Safe-Guard vs Ivomec Plus
Written by Administrator-GL   
Wednesday, 07 May 2008

Safe-Guard Dewormer Paste vs Ivomec Plus Injectable Dewormer Comparison


Are the same thing Both are 10%Fenbendazole and only effective for treating tapeworms in goats:

See the little grooves in the plunger? These are marked for weight increments. You dial the little round dial to the weight of the animal and the plunger stops at the correct dosage- This is where you will see 500lbs (one 'click' as we call it)- one click or 500lbs will treat a 165 pound goat (3 times the recommended dosage per pound as for cattle or horses) NOTE: Look at the top image - see the white dial on the end of the plunger? Before you use this the first time you need to screw this all the way to the other end close to the actual tube of medication, Then you start screwing it up in increments according to weight
I have created this side by side comparison chart to show you why safeguard is not as effective against internal gastrointestinal parasites as Ivomec and Ivomec PLUS- Keep in mind when ever you use Safe-Guard you MUST use it at TRIPLE the recommended dose on the package when administering to goats! So when a click on the tube says it will treat a 500lb calf, this means it will treat a 165lb goat.
IN Addition: Safeguard and Panacur have been discovered that they really only work well on tapeworms in goats - they are barely effective against any of the gastrointestinal "killer" worms

Safe-Guard


(fenbendazole)

Ivomec PLUS


(ivermectin and clorsulon)
Lungworm: (Dictyocaulus viviparus)   Lungworm: (Dictyocaulus viviparus)
(adults and fourth-stage larvae)
Brown Stomach worm (Ostertagia ostertagi)   Brown Stomach worm (Ostertagia ostertagi)
(including inhibited O. ostertagi)AND O. lyrata
Barberpole Worm (Haemonchus contortus/placei)   Barberpole Worm (Haemonchus contortus/placei)
Small Stomach Worm (Trichostrongylus axei)   Small Stomach Worm (Trichostrongylus axei)
AND T. colubriformis
Hookworm (Bunostomum phlebotomum)   Hookworm (Bunostomum phlebotomum)
Threadneck Intestinal Worm (Nematodirus helvetianus)   Threadneck Intestinal Worm (Nematodirus helvetianus)
Small Intestinal Worms (Cooperia oncophora, Cooperia punctata)   Small Intestinal Worms (Cooperia oncophora, Cooperia punctata,
AND Cooperia pectinata)
     Brown Stomach worm (Ostertagia ostertagi)
     Nodular Worm (Oesophagostomum radiatum)
     Nematodirus helvetianus (adults only)(thread-necked worm)
AND N. spathiger (adults only)
     Fasciola hepatica (adults only)(Liver Flukes)
     Cattle Grubs (parasitic stages):
Hypoderma bovis AND H. lineatum
     Sucking Lice:
Linognathus vituli, Haematopinus eurysternus,
AND Solenopotes capillatus
     Mites (Scabies):
Psoroptes ovis (syn. P. communis var. bovis)
AND Sarcoptes scabiei var. bovis
  

IVOMEC PLUS

Injection has been proved to effectively control infections and to protect cattle from re-infection with Dictyocaulus viviparus and Ostertagia ostertagi for 21 days after treatment; Oesophagostomum radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora for 14 days after treatment.

Extend the period of persistent activity against Dictyocaulus viviparus (Lungworm) from 21 days to 28 days after treatment.

*Comparison Tables and information compiled by goatlady 2006

NADA information for both Ivomec Plus and Safe-Guard Paste follows Keep in mind this is a cattle medication and goat owners use this OFF Label- the Goat metabolic system is different than that of cattle and therefore the dose information for cattle does not apply to goats

NADA 140-833 for Ivomec PLUS

 

Approval Date: Feburary 24, 1997

Freedom of Information Summary
NADA 140-833

I. GENERAL INFORMATION:

NADA 140-833
Sponsor:

Merck & Co., Inc.
P.O. Box 2000
Rahway, New Jersey 07065

Generic Name: Ivermectin and clorsulon
Trade Name: IVOMEC® PLUS Injection for Cattle
Marketing Status: Over-the-counter (OTC)
Effect of Supplement: New claims for persistent control of gastrointestinal roundworms and lungworms

II. INDICATIONS FOR USE

Gastrointestinal Roundworms(adults and 4th stage larvae):
Ostertagia ostertagi (including inhibited O. ostertagi)
O. lyrata
Haemonchus placei
Trichostrongylus axei
T. colubriformis
Cooperia oncophora
C. punctata
C. pectinata
Oesophagostomum radiatum
Bunostomum phlebotomum
Nematodirus helvetianus (adults only)
N. spathiger (adults only)

Lungworms (adults and fourth-stage larvae):
Dictyocaulus viviparus

Liver Flukes
Fasciola hepatica (adults only)

Cattle Grubs (parasitic stages):
Hypoderma bovis
H. lineatum

Sucking Lice:
Linognathus vituli
Haematopinus eurysternus
Solenopotes capillatus

Mites (Scabies):
Psoroptes ovis (syn. P. communis var. bovis)
Sarcoptes scabiei var. bovis

Additional indications contained in this supplemental NADA are for control of infections of Dictyocaulus viviparus and Ostertagia ostertagi for 21 days after treatment, and Oesophagostomum radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora for 14 days after treatment.

