies were performed 21 days after termination of treatment and
the reductions in nematode counts are summarized below. The medicated feed was
readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Ascaris suum 100
Ascarops strongylina 99
Metastrongylus spp. 100
Oesophagostomum spp. 99
Investigator:
Dr. J.E. Holste
Merck Research Farm
Route
2, P.O. Box 136
Fulton, Missouri 65251
- Study 12755 was conducted in the United States to confirm that ivermectin in
feed is effective against immature nematodes in swine. Fifty-six pigs with
induced infections were randomly allocated to two groups of equal size. When the
infections had reached the fourth larval stage, one group received ivermectin in
feed at 2 ppm for seven days and the other group was not treated. Necropsies were
performed 21-23 days after the termination of treatment and the reductions in
counts of fourth-stage larvae (L4) are summarized below. The medicated feed
was readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (L4) % Reduction at 2 ppm/7 days
Ascaris suum 100
Hyostrongylus rubidus 100
Oesophagostomum spp. 84
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2, P.O. Box 136
Fulton, Missouri 65251
- Study 12853 was conducted in the United States to confirm that ivermectin
in feed is effective against L4Oesophagostomum spp. in swine. Fifty-six
pigs with induced infections were randomly allocated to two groups of equal
size. When the infection had reached the fourth larval stage, one group
received ivermectin in feed at 2 ppm for seven days and the other group was not
treated. Necropsies were performed 17-19 days after the termination of
treatment and the reduction in counts of L4 Oesophagostomum spp. is
shown below. The medicated feed was readily consumed. No adverse reactions were
observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (L4) % Reduction at 2 ppm/7 days
Oesophagostomum spp. 96
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2, P.O. Box 136
Fulton, Missouri 65251
- Study 13073 was conducted in the United Kingdom to confirm that ivermectin
in feed is effective against immature Hyostrongylus rubidus . Sixteen
pigs with induced infections were randomly allocated to two groups of 8 pigs.
When the infections reached the fourth larval stage, one group received
ivermectin in feed at 2 ppm for seven days and the other group was not treated.
Necropsies were performed 14 days after the termination of treatment and the
reduction in counts of L4 H. rubidus is shown below. The medicated
feed was readily consumed. No adverse reactions were observed.
(Eds. note: The following table consists of 2 columns.)
Nematodes (L4) % Reduction at 2 ppm/7 days
Hyostrongylus rubidus 88
Investigator:
Dr. R.M. Connan
Department of Clinical Veterinary
Medicine
University of Cambridge,
Madingley Road, Cambridge CB3 OES,
England
- Study 12778 was conducted in the United States to confirm that ivermectin
in feed is effective against immature Stephanurus dentatus . Thirty pigs
with induced infections were randomly allocated to three groups of ten. When
infections had reached the fourth larval stage, one group was not treated and
one group received ivermectin in feed at 2 ppm for seven days. Necropsies were
performed 13-18 days after the termination of treatment and the reduction in
counts of L4 S. dentatus is shown below. The medicated feed was
readily consumed. No adverse reactions were observed. The third group of pigs
was given an injectable formulation of ivermectin; however, the data from that
treatment are not pertinent to this summary and have been omitted.
(Eds. note: The following table consists of 2 columns.)
Nematodes (L4) % Reduction at 2 ppm/7 days
Stephanurus dentatus 100
Investigator:
Dr. D.J. Moncol
School of Veterinary Medicine
North Carolina State University
4700 Hillsborough
Raleigh, North
Carolina 27606
- Study 12833 was conducted in the United States to confirm that ivermectin
in feed is effective against immature Stephanurus dentatus . Thirty pigs
with induced infections were randomly allocated to three groups of ten. When
the infection had reached the fourth larval stage, one group was not treated
and one group received ivermectin in feed at 2 ppm for seven days. Necropsies
were performed approximately 180 days after the termination of treatment when
all nematodes in treated and nontreated animals were adults, and the reduction
in counts of L4 S. dentatus is shown below. The medicated feed was
readily consumed. No adverse reactions were observed. The third group of pigs
was given an injectable formulation of ivermectin; however, the data from that
treatment are not pertinent to this summary and have been omitted.
(Eds. note: The following table consists of 2 columns.)
