NADA 140-841

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Approval Date: August 30, 1990

Freedom of Information Summary
NADA 140-841

I. GENERAL INFORMATION:

NADA 140-841

Sponsor:
Merck Sharp and Dohme Research Laboratories
Division of Merck & Co.
P. O. Box 2000
Rahway, N.J. 07065.

Generic Name: Ivermectin

Trade Name: IVOMEC Pour-On for Cattle

Marketing Status: OTC.

II. INDICATIONS FOR USE

For the treatment and control of gastrointestinal nematodes (including inhibited immature Ostertagia ostertagi); lungworms (Dictyocaulus viviparus ); cattle grubs (Hypoderma spp.); sucking and biting lice; sarcoptic mange mites. The following species are included:
Gastrointestinal roundworms:
Ostertagia ostertagi(adults and L4, including inhibited)
Haemonchus placei(adults and L4)
Trichostrongylus axei(adults and L4)
T. colubriformis(adults and L4)
Cooperiaspp. (adults and L4)
Strongyloides papillosus(adults)
Oesophagostomum radiatum(adults and L4)
Trichurisspp. (adults)
Lungworms:
Dictyocaulus viviparus (adults and L4).
Cattle grubs (parasitic stages):
Hypoderma bovis
H. lineatum
Lice:
Linognathus vituli
Haematopinus eurysternus
Damalina bovis
Solenopotes capillatus
Mites:
Sarcoptes scabieivar bovis.
Flies:
Hematobia irritans(adults).

III. DOSAGE

A. DOSAGE FORM A ready-to-use solution containing 5 mg of ivermectin per ml.

B. ROUTE OF ADMINISTRATION The formulation should be applied along the topline in a narrow strip extending from the withers to the tailhead.

C. RECOMMENDED DOSAGES: 1 ml per 22 lb of body weight to supply 500 mcg of ivermectin per kg.

IV. EFFECTIVENESS

Ivermectin is currently approved for use in cattle as an injectable formulation (NADA 128-409, approved by Final Rule in Federal Register 49:30, pp 5343-4; February 13, 1984), and as a paste formulation (NADA 137-006, approved by Final Rule in Federal Register 51:237, pp 44449; December 10, 1986). Trials conducted for approval of these two formulations provided efficacy data for a variety of both internal and external parasites of cattle. In addition to data from previously cited NADA's, efficacy studies were conducted to demonstrate the effectiveness of the pour-on formulation against the dose-limiting parasites. The aforementioned NADAs, plus the NADA that is the subject of this summary, provide acceptable efficacy data for the parasites on the labeling.
Trial 11258 was conducted to determine the effective dose to control nematodes. Cattle were randomly allocated to treatments. Necropsies for worm counts were done 14-16 days after treatment. Doses of ivermectin were 200, 500 and 1000 mcg/kg. The data show significantly (p<0.05) less reduction in parasite counts at 200 mcg/kg compared to higher levels for several parasites, but no significant difference between 500 and 1000 mcg/kg.
Eight trials (11076, 11258, 11383, 11384, 11498, 11506, 11759, 12543) were conducted to test the efficacy of IVOMEC Pour-On against nematodes in cattle. Animals were randomized between control and treatment group in each trial and the appropriate amount of the formulation was applied (1 ml per 22 lb). After a suitable period, depending on the parasite, the animals were necropsied for parasite recovery. The results of each trial are shown in the corresponding trial summary.
Trial 11261 was conducted to evaluate the effect of IVOMEC Pour-On on Hypodermaspp. in cattle. Animals with grubs in the second and third stages were randomized between control and treatment groups. The dose given was 500 mcg/kg. Animals were examined for grub emergence in the spring. Data were statistically analyzed and the results showed that there was a significant (p<0.05) reduction in the proportion of animals with emerging grubs in the ivermectin-treated animals.
Three trials (11260, 11267, 11503) were conducted to evaluate the effect of IVOMEC Pour-On (500 mcg/kg) against lice on cattle. Both biting and sucking lice were present. The animals were randomly assigned among control and treatment groups. The trials lasted 49 to 56 days with animals examined every 7 to 14 days throughout the trials. The lice were counted in selected areas and the data were statistically analyzed. The results showed that both biting lice and sucking lice were significantly (p<0.05) reduced on treated animals.
Two trials were conducted to investigate the effect of IVOMEC Pour-On on Sarcoptes scabieivar. bovisin cattle. In Trial 11202, mites were not completely controlled in all animals at 1 ml/22 lb (500 mcg/kg) due to interference with absorption of ivermectin when the formulation was applied to skin damaged by mites. Care was taken in Trial 11774 to apply the drug only to clinically healthy skin. Live mites were recovered from only on treated animals on one occasion from Day 21 to 56 after treatment.
Six trials (11616, 11704, 11943, 11944, 12100 and 12244) evaluated the efficacy of IVOMEC Pour-On in controlling extant infestations of horn flies (Haematobia irritans) and reducing the numbers acquired by reinfestation. The results indicate that ivermectin applied topically at 500 mcg/kg effectively controls horn flies on cattle for up to 28 days.
Sunshine:
Trials 11383 and 11498 were conducted to determine if exposing cattle treated with IVOMEC Pour-On to sunshine results in any loss of efficacy. Cattle were treated with IVOMEC Pour-On at 1 ml/22 lb and housed inside or kept outside in sunshine. Animals in each trial were randomly allocated among treatments. There was no significant (p>0.10) difference in the reduction of parasite burden between treated cattle housed inside and those left out or maintained in the sunshine.
Grooming:
In Trial 11503, a 56-day pasture trial, cattle were maintained in outdoor paddocks. There were five paddocks in each of two treatments with cattle and paddocks randomly assigned to treatment. One treatment group was unmedicated and the other was given IVOMEC Pour-On at 1 ml/22 lb. Louse burdens were reduced on the cattle treated with IVOMEC Pour-On as were the number of nematode parasite eggs shed.