III. DOSAGE

A. DOSAGE FORM IVOMEC PLUS is a sterile solution available in 50, 200, 500, and 1000 mL plastic bottles. Each milliliter contains 10 mg/mL ivermectin and 100 mg/mL clorsulon.
B. ROUTE OF ADMINISTRATION IVOMEC PLUS should be administered by subcutaneous injection.
C. APPROVED DOSAGES: 200 g ivermectin and 2 mg clorsulon/kg body weight (1 mL/110 lb body weight).
     

IV. EFFECTIVENESS

IVOMEC Injection for Cattle is identical to IVOMEC PLUS except that it does not contain clorsulon. Because clorsulon is not active against nematodes, the two products would be expected to show similar efficacy. Data demonstrating the effectiveness of IVOMEC PLUS Injection for Cattle for previously registered therapeutic indications are discussed in the parent NADA 140-833 FOI Summary (approval date September 17, 1990). In this original approval, demonstration of equivalence of IVOMEC and IVOMEC PLUS was considered sufficient for the therapeutic claims. For the persistence claims for IVOMEC PLUS, only one study in a representative parasite species was necessary to include all species that were granted a persistence claim under NADA 128-409. The effectiveness of IVOMEC Injection for Cattle for the persistent efficacy indications listed above was demonstrated by data discussed in the supplemental NADA 128-409 FOI Summary (approval date xxxxx).

Data from the following dose confirmation trials demonstrate that IVOMEC PLUS Injection for Cattle given at the recommended dosage is similar to IVOMEC Injection for Cattle with respect to control of infections of Dictyocaulus viviparus and Ostertagia ostertagi for 21 days after treatment, and Haemonchus placei, Trichostrongylus axei, Cooperia punctata and Cooperia oncophora for 14 days after treatment. The claim for Oesophagostomum radiatum is granted based on the premise that at least one study was accomplished in a representative species of parasite for IVOMEC PLUS. There were sufficient studies using IVOMEC PLUS to show efficacy against 6 of the 7 parasites for which the additional persistence claims are warranted for IVOMEC.

A. Dose Confirmation

Trial ASR 15065

1. Type of study: Dose confirmation study in cattle with induced infections of gastrointestinal roundworms.

2. Investigator:

Bruce N. Kunkle, D.V.M., M.S., Ph.D.
Merck & Co., Inc.
Fulton, Missouri
3. General design:

a. Purpose: To determine the period after treatment during which infections of gastrointestinal roundworms are controlled.

b. Animals: Thirty (30) Holstein calves (10 per group). Animals were approximately 4 to 5 months old and weighed 157 to 234 kg at the start of the study. Animals were free of patent infections at the time of treatment.

c. Controls: Negative controls received the vehicle for IVOMEC Injection for Cattle subcutaneously at 1 mL/50 kg body weight.

d. Infection: Infective larvae were given to each animal daily, starting on the day after treatment, according to the following schedule: Ostertagia ostertagi (1000 per day for 21 days).

e. Dosage form: The dosage form of IVOMEC PLUS was an injectable solution containing 10 mg ivermectin and 100 mg clorsulon per mL.

f. Route of administration: Subcutaneous injection

g. Dose: Ten animals received IVOMEC PLUS at 1 mL/50 kg body weight (200 mcg ivermectin and 2 mg clorsulon/kg body weight) once and ten animals received IVOMEC at 1 mL/50 kg body weight (200 mcg ivermectin/kg body weight).

h. Test duration: 49 to 50 days after treatment

i. Pertinent variables measured: Worm counts were determined at necropsy which was 49 to 50 days after treatment and 28 to 29 days after the last larvae were administered.

4. Results - The following parasites had a minimum of six adequately infected control animals:



                                  Arithmetic mean (percent reduction)
                               ----------------------------------------  
  Parasite                      Control        IVOMEC       IVOMEC PLUS
  --------------------          -------        ------       -----------   
  Ostertagia ostertagi           1258.0     82.0 (93.5%)    68.9 (94.5%)  
                                                              

5. Statistical methods:

Nematode percentage efficacies were calculated for each medication using the following formula:

[Arithmetic mean number of nematodes in non-medicated cattle) - (Arithmetic mean number of nematodes in each group of medicated cattle)] ÷ (Arithmetic mean number of nematodes in non-medicated cattle) x 100 = Percentage Efficacy

6. Conclusion:

Under the conditions of this study, both IVOMEC PLUS and IVOMEC Injection for Cattle controlled infections of Ostertagia ostertagi for 21 days after treatment.

7. Adverse reactions:

One animal died 22 days after treatment. The apparent cause of death was an esophageal impaction, which was not believed to be related to the experimental treatment.

Trial ASR 15071

1. Type of study: Dose confirmation study in cattle with induced infections of gastrointestinal roundworms and lungworms.