Nematodes (L4) % Reduction at 2 ppm/7 days
Stephanurus dentatus 100
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2,
Box 136
Fulton, Missouri 65251
- Study 12594 was conducted in the United States to confirm that ivermectin
in feed is effective against adult Stephanurus dentatus . Thirty-three
sows with natural infections were randomly allocated to three groups of equal
size. One group was not treated and one group received ivermectin in feed at 2
ppm for seven days. Necropsies were performed 21 days after the termination of
treatment and the reduction in counts of adult S. dentatus is shown
below. The medicated feed was readily consumed. No adverse reactions were
observed. The third group of pigs was given an injectable formulation of
ivermectin; however, the data from that treatment are not pertinent to this
summary and have been omitted.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Stephanurus dentatus 100
Investigator:
Dr. H.N. Becker
Becker Veterinary Clinic
8702 SR 21 N.
Melrose,
Florida 32666
- Study 12832 was conducted in the United States to confirm that ivermectin
is effective against adult Stephanurus dentatus . Thirty pigs with
induced infections were randomly allocated to three groups of equal size. One
group was not treated and one group received ivermectin in feed at 2 ppm for
seven days. Necropsies were performed 21 days after the termination of
treatment and the reduction in counts of adult S. dentatus is shown
below. The medicated feed was readily consumed. No adverse reactions were
observed. The third group of pigs was given an injectable formulation of
ivermectin; however, the data from that treatment are not pertinent to this
summary and have been omitted.
(Eds. note: The following table consists of 2 columns.)
Nematodes (adult) % Reduction at 2 ppm/7 days
Stephanurus dentatus 100
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2,
Box 136
Fulton, Missouri 65251
C. Field Studies
Three field studies were conducted in the United States in which ivermectin in
feed was administered at use level (Table 3). Three hundred six pigs were given
ivermectin in feed at 2 ppm for seven days and 76 were untreated controls.
The percentage of fecal samples with nematode eggs was markedly reduced after
treatment with ivermectin. The effects of ivermectin on fecal nematode eggs,
Sarcoptes scabiei var suis and Haematopinus suis in these
studies are summarized in Table 4. No adverse reactions were observed following
treatment. All medicated rations were readily consumed.
(Eds. note: The following table consists of 4 columns.)
Table 3
Field Studies
Total # of Pigs treated with
Trial No. Location # Pigs 2 ppm ivermectin in feed
12943a Stillwater, OK 127 102
13031b Pittsfield, IL 130 104
13035c Kingdom City, MO 125 100
a Investigator: Dr. J.A. Hair, Research Cooperators
Stillwater, Oklahoma 74074
b Investigator: Dr. J.E. Hoiste, R. Ghrist Farm
Pittsfield, Illinois 62363
c Investigator: Dr. J.E. Hoiste, J. Gilmore Farm
Kingdom City, Missouri 65252
(Eds. note: The following table consists of 7 columns.)
Table 4 Summary of Parasite Evaluation in Field Studies
with positive EPG/ # with lice present/ # with mites present/
# evaluated # evaluated # evaluated
Study number Control Ivermectin Control Ivermectin Control Ivermectin
ASR 12943
Day 1 12/22 54/67 20/25 47/72 25/25 30/72
Day 19-20 9/22 5/61 23/25 2/72 13/25 9/72
ASR 13031
Day 0 25/26 23/26 26/26 26/26 - -
Day 21 25/26 2/26 26/26 8/26 - -
ASR 13035
Day 0 7/25 5/25 25/25 25/25 - -
Day 21 13/25 0/25 13/25 0/25 - -
V. ANIMAL SAFETY
Study 12768 was conducted in the United States to assess the safety of the
in-feed formulation of ivermectin in pigs when included in the ration at levels
up to 10 ppm (five times the recommended dose) for 21 consecutive days (three
times the recommended treatment period). Twelve castrated males and an equal
number of female eight-week old pigs were assigned randomly to four treatment
groups and housed individually. They were fed a basal ration that contained
ivermectin in feed at 0, 2, 6 or 10 ppm for 21 days. Weight gain, feed
consumption and clinical health during the study were recorded. Blood was
collected for clinicopathologic evaluation.