V. SAFETY

Animal Safety:
Three trials were conducted to investigate the safety and acceptability of applying IVOMEC Pour-On to cattle. .
Trial 11824 was a tolerance study to examine the effects of 2 ml/22 lb, 5 ml/22 lb and 10 ml/22 lb (2X, 5X and 10X recommended dose, respectively) on cattle and compare the effects to those in a control group. There were four randomly selected animals per group. Animals were examined daily for 14 days after dosing. Minor signs of irritation (skin flaking) at the application sites were seen in all groups, including the vehicle control. No treatment-related effects on feed intake or body temperature were observed.
Trial 11753 was conducted to examine the effects on skin. Sixteen animals were given IVOMEC Pour-On (1 ml/22 lb) on Day 0 of the trial. Four animals were randomly selected for collection of skin samples on each of Days 7, 14, 28 and 42 after dosing. Skin sections were examined histologically. The epidermis, dermis, subcutaneous tissue and underlying muscle at the application site appeared normal at all four time periods. The histopathologic effects were minimal degrees of dermal perivascular cuffing of mononuclear cells, lymphocytes, esinophils and plasma cells. The lesions ranged from none to mild degrees of acathosis, hyperkeratosis and parakeratosis in the control and application site skin. These histologic lesions reflect mild site irritation and are biologically insignificant.
Trial 11663 was conducted to determine the effects of accidental application of the formulation to the eye of the cattle. Four randomly selected steers were assigned to each of the four treatments; saline, 1.0 ml; IVOMEC Pour-On, 0.25 ml; IVOMEC Pour-On, 0.5 ml; IVOMEC Pour-On, 1.0 ml, each instilled into the lower conjunctival fornix. The animals were observed for seven days after treatment. There was a slight increase in Ocular Lesion Scores (Draize Method) on Days 1 and 3 after dosing in the 0.5 and 1.0 groups. These subsided by Day 7. No increased lacrimation was seen nor did the animals show signs of ocular irritation or discomfort other than that at the time the formulation was given.
Breeding Animal Safety:
Safety in breeding animals was determined by comparison with IVOMEC Injection for cattle. Data were previously presented to show that the subcutaneous administration of ivermectin at 400 mcg/kg had no adverse effects on breeding cattle. To evaluate if topical application of ivermectin posed any risk to breeding animals, a comparative bioavailability trial was conducted. IVOMEC Injection was given to eight animals at 2 ml/110 lb (400 mcg/kg) and eight animals were given IVOMEC Pour-On at 1 ml/22 lb (500 mcg/kg). The levels of ivermectin in the plasma of the two groups of animals were compared. The groups given ivermectin topically had a significantly (p<0.01) lower area under the curve and a significantly (p<0.01) lower peak plasma level than did the group given ivermectin subcutaneously. Ivermectin given subcutaneously has well documented safety in breeding animals and the data presented here show that ivermectin applied topically will also be safe in these animals.
Trial: 11076
Name: T. A. Yazwinski, Ph.D
Location:
University of Arkansas
Fayetteville, Arkansas
Test Duration: 15 days
Treatments (Number of Animals):
Vehicle Control (6)
Ivermectin Topical, 500 mcg/kg (6).
Summary:
(Eds. note: The following table consists of 3 columns.)

Parasite % Reduction P-value Cooperia spp, adult >99 .0022 Haemonchus placei, adult 100 .0022 Ostertagia spp, adult >99 .0022 Ostertagia spp, inhibited L4 >99 .0022 Ostertagia spp, L4 >99 .0022 Strongyloides papillosus, adult 97.3 .0281 Trichostrongylus axei, adult 98.8 .0022 Trichuris spp, adult 89.9 .0693
Trial: 11202 Name: D. Barth, D.V.M
Location:
MSD Sharp & Dohme G.m.b.H kathrinenhof
Merck Research Farm
Lauterbach
West Germany
Test Duration: 56 days
Treatments (Number of Animals):
Vehicle Control (6)
Ivermectin Topical, 500 mcg/kg, (6).
Summary:
(Eds. note: The following table consists of 4 columns.)