2. Investigator:

Bruce N. Kunkle, D.V.M., M.S., Ph.D.
Merck & Co., Inc.
Fulton, Missouri
3. General design:

a. Purpose: To determine the period after treatment during which infections of gastrointestinal roundworms and lungworms are controlled.

b. Animals: Thirty (30) crossbred calves (10 per group). Animals were approximately 8 to 9 months old and weighed 235 to 275 kg at the start of the study. Animals were free of patent infections at the time of treatment.

c. Controls: Negative controls received the vehicle for IVOMEC Injection for Cattle subcutaneously at 1 mL/50 kg body weight.

d. Infection: Infective larvae were given to each animal daily, starting on the day after treatment, according to the following schedule: Haemonchus placei (500 per day for 14 days); Trichostrongylus axei (1000 per day for 14 days); and Cooperia punctata (1000 per day for 14 days).

e. Dosage form: The dosage form of IVOMEC PLUS was an injectable solution containing 10 mg ivermectin and 100 mg clorsulon per mL.

f. Route of administration: Subcutaneous injection

g. Dose: Ten animals received IVOMEC PLUS at 1 mL/50 kg body weight (200 mcg ivermectin and 2 mg clorsulon/kg body weight) once and ten animals received IVOMEC 1 mL/50 kg body weight (200 mcg ivermectin/kg body weight).

h. Test duration: 42 or 43 days after treatment

i. Pertinent variables measured: Worm counts were determined at necropsy which was 42 or 43 days after treatment and 28 or 29 days after the last larvae were administered.

4. Results - The following parasites had a minimum of six adequately infected control animals:


                                   Arithmetic mean (percent reduction)
                               ---------------------------------------  
  Parasite                      Control        IVOMEC      IVOMEC PLUS
  ---------------------         -------        ------      -----------   
  Haemonchus placei              1022.0     16.0 (98.4%)   2.0  (99.8%)   
                                                              
  Trichostrongylus axei          1578.0      4.0 (99.7%)   4.0  (99.7%)   
                                                              
  Cooperia punctata              1996.2     11.0 (99.4%)   0.0 (100%)   
                                                              


5. Statistical methods:

Nematode percentage efficacies were calculated for each medication using the following formula:

[Arithmetic mean number of nematodes in non-medicated cattle) - (Arithmetic mean number of nematodes in each group of medicated cattle)] ÷ (Arithmetic mean number of nematodes in non-medicated cattle) x 100 = Percentage Efficacy

6. Conclusion:

Under the conditions of this study, both IVOMEC PLUS and IVOMEC Injection for Cattle controlled infections Haemonchus placei, Trichostrongylus axei and Cooperia punctata for 14 days after treatment.

7. Adverse reactions:

One animal exhibited lameness of the left rear leg during the trial. This event was not believed to be related to the experimental treatments.

Trial ASR 15073

1. Type of study: Dose confirmation study in cattle with induced infections of gastrointestinal roundworms and lungworms.

2. Investigator:

Edward G. Johnson, D.V.M.
Johnson Research
Parma, Idaho
3. General design:

a. Purpose: To determine the period after treatment during which infections of gastrointestinal roundworms and lungworms are controlled.

b. Animals: Thirty (30) crossbred calves (10 per group). Animals were approximately 6 to 10 months old and weighed 215 to 283 kg at the start of the study. Animals were free of patent infections at the time of treatment.

c. Controls: Negative controls received the vehicle for IVOMEC Injection for Cattle subcutaneously at 1 mL/50 kg body weight.

d. Infection: Infective larvae were given to each animal daily, starting on the day after treatment, according to the following schedule: Haemonchus placei (500 per day for 14 days); Trichostrongylus axei (1000 per day for 14 days); Cooperia punctata (1000 per day for 14 days); Cooperia oncophora (1000 per day for 14 days); and Dictyocaulus viviparus (50 per day for 21 days).

e. Dosage form: The dosage form of IVOMEC PLUS was an injectable solution containing 10 mg ivermectin and 100 mg clorsulon per mL.

f. Route of administration: Subcutaneous injection

g. Dose: Ten animals received IVOMEC PLUS at 1 mL/50 kg body weight (200 mcg ivermectin and 2 mg clorsulon/kg body weight) once and ten animals received IVOMEC at 1 mL/50 kg body weight (200 mcg ivermectin/kg body weight).

h. Test duration: 42 or 43 days after treatment

i. Pertinent variables measured: Worm counts were determined at necropsy which was 42 or 43 days after treatment, 28 or 29 days after the last Haemonchus placei, Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora larvae were administered, and 21 or 22 days after the last Dictyocaulus viviparus larvae were administered.

4. Results - The following parasites had a minimum of six adequately infected control animals:


                                   Arithmetic mean (percent reduction)
                               ----------------------------------------  
Parasite                        Control        IVOMEC       IVOMEC PLUS
----------------------          -------        ------       -----------   
Haemonchus placei                1353.5      10.0  (99.3%)   136.0  (90.0%)      
                                                      
Trichostrongylus axei            1202.0       0.0 (100%)       8.0  (99.3%)   
                                                               
Cooperia punctata                3067.8       0.7 (>99.9%)     0.0 (100%)   
                                                              
Cooperia oncophora                696.0       0.7 (>99.9%)     6.0  (99.1%)   
                                                             

Dictyocaulus viviparus             32.4       0.0 (100%)       0.0 (100%)   
                                             
5. Statistical methods:

Nematode percentage efficacies were calculated for each medicated group using the following formula:

[Arithmetic mean number of nematodes in non-medicated cattle) - (Arithmetic mean number of nematodes in each group of medicated cattle)] ÷ (Arithmetic mean number of nematodes in non-medicated cattle) x 100 = Percentage Efficacy

6. Conclusion:

Under the conditions of this study, both IVOMEC PLUS and IVOMEC Injection for Cattle controlled infections of Dictyocaulus viviparus for 21 days after treatment, and Haemonchus placei, Trichostrongylus axei, Cooperia punctata and Cooperia oncophora for 14 days after treatment.

