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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 140-841 IVOMEC Pour-On for Cattle - original approval

Approval Date: August 30, 1990

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:  

 

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        0    .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 (IVOMECĀ® 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