% Animals Infested Ivermectin Vehicle Topical Parasite Control 500 mcg/kg P-value Sarcoptes scabiei var bovis Day -1 100 100 - Day 7 100 33 .0152 Day 14 100 33 >.10 Day 21 100 33 .0801 Day 28 100 33 .0260 Day 35 100 17 .0260 Day 42 100 17 .0260 Day 49 100 17 .0260 Day 56 100 17 .0260

Trial: 11203 Name: D. Barth, D.V.M
Location:
MSD Sharp & Dohme G.m.b.H Kathrinenhof
Merck Research Farm
Lauterbach, West Germany
Test Duration: 35 days
Treatments (Number of animals):
Vehicle Control, (1)
Ivermectin Topical, 500 mcg/kg, (8)
Ivermectin Subcutaneous, 200 mcg/kg, (8)
Ivermectin Subcutaneous, 400 mcg/kg, (8)
Summary:
(Eds. note: The following table consists of 4 columns.)

Ivermectin Ivermectin Ivermectin Topical Subcutaneous Subcutaneous Plasma Values 500 mcg/kg 200 mcg/kg 400 mcg/kg Area under the curve, 196.2 264.1 457.4 ng/day/ml Peak concentration, 17.3 37.1 44.9 ng/ml Time to peak 4.5 2.8 2.9
Trial: 11258 Name: R. Alva-Valdes, M.V.Z., M.S., Ph.D
Location:
Merck Research Farm
Fulton, Missouri
Test Duration: 16 days
Treatments (# of animals):
Vehicle Control, (6)
Ivermectin Topical, 200 mcg/kg, (6)
Ivermectin Topical, 500 mcg/kg, (6)
Ivermectin Topical, 1000 mcg/kg, (6).
Summary:
(Eds. note: The following table consists of 4 columns.)

% Reduction Ivermectin Topical (mcg/kg) Parasite 200 500 1000 Cooperia spp, adult 92.2 100 >99 Cooperia spp, L4 73.0 100 85.4 Dictyocaulus viviparus, adult 100 100 100 Haemonchus placei, adult 100 100 100 Haemonchus spp, L4 76.2 100 100 Oesophagostomum radiatum, adult 100 100 100 Ostertagia ostertagi, adult >99 100 100 Ostertagia ostertagi, L4 100 100 100 Trichostrongylus axei, adult 90.1 100 >99 Trichostrongylus colubriformis, adult 85.1 >99 100 Trichostrongylus spp (abomasal), L4 90.4 100 100 Trichostrongylus spp (sm. intestine), L4 74.7 100 100
(Eds. note: The following table consists of 4 columns.)

P-values for Treatment Comparisons Vehicle Control Ivermectin: Ivermectin: vs Ivermectin 200 vs 500, 500 vs Parasite Groups 100 mcg/kg 1000 mcg/kg Cooperia spp, adult .0001 .0007 >.10 Cooperia spp, L4 .0421 >.10 >.10 Dictyocaulus viviparus, adult .0001 >.10 >.10 Haemonchus placei, adult .0001 >.10 >.10 Haemonchus spp, L4 .0076 .0980 >.10 Oesophagostomum radiatum, adult .0001 >.10 >.10 Ostertagia ostertagi, adult .0000 >.10 >.10 Ostertagia ostertagi, L4 .0014 >.10 >.10 Trichostrongylus axei, adult .0000 .0002 >.10 Trichostrongylus colubriformis, adult .0004 .0049 >.10 Trichostrongylus spp (abomasal), L4 .0040 >.10 >.10 Trichostrongylus spp (sm. intestine), .0543 >.10 >.10 L4
Trial: 11260 Name: J. E. Holste, B.S., D.V.M
Location:
Merck Research Farm
Fulton, Missouri
Test Duration: 56 days
Treatments (# of animals):
Vehicle Control, (6)
Ivermectin Topical, 500 mcg/kg, (6).
Summary:
(Eds. note: The following table consists of 4 columns.)

Geometric Mean Count of Live Lice Vehicle Ivermectin Topical Parasite Control 500 mcg/kg P-value Damalinia bovis Day -1 >346.0 >334.1 - Day 7 >176.1 0 .0022 Day 14 >256.9 0 .0022 Day 21 >118.4 0 .0022 Day 28 >162.9 0 .0022 Day 35 >102.9 0 .0022 Day 42 60.5 0 .0022 Day 49 >52.4 0 .0152 Day 56 45.4 0 .0152
Trial: 11261 Name: D. H. Wallace, D.V.M
Location:
Merck Research Farm
Fulton, Missouri
Test duration: 40 days
Treatments (# of animals):
Vehicle Control, (6)
Ivermectin Topical, 500 mcg/kg, (6).
Summary:
(Eds. note: The following table consists of 4 columns.)

% Animals with Live Grubs (range of counts) Parasite Control Ivermectin P-value Hypoderma bovis and H. lineatum, 100 17 .016 second and third stage larvae (4-20) (0-1)
Trial: 11267 Name: R. Alva-Valdes, M.V.Z.,M.S.,Ph.D
Location:
Merck Research Farm
Fulton, Missouri
Test Duration: 49 days
Treatments (# of Animals):
Vehicle Control, (6)
Ivermectin Topical, 500 mcg/kg(6).
Summary:
(Eds. note: The following table consists of 4 columns.)