7. Adverse reactions:

Signs of respiratory disease, arthritis and bloat were seen in two animals during the trial. These health problems were not believed to be related to the experimental treatments.

V. ANIMAL SAFETY

As discussed in the parent NADA 140-833 FOI Summary (approval date September 17, 1990).

VI. HUMAN SAFETY

As discussed in the parent NADA 140-833 FOI Summary (approval date September 17, 1990) and in the supplement to NADA 128-409 FOI Summary (IVOMEC Injection for Cattle; approval date September 12, 1994).

VII. AGENCY CONCLUSIONS

The data submitted in support of this supplemental NADA comply with the requirements of section 512 of the Act and demonstrate that ivermectin and clorsulon injection, when used under the proposed conditions of use, is safe and effective for the control of infections of Dictyocaulus viviparus and Ostertagia ostertagi for 21 days after treatment, and Oesophagostomum radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora for 14 days after treatment.

For cattle the tolerance of residues are specified in 21 CFR 556.344 and 21 CFR 556.163. A tolerance for the marker residue (22, 23-dihydro-avermectin B1a) of ivermectin is 100 ppb in the liver (target tissue) and the tolerance for clorsulon (marker residue) in kidney (target tissue) is 1.0 ppm. The withdrawal time is 49 days following one subcutaneous injection of IVOMEC PLUS as specified in 21 CFR 522.1193.

The original approval of ivermectin and clorsulon injection was as an over-the-counter drug. Adequate directions for use have been written for the layman, and the conditions for use prescribed on the labeling are likely to be followed in practice. Therefore, the Center for Veterinary Medicine (CVM) has concluded that this product shall retain over-the-counter marketing status.

Under the Center's supplemental approval policy 21 CFR 514.106(b)(2)(v), this is a Category II change. The approval of this change did not require a reevaluation of the safety or effectiveness data in the parent application.

Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the supplemental application contains substantial evidence of the effectiveness of the drug involved, any studies of animal safety, or, in the case of food producing animals, human food safety studies (other than bioequivalence or residue studies) required for the approval of the application and conducted or sponsored by the applicant. The three years of marketing exclusivity applies only to the new claim for the control of Dictyocaulus viviparus and Ostertagia ostertagi for 21 days after treatment and Oesophagostomum radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora for 14 days after treatment for which the supplemental application was approved.

VIII. LABELING (Attached)

Facsimile base label and package outsert for the 1000 mL container, bottle label and package insert for the 50, 200, and 500 mL containers, and the box carton for the 50mL bottle.

Copies of applicable labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855


NADA 132-872 for Safe-Guard Paste

Approval Date: March 28, 1996

Freedom of Information Summary
NADA 132-872

I. GENERAL INFORMATION:

NADA 132-872
Sponsor:

Hoechst-Roussel Agri-Vet Co.
P. O. Box 2500
Route 202-206
Somerville, NJ 08876-1258

Generic Name: fenbendazole
Trade Name: Safe-Guard® Paste 10%; Panacur® Paste 10%
Marketing Status: Over the Counter (OTC)
Effect of Supplement: This supplement provides for the use of fenbendazole for the removal and control of gastrointestinal parasites and lungworm in dairy cattle of breeding age.

II. INDICATIONS FOR USE AND LABEL DOSE:

BEEF AND DAIRY CATTLE- INDICATIONS DOSAGE

For the removal and control of: 5 mg/kg

Lungworm: (Dictyocaulus viviparus)

Stomach Worm (adults):
Brown Stomach worm (Ostertagia ostertagi).

Stomach Worm (adults & 4th stage larvae):
Barberpole Worm (Haemonchus contortus/placei),
Small Stomach Worm (Trichostrongylus axei).

Intestinal Worms (adults & 4th stage larvae):
Hookworm (Bunostomum phlebotomum),
Threadneck Intestinal Worm (Nematodirus helvetianus),
Small Intestinal Worms (Cooperia oncophora, Cooperia punctata),
Bankrupt Worm (Trichostrongylus colubriformis),
Nodular Worm (Oesophagostomum radiatum).

III. EFFECTIVENESS:

Efficacy was established in the original approval under NADA 132-872 and its supplements (46 FR 32018, June 19, 1981; 47 FR 15327, April 9, 1982; 49 FR 8433, March 7, 1984; and 50 FR 26358, June 26, 1985). No new studies were conducted to establish effectiveness associated with the use of fenbendazole in dairy cattle of breeding age.

IV. TARGET ANIMAL SAFETY:

Animal safety was established in the original approval under NADA 132-872 and its supplements (46 FR 32018, June 19, 1981; 47 FR 15327, April 9, 1982; 49 FR 8433, March 7, 1984; and 50 FR 26358, June 26, 1985). No new studies were conducted to establish animal safety associated with the use of fenbendazole in dairy cattle of breeding age.