No treatment-related adverse findings were observed during routine clinical
evaluation or during necropsy and histopathological review. No significant
treatment effects on weight gain and feed consumption were detected.
Investigator:
Dr. R. Alva-Valdes
Merck Research Farm
Route 2,
Box 136
Fulton, Missouri 65251
VI. HUMAN FOOD SAFETY:
A. Toxicity Tests
The toxicology studies conducted to support the safe concentration of
ivermectin in swine edible tissues are summarized in NADA 135-008.
B. Safe Concentration of Residues
The lowest no-observable-effect-levels (NOEL) in the battery of toxicity studies
described above were determined in the multigeneration study in rats (0.1
mg/kg/day) and in the oral teratogenic study in the mouse (0.1 mg/kg/day for
maternotoxicity and 0.2 mg/kg/day for teratogenicity). The minimum safety
margins required for the effects observed in these studies are 100x for the
multigeneration study and for the maternotoxicity in the mouse teratological
study and 1000x for the teratological effects also seen in the latter study.
Due to the significance of the terata (cleft palate) seen in the teratology
study the 1000x safety factor was used for determining an acceptable daily
intake (ADI) of up to 0.2 micrograms per kg per day of ivermectin residue by an
individual in food.
0.2 mg/kg/day
ADl = --------------------------- = 0.2 mcg/kg/day
1000 safety factor
A safe concentration in muscle tissue of swine 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 g, as follows:
(60 kg)(0.2 mcg/kg/day)
safe concentration = ----------------------------------- = 24 ppb
in muscle 500 g/day
When rounded to the nearest 5 ppb, the safe concentration in muscle then
becomes 25 ppb. The safe concentration of residues in liver, kidney and fat are
determined from this number using appropriate food consumption values (food
factor) for these tissues. Therefore, the safe concentrations are:
Liver: 25 ppb x 3 (food factor) = 75 ppb
Kidney: 25 ppb x 4 (food factor) = 100 ppb
Fat: 25 ppb x 4 (food factor) = 100 ppb
C. Metabolism and Total Residue Depletion Studies
Total radioactive residue (averaged value from three animals) in edible tissues
of swine dosed with 3H-labeled MK-933 orally at 100 g/kg body weight/day for 7
days in the feed is shown in the table below:
(Eds. note: The following table consists of 6 columns.)
----------Days 0FF DRUG-----------
Tissue 0 3 7 14 21
-------TOTAL RESIDUE (ppb)--------
Liver 237 43 11 4 3
Fat 207 64 18 8 5
Kidney 117 20 3 0 0
Muscle 58 12 3 1 0
Examination of the residue data and unaltered drug depletion patterns shows that
fat and liver generally contain the highest and most persistent residue. The
fat residue levels are slightly higher than the liver at almost all time
points, although the unaltered drug depletion pattern in both tissues is
essentially similar, i.e., the unaltered drug is a satisfactory marker
substance. Because of the integrity of the liver as one organ
and the relative difficulty in extracting and isolating the marker substance
from fat, the liver is considered the preferred target tissue.
The radioactive residue in the edible tissues examined is essentially all
extractable into organic solvents indicating that there is very little, if any,
intractable, covalently bound residue in these tissues. The unaltered drug
( H2B1a and H2Blb, respectively) acoounts for about 45% (33 + 12%) and 34% (26
+ 8%) of the total radioactive residue in liver on-drug and 3 days off-drug,
respectively. In fat, the unaltered drug accounts for about 77% (66 + 11%) of
the total residue on-drug and 64% (56 + 8%) at 3 days off-drug.
Livers from two on drug (1 barrow and 1 gilt) and three 3-day off-drug (1 barrow
and 2 gilts) swine were used for metabolism studies. In these samples,
unaltered drug accounts for about 38 and 34% [by normal-phase (NP) HPLC] of the
residue, respectively. Metabolites can be separated into a polar group (17 and
12%, respectively), 3"-O-desmethyl and drug-like (43 and 50%, respectively) and
nonpolar (4 and 5%, respectively). By reversed-phase high performance liquid
chromatography (RP-HPLC), H2Bla component comprised about 34% of the total
radioactivity in the on-drug livers and about 28% in the 3-day off-drug livers.