Geometric Mean Count of Live Lice Vehicle Ivermectin Topical Parasite Control 500 mcg/kg P-value Linognathus vituli Day -1 131.8 126.8 Day 7 98.0 0.0 0.031 Day 14 58.9 0.0 0.031 Day 21 42.7 0.0 0.031 Day 28 16.4 0.0 0.031 Day 35 5.2 0.0 0.031 Day 42 3.3 0.0 0.031 Day 49 1.8 0.0 >0.10
Trial: 11383 Name: B. M. Thomson, A.I.M.L.T
Location:
Merck Sharp & Dohme (Australia) Pty Ltd
Veterinary Research & Development Laboratory
Ingleburn, New South Wales
Australia
Test Duration: 30 days
Treatments (# of Animals):
Vehicle Control, (6)
Ivermectin Topical, 500 mcg/kg in shade, (6)
Ivermectin Topical, 500 mcg/kg in sunshine, (6).
Summary:
(Eds. note: The following table consists of 3 columns.)

% Reduction Ivermectin Topical, 500 mcg/kg Parasite Shade Sunshine Cooperia spp, adult >99 >99 Haemonchus placei, adult 100 100 Oesophagostomum radiatum, adult 100 100 Ostertagia ostertagi, adult >99 >99
(Eds. note: The following table consists of 3 columns.)

P-values for Treatment Comparisons Control vs Ivermectin Ivermectin Topically: Parasite Topically Shade vs Sunshine Cooperia spp, adult .0004 >.10 Haemonchus placei, adult .0001 >.10 Oesophagostomum radiatum, adult .0001 >.10 Ostertagia ostertagi, adult .0001 >.10
Trial: 11384 Name: M. Thompson, A.I.M.L.T
Location:
Merck Sharp & Dohme (Australia) Pty Ltd
Veterinary Research & Development Laboratory
Ingleburn, New South Wales
Australia
Test Duration: 24 days
Treatments (# of Animals):
Vehicle Control, (6)
Ivermectin Topical, 500 mcg/kg, (6)
Summary:
(Eds. note: The following table consists of 3 columns.)

Parasite% Reduction P-value Cooperia spp, adult >99 .0022 Cooperia spp, L4 100 >.10 Haemonchus spp, adult 100 >.10 Oesophagostomum radiatum, adult 100 .0022 Ostertagia ostertagi, adult 100 .0022 Ostertagia ostertagi, inhibited >99 .0152 L4 Ostertagia ostertagi, L4 100 >.10 Trichostrongylus axei ,adult 100 .0022 Trichostrongylus spp, adult 100 .0606 Trichuris spp, adult 43.9 >.10
Trial: 11498 Name: J. S. Eagleston, B.V.Sc., M.V.Sc
Location:
Merck Sharp & Dohme (Australia) Pty Ltd
Veterinary Research & Development Laboratory
Ingleburn, New South Wales
Australia
Test Duration: 31 days
Treatments (# of Animals):
1. Vehicle Control, sunshine with adaptation, (6)
2. Ivermectin Topical, 500 mcg/kg - sunshine with adaptation, (6)
3. Ivermectin Topical, 500 mcg/kg - sunshine without adaptation, (6)
4. Ivermectin Topical, 500 mcg/kg - sunshine with UVabsorber, (6)
5. Ivermectin Topical, 500 mcg/kg - indoors, (6).
Summary:
(Eds. note: The following table consists of 5 columns.)

----------------% Reduction------------ Parasite 2 3 4 5 Cooperia spp, adult 85.3 73.3 95.5 88.9 Haemonchus placei, adult 100 >99 >99 100 Ostertagia ostertagi, adult 100 100 100 100 Ostertagia ostertagi, 100 74.2 33.3 100 inhibited L4
(Eds. note: The following table consists of 5 columns.)

P-values for Treatment Comparisons Parasite 1 vs 2,3,4,5 2 vs 3 2 vs 4 2 vs 5 Cooperia spp, adult .0010 >.10 >.10 >.10 Haemonchus placei, adult .0001 >.10 >.10 >.10 Ostertagia ostertagi, adult .0000 >.10 >.10 >.10 Ostertagia ostertagi, inhibited L4 >.10 >.10 >.10 >.10
Trial: 11503 Name: R. O. Burrows, B.V.M.& S., M.R.C.V.S
Location:
Merck Sharp & Dohme (Australia) Pty, Ltd.
Veterinary Research & Development Laboratory
Ingleburn, New South Wales, Australia
Test Duration: 56 days
Treatments (# of Animals):
1. Vehicle Control, (10)
2. Ivermectin Topical, 500 mcg/kg, (10)
Summary:
(Eds. note: The following table consists of 4 columns.)

Geometric Mean Count of Live Lice Ivermectin Topical Parasite Vehicle Control 500 mcg/kg P-value Damalinia bovis Day -7 35.9 36.3 - Day 0 50.1 44.1 - Day 7 46.1 0.1* .027 Day 14 34.8 0* .027 Day 28 35.4 0* .011 Day 42 36.4 0* .027 Day 56 32.1 0* .027 *At least one animal had no lice at the count sites, but lice were found elsewhere.
(Eds. note: The following table consists of 4 columns.)