V. HUMAN FOOD SAFETY:

A. Toxicity Tests:

Toxicity and teratogenicity studies were presented in the original NADA 128-620 and were conducted in Hoechst Research Laboratories in Frankfurt, Germany and in the United States. Fenbendazole was determined to be safe to human health when food derived from treated animals is ingested (48 FR 42809, September 20, 1983).

B. Safe Concentrations and Tolerances

Safe concentrations for fenbendazole total residues in cattle tissues were established with the original NADA 128-620 and are listed below along with the tissue consumption factors that were used.

Tissue           Safe Concentration

muscle           5 ppm
liver            10 ppm (factor of 2)
kidney           l5 ppm (factor of 3)
fat              20 ppm (factor of 4)

The tolerance and marker residue for fenbendazole in cattle also were assigned with the original NADA 128-620. The tolerance in cattle liver (the target tissue) is 0.8 ppm parent fenbendazole (the marker residue) as measured by the regulatory assay.

Newly established with this supplement to NADA 132-872 are a safe concentration and a tolerance for residues of fenbendazole in milk. The safe concentration for fenbendazole total residues in milk is set at 1.67 ppm (1/3 of the 5 ppm safe concentration in muscle tissue). The 1.67 ppm value was determined using FDA's approach to assigning safe concentrations based on food factors (44 FR 17070, March 20, 1979).

As explained in Part C below, the marker residue for fenbendazole in milk is the sulfoxide of parent fenbendazole. The tolerance is assigned at 0.6 ppm, although the marker residue never reaches that level in the milk from cattle treated at the approved dosing rate of 5 mg/kg body weight. The tolerance value was calculated from the marker residue to total residue percentage when total fenbendazole residues are at a maximum in milk. That maximum occurs in the range of 24 to 36 hours following dosing, and at that time, the sulfoxide represents approximately 35% of the total residue present. Accordingly, the tolerance for the fenbendazole sulfoxide is set at 0.6 ppm (35% of the 1.67 ppm safe concentration).

C. Total Residue and Metabolism Studies

Tissue residue depletion and metabolism studies in cattle were presented in the original NADA 128-620. Based on data from those studies, an eight (8) day withdrawal time in edible tissues (muscle, liver, fat, kidney) was established (48 FR 42809, September 20, 1983). The total residue studies summarized below were submitted with this supplement to describe fenbendazole residues in milk.

Milk Total Residue Study.

A study designed to measure residues in milk from one untreated and five 14C fenbendazole-treated lactating dairy cattle was conducted to determine the total residue profile as a function of time, to identify metabolites of fenbendazole in milk, and to select a marker substance to monitor residues in milk of lactating dairy cattle.


Study No.                         U.S. Dairy Cow Milk Residue Study LAV #1506    
                                  SVM (LSU Account # 166-60-6166)
                                                  
Starting Date                     January 31, 1992
                               
End Date                          August 5, 1993
                                 
Study Director                    Dr. Steven A. Barker
                                  School of Veterinary Medicine       
                                  Louisiana State University     
                                  Baton Rouge, LA 70803 
                                                                 
Identification of Substance and   14C-fenbendazole 1.89 mCi/g in aqueous         
Dosage Form                       suspension
                                     
Species and Age                   Holstein, 33 months to 7 years
                 
Number of Animals/weight          Six lactating dairy cows; average 603 kg
       
Drug Level Tested                 5.0 mg/kg body weight
                          
Route of Administration           Oral, administered once                        


After an acclimatization period, a morning milk sample was taken from each cow prior to treatment. This sample served as a blank control for the study. Following this milking, five cows received fenbendazole suspension by stomach tube. This aqueous suspension of labeled (14C) fenbendazole and unlabeled fenbendazole contained approximately 2 mCi activity/g. The amount of fenbendazole administered to each cow by stomach tube was calculated to equal 5.0 mg/kg body weight. The stomach tube was flushed with suspension solution to assure complete delivery. A control cow received suspension solution which did not contain fenbendazole. Morning and afternoon milk samples were collected for six days following drug administration. After six days the residues were below the level of detection.

Total residues for each whole milk sample from each cow were determined by scintillation counting. Each sample was assayed in triplicate by dissolving 0.5 mL aliquots of blended sample in 12 mL of scintillation cocktail. Before counting, each sample was placed in the dark for one hour to reduce contributions from chemiluminescence. Selected whole milk samples were also centrifuged, and 0.5 mL aliquots of fat and water portions were counted to determine label distribution.

For metabolic profiling, milk samples were extracted by matrix solid phase dispersion (MSPD) techniques, and the absolute recovery of total label was determined by scintillation counting of the extracts. The distribution of the extracted label between remaining parent drug and metabolites was determined by HPLC analyses using UV diode array and in-line radiolabel detection. The identity of radiolabeled peaks was matched with known standards for the metabolites of fenbendazole based on retention time and UV-diode array spectra. Samples were also assayed quantitatively by HPLC using an internal (mebendazole) standard and correcting for recovery.