The H2Blb component coeluted with 3"-O-desmethyl-H2Bla, but these compounds
were separated by NP-HPLC. The H2Blb component comprised about 7% of the
radioactivity in the on-drug and about 6% in 3-day off-drug livers while the
3"-O-desmethyl H2B1a component was about 27% and 30% of the radioactivity in the
on-drug and 3-day off-drug livers, respectively. There were at least two
metabolites that eluted in the polar fraction during the NP-HPLC where the
24-hydroxymethyl metabolites would be expected. Metabolites less polar than the
H2B1a component comprised only 3-7% of the radioactivity in any of the
liver samples. The remainder of the radioactivity in the livers, about 12%
on-drug and about 16% 3-days off-drug, was comprised of at least two "drug-like"
components, one of which was identified as 3"-0-desmethyl-H2Blb by its
chromatographic behavior on NP and RP-HPLC. None of the unidentified components
of the residue in liver represented as much as 10% of the total residue nor
were present at a concentration of >0.1 ppm.
The metabolism of MK-933 in swine fat is qualitatively similar to that in the
swine liver. The compositions of the radioactive residues (determined by
NP-HPLC) in on-drug and 3-day off-drug swine fat samples are respectively;
unaltered drug, 75 and 64%; non-polar metabolites, 10 and 23%; drug-like
metabolites, 11 and 9%; and polar metabolites, 7 and 6%. The distribution of
radioactive components in the livers and fat of the swine fed ivermectin is
qualitatively similar to the distribution of components following subcutaneous
dosing.
Comparative metabolism studies indicate that the metabolism of MK-933 in swine
and rat, the toxicity test species, is qualitatively similar. In both species,
the unaltered drug is the major residue. The HPLC profiles of the radioactive
residue in the liver are qualitatively similar with respect to the metabolite
components, but quantitatively different in the abundance of some metabolite
components. The major metabolites in swine liver are 3"-O-desmethyl-H2B1a and
3"-O-desmethyl-H2B1b, whereas in rat liver, the major polar metabolites are
24-hydroxymethyl-H2B1a and 24-hydroxymethyl-H2B1b. The presence of
24-hydroxymethylH2B1a and 24-hydroxymethyl-H281b in the on-drug and 3 days
off-drug livers of the swine dosed orally with MK-933 in feed is indicated by
radioactive peaks with retention times characteristic of these components. The
presence of a small amount of 3"-O-desmethyl products in rat liver is suggested
by the presence of a small radioactive peak with retention time identical to
the 3"-O-desmethyl compounds. Thus, the test species is exposed to the major
drug residue components known to be present in swine tissues.
D. Studies Demonstrating a Withdrawal Time
A tissue residue depletion study was performed to determine the marker residue
(component H2B1a) concentration in swine tissues resulting from the feeding
of animals continuously for seven days with ivermectin premlx combined in a
complete feed at 2 ppm. Three barrows and two gilts were sacrificed at each
withdrawal time. The withdrawal times following the end of the medication
period were 0 (on the seventh day of medication), 0.5, 1, 1.5, 2, 2.5, 3, 5 and
7 days. Another set of five animals served as unmedicated controls.
Marker residue assays were conducted on swine livers (the target tissue) for
selected withdrawal times using the high pressure liquid
chromatography-fluorescence determinative method. The average marker residue
concentrations found were as follows:
(Eds. note: The following table consists of 8 columns.)
Days withdrawal 0 1.0 1.5 2.0 2.5 3.0 5.0 Control
ppb Found 38 22 19 14 10 12 3 0
The analytical method used to determine the marker residue has a lower limit of
reliable measurement of 10 ppb. The Rm value (marker residue concentration
tolerance) for swine derived from toxicity and metabolism data has been
determined to be 20 ppb, which is the same tolerance established for swine in
NADA 135-008. Statistical analysis of the depletion data, using the upper
tolerance limit containing 99 percentile of the population with 95% confidence,
yields a withdrawal period of 5 days.
E. Regulatory Methods
Ivermectin Determinative Assay Scheme
The determinative assay measures the marker residue, 22,23-dihydroavermectin
Bla by high pressure liquid chromatography (HPLC) of a fluorescent derivative.