Geometric Mean Count of Live Lice Ivermectin Topical Parasite Vehicle Control 500 mcg/kg P-value Linognathus vituli Day -7 11.2 9.3 - Day 0 4.7 8.9 - Day 7 9.6 0 <.01 Day 14 8.3 0 <.01 Day 28 5.1 0 <.01 Day 42 6.2 0 <.01 Day 56 4.9 0 <.01
Trial: 11506 Name: J. S. Eagleson, B.V.Sc., M.V.Sc
Location:
Merck Sharp & Dohme (Australia) Pty Ltd
Veterinary Research & Development Laboratory
Ingleburn, New South Wales
Australia
Test Duration: 29 days
Treatments (# of Animals):
Vehicle Control, (6)
Ivermectin Topical, 500 mcg/kg, (6).
Summary:
(Eds. note: The following table consists of 3 columns.)

Parasite % Reduction P-value Cooperia spp, L4 >99 .0108 Haemonchus placei, L4 >99 .0022 Oesophagostomum radiatum, L4 100 .0022 Ostertagia ostertagi, L4 >99 .0022
Trial: 11616 Name: B. Robin, D.V.M. - Merck & Co., Inc
Location:
INRA - Le Pin au Haras
61310 Exmes, France
Test Duration: 46 days
Treatments (# of Animals):
Vehicle Control, (12)
Ivermectin Topical, 500 mcg/kg, (12).
Summary:
(Eds. note: The following table consists of 3 columns.)

Geometric Mean Count of Horn Flies Vehicle Ivermectin Topical Day Control 500 mcg/kg 0 22.3 22.3 22 14.0 5.0 28 12.1 1.1 32 16.0 2.7 37 25.8 10.4 46 19.8 13.4
Trial: 11663 Name: J. D. Pulliam, D.V.M., M.S
Location:
Merck & Co., Inc
P. O. Box 2000
Rahway, New Jersey 07065
Test Duration: 7 days
Treatments (# of Animals): Instilled in lower conjunctival fornix of one eye
Saline 1.0 ml, (4)
Ivermectin Topical,0.5% solution .25 ml, (4)
Ivermectin Topical, 0.5% solution .5 ml, (4)
Ivermectin Topical, 0.5% solution 1.0 ml, (4).
Summary:
Instilling the topical formulation into the conjunctival fornix produced mild conjunctival vascular congestion with mild chemises. The conjunctival edema did not involve the nictitating membrane. One animal had a mild discharge during the first day. There were no effects on the cornea or iris detected by pupillary light reaction, corneal fluorescein staining or fundoscopic examination. There was a slight increase in Ocular Lesion Scores (Draize Method) on days 1 and 3 after dosing in the 0.5 ml and 1.0 ml groups. These subsided by day 7. No increased lacrimation was seen nor did the animals show signs of ocular irritation or discomfort other than at the time the formulation was given.
Trial: 11704
Name: Maxcy P. Nolan Jr., Ph.D
Location:
Cooperative Extension Service
University of Georgia
Athens, GA 30605
Test Duration: 42 days
Treatments (# of Animals):
Vehicle Control, (34)
Ivermectin Topical, 500 mcg/kg, (30)
Summary:
(Eds. note: The following table consists of 3 columns.)

Geometric Mean Count of Horn Flies Vehicle Ivermectin Topical Day Control 500 mcg/kg 0 29.7 28.7 3 62.1 1.5 7 80.2 0.9 14 81.6 0.1 21 106.8 0.8 28 85.3 3.1 35 107.9 0.2 42 101.1 0.3
Trial: 11753 Name: J. D. Pulliam, D.V.M., M.S
Location:
Merck & Co., Inc
P. O. Box 2000
Rahway, New Jersey 07065
Test Duration: 42 days
Treatments (# of Animals):
Ivermectin Topical, 500 mcg/kg, necropsy Day 7, (4)
Ivermectin Topical, 500 mcg/kg, necropsy Day 14, (4)
Ivermectin Topical, 500 mcg/kg, necropsy Day 28, (4)
Ivermectin Topical, 500 mcg/kg, necropsy Day 42, (4).
Summary:
Application sites remained clinically normal until necropsy (7, 14, 28 or 42 days after dosing). No treatment-related adverse reactions were observed. At necropsy the epidermis, dermis, subcutaneous tissue and underlying muscle at the application site appeared normal at all four time periods. The histopathologic effects were minimal degrees of dermal perivascular cuffing of mononuclear cells, lymphocytes, eosinophils and plasma cells. The lesions ranged from none to mild degrees of acanthosis, hyperkeratosis and parakaratosis in the control and application site skin. The peak effects were seen at 14 days after treatment when two animals had mild acanthosis and one of the two also had mild perivascular cuffing. These histologic lesions reflect mild site irritation and are biologically insignificant.
Trial: 11759
Name: M. D. Soll, B.V.Sc
Location:
Merck Sharp & Dohme (Pty) Ltd
MSD Research Centre
Hennops River, Pretoria
R.S.A
Test Duration: 17 days
Treatments (# of Animals):
Vehicle Control, (15)
Ivermectin Topical, 500 mcg/kg(15)
Summary:
(Eds. note: The following table consists of 3 columns.)