The results from the radiolabel assay for total residues in whole milk and the HPLC analyses of metabolites in whole milk averaged for the five cows as a function of time are presented in Table 1.



Table 1. Average Concentrations of Total Residues and Metabolites of
Fenbendazole in Whole Milk as a Function of Time Following Oral Administration
of 5.0 mg Fenbendazole/kg Body Weight to Five Lactating Dairy
Cows*.


Day, Milking    Total Residue   FBZ-SO (± SD)   FBZ-SO2 (±      FBZ/Total       
                (± SD) µg/mL    µg/mL n = 5     SD) µg/mL n =   Residue x 100   
                n = 5           (Sulfoxide)     5 (Sulfone)     Ratio %
                         
1, am (Time 0)  0.000 ± 0.000   0.000 ± 0.000   0.000 ± 0.000   0.000           
1, pm           0.060 ± 0.043   0.026 ± 0.025   0.000 ± 0.000   43.333          
2, am           0.482 ± 0.076   0.232 ± 0.045   0.018 ± 0.011   48.133          
2, pm           0.526 ± 0.111   0.186 ± 0.005   0.024 ± 0.013   35.361**         
3, am           0.408 ± 0.102   0.158 ± 0.026   0.062 ± 0.016   38.725          
3, pm           0.298 ± 0.086   0.088 ± 0.034   0.046 ± 0.033   29.530          
4, am           0.186 ± 0.080   0.030 ± 0.030   0.046 ± 0.024   16.129          
4, pm           0.108 ± 0.044   0.006 ± 0.013   0.014 ± 0.017   5.555           
5, am           0.054 ± 0.030   0.000 ± 0.000   0.010 ± 0.017   0.000           
5, pm           0.024 ± 0.015   0.000 ± 0.000   0.000 ± 0.000   0.000           
6, am           0.012 ± 0.008   0.000 ± 0.000   0.000 ± 0.000   0.000           
6, pm           0.000 ± 0.000   0.000 ± 0.000   0.000 ± 0.000   0.000           


*All residue levels were below the target of 0.83 ppm for the 1X tracer study
(one-half the 1.67 ppm established safe concentration).  No residues were
detected in milk from the placebo (control) cow.
**Ratio percent used to calculate tolerance level.


At all times following administration of fenbendazole to lactating dairy cattle, residues in milk of fenbendazole and its metabolites were below the established safe concentration, and the total residue was evenly distributed between the fat and aqueous fractions of the whole milk.

Metabolic profiling of the total residues indicated that the concentration of parent drug in milk was negligible. The sulfoxide and sulfone metabolites of fenbendazole were the compounds that contributed to milk residues. The sulfoxide metabolite of fenbendazole was established to be the marker residue as it was present at levels significantly higher than parent fenbendazole or its sulfone metabolite. No other metabolites of fenbendazole were found in milk.

Milk Tolerance Calculation.

In Table 1 above, the ratio percent value of fenbendazole sulfoxide, the marker residue, to total residues was 35.4% at 36 hours following fenbendazole administration. At this time total residues in milk were greatest. The tolerance was calculated by multiplying the ratio percent of fenbendazole sulfoxide to total residues by the safe concentration (1.67 ppm). The tolerance was established to be 0.6 ppm (600 ppb).

D. Calf Tissue Total Residue Study.

A study was conducted to measure residues in calves born to 14C fenbendazole-treated dairy cattle. Total residue profiles in calf liver, kidney, fat and muscle were measured to provide data demonstrating the extent to which fenbendazole and its metabolites are transferred to and retained by the tissues of calves born to fenbendazole-treated cows.


Study No.                         U.S. Dairy Calf Tissue Residue Study LAV       
                                  #1507 SVM (LSU Account # 166-60-6167)
                                            
Starting Date                     April 21, 1992
                                 
End Date                          August 5, 1993
                                 
Study Director                    Dr. Steven A. Barker
                                  School of Veterinary Medicine      
                                  Louisiana State University      
                                  Baton Rouge, LA 70803 
                                                                 
Identification of Substance and   14C-fenbendazole, 1.89, 1.95 and 2.09 mCi/g    
Dosage Form                       in aqueous suspension
                          
Species and Age                   Holstein, 3 years old or older
                 
Number of Animals/weight          Six pregnant dairy cows; average 616 kg 
       
Drug Level Tested                 5.0 mg/kg body weight
                          
Route of Administration           Oral, administered once to the cow             

Eight days prior to anticipated calving, six pregnant dairy cows were moved to an approved facility for acclimation and for study conduct. Three days after the start acclimation, each cow was administered fenbendazole by stomach tube at a dose calculated to equal 5.0 mg/kg body weight. The drug was administered as an aqueous suspension of labeled (14C) and unlabeled fenbendazole and contained approximately 2 mCi activity/g. One of the six cows was administered carrier only and was the control for the study. The calf from the control cow and calves from three cows receiving fenbendazole were delivered by cesarean surgery approximately 70 hours after dosing; the other two calves from treated cows were delivered by natural birth at 4 and 25 hours post-dosing. One calf died 5 hours after delivery, three treated calves and the control calf were sacrificed 24 hours after delivery, and one treated calf was sacrificed 48 hours after delivery. Surviving calves received colostrum from treated dams and milk replacer as needed for 24 to 48 hours after birth and prior to sacrifice.