The marker residue is extracted into isooctane from an aqueous acetone
homogenate of liver tissue. The isooctane is removed by evaporation and the
extract purified by a series of acetonitrile-hexane-water partitions. The
fluorescent derivative is formed by heating with an acetic anhydride +
methylimidazole reagent. A chloroform solution is purified over a silica column
and concentrated by evaporation; reverse phase HPLC is performed using
methanol/water and fluorescence detection. Quantitation is obtained by using a
standard curve for the marker residue carried through the derivatization and
subsequent steps. Recoveries are in the range of 75-95% with a lower limit of
reliable measurement of 10 ppb.
Ivermectin Confirmatory Assay Scheme
The sample preparation and purification steps of the confirmatory assay are
essentially the same as the determinative assay. The specificity is obtained by
the production of two new species just prior to derivatization. The new species
are produced by removing one of the saccharide groups with 1% sulfuric acid in
isopropanol to form the
monosaccharide or removing both saccharide groups with 1% sulfuric acid in
methanol to form the aglycone of 22,23-dihydroavermectin B1a. Since these
two treatments are so
similar, the formation of the two new species and their chromatographic
properties are unique and hence confirm the presence of the marker
residue.
In the confirmatory test, the liver extract is split into three parts. One part
is used for each of the sulfuric acid treatments. These samples are separated
from sulfuric acid by extractions and the fiuorescent derivatives of the two
new compounds are made. The third aliquot is derivatized without pretreatment.
All three derivatives are then extracted into hexane with a small amount of
isobutyl alcohol present. The high pressure liquid chromatography determination
is made as in the determinative assay. Three separate peaks are observed at
three separate retention times which are compared with standards run through
the procedure from the sulfuric acid addition step onward. Presence of and
quantitation of the three peaks is confirmation that ivermectin is present.
Validation
The determinative and confirmatory methods were validated satisfactorily by FDA
and USDA laboratories utilizing bovine and ovine tissue. It was not deemed
necessary to repeat these methods trials with porcine tissue. The validated
regulatory analytical methods for detection of residues of ivermectin are filed
in the Food Additives Manual on display in FDA's Freedom of Information Public
Room (Room 12A-30, 5600 Fishers Lane, Rockville, MD 20857).
VII. AGENCY CONCLUSIONS:
The data submitted in support of this original NADA comply with the
requirements of section 512 of the Act and demonstrate that ivermectin 0.6%
Type A medicated artide when used under the proposed conditions of use, is safe
and effective. These data from the controlled studies demonstrate the
effectiveness of ivermectin for its labeled indications in swine feeds when fed
at 100 mcg/kg body weight for a period of 7 consecutive days. These studies
demonstrate the efficacy of a 7 consecutive day regimen for treatment and
control of Ascaris suum- adult and fourth-stage larvae; Ascarops
strongylina- adults; Hyostrongylus rubidus- adult and fourth-stage larvae;
Oesophagostomum spp.- adult and fourth-stage larvae; Stephanurus
dentatus- adult and fourth-stage larvae; Metastrongylus spp.- adult;
Haernatopinus suis; and Sarcoptes scabiei var. suis .
The withdrawal period for swine is 5 days. The safe concentration for total
ivermectin residues in uncooked edible swine tissues has been established as 25
ppb in muscle, 75 ppb in liver, 100 ppb in kidney, and 100 ppb in fat. A
regulatory tissue residue method has been developed for the determination of
the marker compound, parent ivermectin, with a tolerance of 20 ppb in swine
liver (21 CFR 556.344).
Ivermectin products for use in food producing animals are generally
over-the-counter products. Accurate diagnosis can be made with reasonable
degree of certainty by the layman. 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 have over-the-counter
marketing status.
Under Section 512(c)(2)(F)(ii) of the FFDCA, this approval for food producing
animals qualifies for THREE years of marketing exclusivity beginning on the
date of approval because the application contains reports of new clinical or
field investigations essential to the approval of the application and conducted
or sponsored by the applicant.
VIII. LABELING (Attached)
1. Front Panel: Ivomec® Premix for Swine, Type A Medicated Article, 50#
bag (22.68 kg).
2. Back Panel; Ivomec® Premix for Swine, Type A Medicated Article, 50#
bag (22.68 kg).
Copies of these labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
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