Parasite % Reduction P-value Cooperia spp, adult 80.9 .0453 Cooperia spp, L4 94.6 <.01 Haemonchus placei, adult 100 <.01 Oesophagostomum radiatum, adult >99 <.01 Ostertagia ostertagi, adult 90.5 .0656 Trichostrongylus axei, adult 97.4 <.01 Trichostrongylus axei, L4 >99 <.01 Trichostrongylus spp, (sm. intest.) 44.0 >.10 adult Trichuris spp, adult 75.6 >.10
Trial: 11774 Name: M. D. Soll, B.V.Sc
Location:
Merck Sharp & Dohme (Pty) Ltd
MSD Research Centre
Hennops River, Pretoria
R.S.A
Test Duration: 56 days
Treatments (# of Animals):
Untreated Control, (6)
Ivermectin Topical, 500 mcg/kg, (6).
Summary:
(Eds. note: The following table consists of 4 columns.)

Geometric Mean Count of Live Mites Ivermectin Topical Parasite Control 500 mcg/kg P-value Sarcoptes scabiei var bovis Day 0 251.4 334.1 - Day 7 297.8 31.1 >.10 Day 14 212.7 2.2 .031 Day 21 146.4 0 .031 Day 28 145.0 0.3 .031 Day 42 164.9 0 .031 Day 56 54.9 0 .031
Trial: 11824 Name: J. D. Pulliam, D.V.M., M.S
Location:
Merck & Co., Inc
P.O. Box 2000
Rahway, New Jersey 07065
Test Duration: 14 days
Treatments (# of Animals):
1. Vehicle Control, (4)
2. Ivermectin Topical, 1000 mcg/kg, (4)
3. Ivermectin Topical, 2500 mcg/kg, (4)
4. Ivermectin Topical, 5000 mcg/kg, (4).
Summary:
(Eds. note: The following table consists of 9 columns.)

Least Squares Means P-Value For Ivermectin Treatment Comparisons Vehicle Topically (mcg/kg) Overall 1 vs 2 vs 3 vs Variable Control 1000 2500 5000 Treatment 2,3,4 3,4 4 Number of Animals 4 4 4 4 Weight (kg) on Day 0 262.6 262.2 260.0 259.2 >.10 - - - Weight Gain (kg) Day 0 to 7 6.9 6.1 11.5 8.8 >.10 - - - Day 0 to 14 16.0 13.8 16.4 19.2 >.10 - - - Daily Feed Consumption (kg) Pretreatment 9.37 9.13 9.20 9.24 >.10 - - - Week 1 8.72 8.26 9.44 9.19 >.05 - - - Week 2 9.29 8.39 9.42 9.62 <.05 >.10 <.01 >.10 Body Temperature (deg.C) Pretreatment 39.42 39.22 39.40 39.51 >.10 - - - Posttreatment 39.03 39.08 39.09 39.06 >.10 - - -
Overt signs of ivermectin toxicity, including depression, ataxia or mydriasis were not seen in these cattle dosed up to 5,000 mcg/kg (10 times proposed use level). Minor signs of application site irritation, i.e., skin flaking, were seen in all groups, including vehicle controls. No treatment-related effects on feed intake or body temperature were observed. Trial: 11943
Name: J. L. Lancaster, Ph.D
Location:
University of Arkansas
Fayetteville, AR 72701
Test Duration: 41 days
Treatments (# of Animals):
Vehicle Control, (20)
Ivermectin Topical, 500 mcg/kg, (20).
Summary:
(Eds. note: The following table consists of 3 columns.)

Geometric Mean Count of Horn Flies Ivermectin Topical Vehicle Control 500 mcg/kg Day -1 59.3 97.1 Day 3 n.d. 0.3 Day 7 122.1 0.7 Day 14 45.5 2.9 Day 21 109.7 11.4 Day 28 130.7 10.0 Day 35 83.8 31.4 Day 41 119.1 11.7 n.d. = not determined.
Trial: 11944 Name: J. L. Lancaster, Ph.D
Location:
University of Arkansas
Fayetteville, AR 72701
Test Duration: 43 days
Treatments (# of Animals):
Vehicle Control, (26)
Ivermectin Topical, 500 mcg/kg, (26).
Summary:
(Eds. note: The following table consists of 3 columns.)

Geometric Mean Count of Horn Flies Ivermectin Topical Vehicle Control 500 mcg/kg Day -1/-2 439.7 809.6 Day 2/3 307.9 8.0 Day 5/6 290.9 10.6 Day 13/14 247.5 21.1 Day 19/20 452.0 76.4 Day 26/27 270.5 32.5 Day 33/34 360.5 179.8 Day 42/43 37.1 208.2
Trial: 12100 Name: H. G. Kinzer, Ph.D
Location:
Veterinary Entomology Research Laboratory
New Mexico State University
Las Cruces, New Mexico
Test Duration: 70 days
Treatments (# of Animals):
Vehicle Control, (20)
Ivermectin Topical, 500 mcg/kg, (20).
Treatments were switched mid season when controls were given ivermectin topically and previously treated animals received no additional treatment.
Summary:
(Eds. note: The following table consists of 3 columns.)