Total residues for the described tissues were determined by oxidation of 0.5 g tissue samples in triplicate and scintillation counting (Table 1). Each sample was placed in the dark for one hour to reduce contributions from chemiluminescence.


Table 1. Concentrations of Total Residues of Fenbendazole and Metabolites in
Calf Tissues Following Administration of 5.0 mg Fenbendazole/kg Body Weight to
Five Pregnant Dairy Cows.

Tissue                            Total Residue (µg/g)                           

liver                             1.398 ± 0.998*                                 
kidney                            0.528 ± 0.383                                  
fat                               0.386 ± 0.400                                  
muscle                            0.306 ± 0.236                                  

*mean ± SD; n = 5

For metabolic profiling, liver tissue from one calf was extracted by matrix solid phase dispersion (MSPD) techniques, and the absolute recovery of total label was determined by scintillation counting of the extracts. The distribution of the extracted label between parent drug and metabolites was determined by HPLC analyses using UV diode array and in-line radiolabel detection. The identity of radiolabeled peaks was matched with known standards for the metabolites of fenbendazole based on retention time and UV-diode array spectra.

Results indicated that the label was distributed between the sulfone (34%) and sulfoxide (58%) metabolites of fenbendazole and parent fenbendazole (8%). No other radiolabeled metabolites were observed in the liver. Profiles of kidney, fat and muscle tissue from all calves using HPLC indicated the presence of the sulfoxide and sulfone metabolites. The parent drug, fenbendazole, was present in trace quantities. No other metabolites were indicated.

It was concluded from the residue data above, that in calves born to and consuming colostrum from fenbendazole-treated dams, residues of fenbendazole in liver, kidney, fat and muscle were below the established safe concentrations. Residue levels in liver, kidney, fat and muscle as a percent of the safe concentrations were 13.98%, 3.52%, 1.93% and 6.12%, respectively. Therefore, meat from calves born to fenbendazole-treated dams is safe even when fenbendazole is administered prior to parturition.

E. Milk Residue Tolerance Study.

A study with non-radiolabeled fenbendazole was conducted to determine the total quantity of fenbendazole and its metabolites in whole milk as a function of time and to expand the examination to include use of the actual market formulation. A further objective was to determine whether incurred fenbendazole residues or its metabolites demonstrate activity in three commonly used milk antibiotic screening tests, Charm II assay, Delvotest P, and Bacillus stearothermophilis disc assay. For this study fenbendazole paste 10% at a rate of 5 mg/kg body weight was administered to ten lactating dairy cows; an additional cow served as a control.


Study No.                         U.S. Dairy Cow Milk Residue Study LAV #1591    
                                  SVM (LSU Account # 166-60-6172)
                                                  
Starting Date                     November 3, 1992
                               
End Date                          July 16, 1993 
                                 
Study Director                    Dr. Steven A. Barker
                                  School of Veterinary Medicine      
                                  Louisiana State University      
                                  Baton Rouge, LA 70803
                                                                  
Identification of Substance and   Fenbendazole, Safe-Guard® Paste 10% (100       
Dosage Form                       mg/g)
                                          
Species and Age                   Holstein, > 20 kg milk per day
                 
Number of Cows/weight             Eleven lactating dairy cows; average 530 kgs
   
Drug Level Tested                 5.0 mg/kg body weight
                          
Route of Administration           Oral, administered once                        


Animals used in this study were selected from the Holstein herd maintained at the LSU Agricultural Experimental Station. All lactating dairy cows were at least thirty days postpartum and were producing a target minimum of 20 kg of milk per day. Animals were managed in the same manner as the remaining cow herd. The ration consisted of concentrate and corn silage, and the cows grazed Bermuda and rye grass. Cows were monitored for reproductive function, were bred by artificial insemination, and were treated for reproductive dysfunction according to standard herd practices.

Cows were weighed within twenty-four (24) hours of drug administration. The ten treated cows received Safe-Guard® Paste 10% in an amount to equal delivery of 5.0 mg fenbendazole/kg body weight. The control cow was untreated.

Cows were machine milked in the morning prior to treatment. Milk samples were collected at that milking and were used as blank controls for the study. Milk samples (100 mL) were then collected at the 4:00 AM and 4:00 PM milkings for seven days following fenbendazole treatment.

For metabolic profiling, milk samples were extracted by matrix solid phase dispersion (MSPD) technique. The amount of parent drug and metabolites was determined quantitatively by HPLC analyses using UV diode array detection. The identity of peaks was matched with known standards for the metabolites of fenbendazole based on retention time and UV-diode array spectra.

The administration of fenbendazole at a target dose of 5.0 mg/kg body weight as paste 10% to lactating dairy cows produced residues in whole milk identifiable as fenbendazole sulfoxide, fenbendazole sulfone and trace quantities of fenbendazole. Peak residue time in milk was twenty-four (24) hours after administration, and the peak fenbendazole sulfoxide marker level was 0.24 ± 0.03 µg/mL (Table 1). No residues of fenbendazole were detected in the control cow.