Geometric Mean Count of Horn Flies Ivermectin Topical Control 500 mcg/kg No. Animals Counted per Treatment per Season 20 20 Early Season Treatment Day 0 143.9 177.8 Day 1 212.8 1.3 Day 3 217.0 0.3 Day 7 311.0 11.7 Day 14 406.1 18.8 Day 21 515.7 117.6 Day 28 405.5 74.8 Day 35 867.1 286.6 Day 43 545.3 338.1 Mid- Season Treatment Day 0 279.2 208.7 Day 1 344.5 0.9 Day 3 777.8 0.7 Day 7 712.3 4.5 Day 14 348.3 110.9 Day 21 227.8 170.3 Day 28 230.4 70.1 Day 35 263.8 107.7 Day 42 539.8 211.1 Day 49 502.2 204.9 Day 56 526.8 426.4 Day 63 894.3 652.2 Day 70 833.6 790.1
Trial: 12244 Name: R. Titchener, Ph.D
Location:
The West of Scotland Agricultural College
Auchincruive, Ayr KA6 5 HW
Test Duration: 56 days
Treatments (# of Animals):
Vehicle Control, (15)
Ivermectin Topical, (15).
Summary:
(Eds. note: The following table consists of 3 columns.)

Geometric Mean Count of Horn Flies Ivermectin Topical Vehicle Control 500 mcg/kg Day -6 2.0 2.3 Day 3 2.7 0 Day 7 7.2 0 Day 14 19.6 0 Day 21 32.1 0 Day 28 31.7 0 Day 33 17.8 0 Day 42 11.3 0 Day 49 1.2 0 Day 56 0.5 0
Trial: 12543 Name: T.A. Yazwinski, PhD
Location:
University of Arkansas
Fayetteville, Arkansas
Test Duration: 16 days
Treatment (# of Animals):
Vehicle Control, (8)
Ivermectin Topical, 500 mcg/kg, (8).
Summary:
(Eds. note: The following table consists of 3 columns.)

Parasite % Reduction P-value Cooperia spp, adult >99 .0002 Cooperia spp, L4 100 .0014 Dictyocaulus viviparus, adult 100 .0769 Haemonchus placei, adult 100 .0002 Haemonchus placei, L4 >99 .0002 Oesophagostomum radiatum, adult 100 .0002 Ostertagia ostertagi, adult male 100 .0002 Ostertagia spp, adult female >99 .0002 Ostertagia spp, inhibited L4 100 .0070 Ostertagia spp, L4 100 .0256 Trichostrongylus axei, adult >99 .0002 Trichostrongylus colubriformis, adult 100 .0256 Trichuris spp, adult 100 .0070
6. Human Safety: a. Drugs for Use in Food Animals:
1. Toxicity Tests:
For a complete summary of the toxicity tests for ivermectin, please consult the FOI Summary for NADA 128-409, IVOMEC (ivermectin) 1% Injection for Cattle.
2. Safe Concentration of Total Residue:
As discussed in the FOI Summary for NADA 128-409, IVOMEC (ivermectin) Injection for Cattle, the following safe concentrations in edible tissues have been calculated from the no-observed-effect-level in the most sensitive study in the most sensitive species:
(Eds. note: The following table consists of 2 columns.)

Tissue Safe Concentration (ppb) Muscle 25 Liver 50 Kidney 75 Fat 100
3. Total Residue Depletion and Metabolism Study (CA 218). a. Investigators:
Study Director:
S.H.L. Chiu, PhD
Senior Research Fellow
Animal Drug Metabolism
Merck & Co., Inc
PO Box 2000
Rahway, NJ 07065.
Principal Biologist:
F.P. Baylis, M. S
Associated Director,
Animal Metabolism
Branchburg Farm
Merck & Co., Inc
203 River Road
Somerville, NJ 08876.
b. Animals: Twelve Angus steer approximately 8-10 months old were used.
c. Route of Administration:
Drug was applied topically along the midline of the back.
d. Time and Duration of Dose:
The animals were dosed once at the start of the experiment.
e. Radio-isotope Used:
Ivermectin, labeled with tritium in the 22,23 positions, was used.
f. Average total residue at various withdrawal times.
(Eds. note: The following table consists of 9 columns.)

Days Post Dose Tissue ---7--- ---14--- ---28--- ---42--- Liver 0.226 %0.102 0.126 %0.053 0.069 %0.092 0.026 %0.012 Fat 0.072 %0.033 0.052 %0.019 0.025 %0.023 0.023 %0.010 Kidney 0.021 %0.10 0.014 %0.005 0.007 %0.007 0.004 %0.002 Muscle 0.008 %0.003 0.005 %0.002 0.002 %0.002 0.002 %0.000 Muscle dosing 0.043 %0.011 0.041 %0.014 0.019 %0.017 0.006 %0.004 site * Each number is the average value % SD for three animals.
g. Summary of Metabolism Studies:
In liver, the tissue with highest residue, the averaged unaltered parent drug (H2B1a and H2B1b) accounts for about 67%, 62%, and 52% of the total radioactive residue at 7, 14, and 28 days, respectively, after dosing. In fat, the tissue with the second highest residue, the unaltered drug accounts for about 86%, 78%, 65%, and 42% of the total radioactive residue at 7, 14, 28, and 42 days after dosing.
The 14 and 28 days cattle liver were used for study of metabolites. In these samples, unaltered drug accounted for about 53% to 57% of the radioactivity. Metabolites were separated into the polar group (2% of the total radioactivity), drug like group (5% of the total radioactivity), and non-polar group (0.5 to 2% of the total radioactivity). The major polar metabolite was identified as 24-hydroxy-H2Bla. Overall, between 85 to 91% of the liver residue in the 14 and 28 days samples were identified either as the unaltered drug or as the 24-OH-H2B1a.
In fat tissue of a 28 days post dose steer, the unaltered drug and a group of non-polar metabolites accounted for 70%and 18% of the total radioactivity, respectively. The non-polar metabolites were identified as the acyl esters of 24-OH-H2B1a.
As discussed in the FOI Summary for NADA 128-409, IVOMEC (ivermectin) Injection for Cattle, these same metabolites occur in the liver and fat of cattle treated with the parenteral formulation of ivermectin.
Comparative metabolism studies indicate that the metabolism of ivermectin in cattle 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 and qualitatively similar. The major metabolite in cattle and rat liver is 24-OH-H2B1a. Thus, the test species is exposed to the major drug residue components known to be present in cattle tissues.
4. Tolerance for the marker residue:
For reasons enumerated in the FOI Summary for NADA 128-409, IVOMEC (ivermectin) Injection for Cattle, liver was selected as target tissue, parent drug component H2B1a was selected as marker residue, and the tolerance for H2B1a in liver was calculated to be 15 ppb.
The residue date contained in Study CA-218 confirm that, for the topical route of administration, 15 ppb is a valid tolerance for ivermectin H2B1a as the marker residue in liver tissue of cattle.
The regulatory method of analysis has a limit of detection of 1-2 ppb and a limit of reliable measurement of 10 ppb.
5. Study establishing the withdrawal period (CA 223):
a. Investigators:
Study Director:
T.A. Wehner, PhD, Senior Research Chemist
Analytical Research
Merck & Co., Inc
PO Box 2000
Rahway, NJ 07065.
Principal Biologist:
F.P. Baylis, M.S
Associate Director,
Animal Metabolism
Branchburg Farm
Merck & Co., Inc
203 River Road
Somerville, NJ 08876.
b. Animals:
Twenty one Angus steers and 14 Angus heifers were treated with drug (500 mcg/kg) and three steers and two heifers served as control.
c. Route of Administration:
Drug was applied topically along the midline of the back.
d. Time and duration of dosing:
The animals were dosed once at the start of the experiment.
e. Summary of average marker residue concentrations:
(Eds. note: The following table consists of 2 columns.)

Average Marker Residue Days Post Dose (H2B1a) in Target Tissue (liver) 7 48 ppb % 32 14 27 ppb % 9 21 19 ppb %7.5 28 12 ppb % 7 35 8 ppb % 8 42 3 ppb % 1.3 56 0 ppb % 0.4 Control 1 ppb % 1.8 Each number is the average value % SD from three steers and two heifers.
f. Statistical method used to calculate the withdrawal period
Based on the tolerance for ivermectin of 15 ppb in cattle liver, a withdrawal time of 48 days was calculated by statistical analysis of the tolerance limit containing the 99th percentile of the population with 95% confidence.

VI. REGULATORY METHOD

(a and b)
A description of the assay and a statement of the results of the method validation trial can be found in the FOI Summary for NADA 128-409, IVOMEC (ivermectin) Injection for Cattle
c. Validation:
The determinative and confirmatory methods have been validated satisfactorily by FDA and USDA laboratories. 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 NADA comply with the requirements of section 512 of the Food, Drug and Cosmetic Act and demonstrate that ivermectin (IVOMEC® Pour-On) when administered to cattle topically at one milliliter per 22 lbs. of body weight is safe and effective for the indications stated on the product labeling.
Ivermectin is currently regulated by (a) Injection: 21CFR522.1192 for use subcutaneously in cattle, reindeer and swine, and intramuscularly in horses; (b) Oral: 21CFR520.1192 for use as a paste in horses and cattle; 21CFR520.1193 for use as tablets in dogs; 21CFR520.1194 for use as a drench in sheep, and 21CFR520.1195 for use as a liquid in horses.
The residue data confirm that for the topical route of administration 15 ppb is the tolerance for ivermectin H2B1a as the marker residue in liver tissue of cattle. Based on the tolerance, a withdrawal time of 48 days was determined.
Under section 512 (c)(2)(F)(ii) of the Federal Food, Drug and Cosmetic Act [21 U.S.C. 360b(c)(2)(F)(ii)], this approval qualifies for three years of marketing exclusivity because new clinical, field investigations and human food safety data were required for its approval.
The agency concludes that adequate directions for over the counter lay use have been written for the proposed conditions of topical use of ivermectin in cattle. Diagnosis of the infections can be made with a degree of certainty by the layman. The conditions described on the labeling are likely to be carried out in practice. Approved products containing ivermectin for the same claims are marketed over the counter and the agency is not aware of any reason this topical product would require the marketing status to be changed.

VIII. LABEL

1) Ivomec Package Insert
2) Ivomec 250mL Back Label
3) Ivomec 1L Label
4) Ivomec 2.5L Label
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