Table 1. Concentrations of Fenbendazole and Marker Metabolites of Fenbendazole
in Whole Milk as a Function of Time Following Oral Administration of Paste 10%
(100 mg/gm) at a Rate of 5.0 mg Fenbendazole/kg Body Weight to Ten Lactating
Dairy Cows.

Time after FBZ      Fenbendazole (±     FBZ-SO (± SD),      FBZ-SO2 (± SD),     
Administration      SD), µg/mL, n= 10   µg/mL, n= 10        µg/mL, n= 10        
                                        (Sulfoxide)**       (Sulfone)
                                                   
0                   nd*                 nd                  nd                  
12                  nd                  0.15 ± 0.06         0.01 ± 0.00         
24                  nd                  0.24 ± 0.03         0.08 ± 0.01         
36                  nd                  0.19 ± 0.03         0.11 ± 0.01         
48                  nd                  0.10 ± 0.02         0.11 ± 0.01         
60                  nd                  0.03 ± 0.01         0.08 ± 0.01         
72                  nd                  0.00 ± 0.00         0.03 ± 0.00         

*No residues detected.
**Marker residue


Antibiotic residue test screening was conducted on milk samples from three (3) treated cows chosen randomly. The samples were collected at 12 hour intervals for 72 hours post-dose . Tests performed included the Charm II assay, Delvotest P, and Bacillus stearothermophilis disc assay. Zero time samples were included in all antibiotic screening tests; Delvotest P and B. stearothermophilis disc assay also included milk collected from the control animal at 12 hour intervals for 72 hours post-dose. Examinations indicated that the incurred residues from cows receiving fenbendazole suspension 10% at a rate of 5.0 mg/kg body weight had no discernible or consistent effect on the assays in term of producing false positive or suspect sample results. No sample from any cow examined gave a "positive" response to the Delvotest P and Bacillus stearothermophilis disc assay. Assay results of ten antibiotic classes indicated that fenbendazole and its metabolites do not interfere or cross-react with any consistency in the Charm II assay.

It was concluded that the fenbendazole sulfoxide marker residue level was below the tolerance level, and therefore, total residues were below the established safe concentration for milk. A zero-day withdrawal period was approved for use of fenbendazole paste 10% in dairy cattle of breeding age. It was further concluded that use of fenbendazole does not interfere with the practice of antibiotic drug screening.

F. Milk Discard and Slaughter Time

A zero (0) milk discard time is established for fenbendazole in dairy cattle of breeding age. The milk residue depletion studies described in Parts C and E above demonstrate that the maximum levels of fenbendazole residues in milk are well below the 1.67 ppm safe concentration and 0.6 ppm tolerance when lactating dairy cows are treated at the approved dosing rate of 5 mg/kg body weight. Accordingly, no discard of milk is required following treatment with fenbendazole.

An eight (8) day withdrawal time in edible tissues (muscle, liver, fat and kidney) was established in the original NADA 128-620 (48 FR 42809, September 20, 1983) and applies to dairy cows treated with fenbendazole.

G. Regulatory Methods:

A regulatory milk assay method is not required because of the establishment of a zero (O) milk withdrawal period in lactating dairy cattle. However, an HPLC assay method is on file at FDA/CVM in Rockville, MD.

A regulatory tissue method was developed as part of the original fenbendazole approval. The method, entitled, "Determination Procedure for the Measurement of Fenbendazole in Bovine Liver Tissue", is on file at the FDA's Freedom of Information Office, 5600 Fishers Lane, Rockville, MD 20857.

VI. AGENCY CONCLUSIONS:

The data submitted in support of this supplement satisfy the requirement of Section 512 of the Federal Food, Drug, and Cosmetic Act (FFDCA). The toxicology data on fenbendazole that were submitted with the original NADA 128-620 have allowed the establishment of a safe concentration of 1.67 ppm for total residues of fenbendazole in milk. From the residue and metabolite data on fenbendazole in dairy cattle that was submitted with this supplement, a tolerance of 0.6 ppm is established as the tolerance for residues in milk of the fenbendazole sulfoxide metabolite (the marker residue). Because the maximum levels of residues found in milk of fenbendazole-treated cattle are well below the safe concentration and tolerance noted above, no discard of milk (zero milk withdrawal) is required. The slaughter withdrawal time of 8 days required for treated dairy cattle is the same as established for beef cattle under the original NADA 132-872.

Under the Center's supplemental approval policy [21 CFR 514.106(b)(2)(v and x)], the addition of dairy cattle to the claim is a Category II change. The approval of this change is not expected to have any adverse effect on the safety or effectiveness of this new animal drug. Accordingly, this approval did not require a reevaluation of the safety and effectiveness data in the parent application.

Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for food producing animals does not qualify for exclusivity because the supplemental application does not contain new clinical or field investigations (other than bioequivalence or residue studies) and new human food safety studies (other than bioequivalence or residue studies) essential to the approval and conducted or sponsored by the applicant.

VII. LABELING (Attached)

Supplement labels: #1. Safe-Guard® (fenbendazole) Paste 10% syringe label for cattle including dairy cattle of breeding age. 3.2 oz.

#2 Panacur® (fenbendazole) Paste 10% syringe label for cattle including dairy cattle of breeding age. 3.2 oz.

Copies of applicable labels may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.

Last Updated ( Sunday, 20 April 2014 )