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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 137-600 SAFE-GUARD(TM) - supplemental approval (August 30, 1989 )

Approval Date: August 30, 1989

I. GENERAL INFORMATION:

NADA 137-600
Sponsor: Hoechst-Roussel Agri-Vet Company
Route 202-206 North
Somerville, New Jersey 98876
Generic Name: fenbendazole
Trade Name: SAFE-GUARD(TM)
Marketing Status: This NADA provides for over-the-counter (OTC) distribution. The original approval for this NADA provided for the use of Type A Medicated Article in complete feeds for cattle for the removal and control of the listed parasites. The Type "C" medicated compl
Effect of Supplement: The original approval for this NADA provided for the use of Type A Medicated Article in complete feeds for cattle for the removal and control of the listed parasites. The Type "C" medicated complete feed was fed as a single dose of 5 mg fenbendazole per kilogram of body weight. This supplemental submission has been filed to provide for that same dosage of 5 mg/kg body weight to be fed free-choice in a vitamin/mineral supplement (Type C feed) administered over a three to six day period for the removal and control of the listed parasites

II. INDICATIONS FOR USE

Cattle dewormer for the removal and control of:

Lungworm: Dictyocaulus viviparus

Stomach worms:
Barberpole worm: Haemonchus contortus
Brown stomach worm: Ostertagia ostertagi
Small stomach worm: Trichostrongylus axei.

Intestinal worms:
Hookworm: Bunostomum phlebotomum)
Threadnecked intestinal worm: Nematodirus helvetianus
Small intestinal worms: Cooperia oncophora and C. punctata
Bankrupt worm: Trichostrongylus colubriformis
Nodular worm: Oesophagostomum radiatum.

III. DOSAGE

A. DOSAGE FORM 4% (18.1 grams per pound) and 20% (90.7 grams per pound) Type A Medicated Article for use in complete feeds and free choice vitamin/mineral mixes (Type C Feeds).
B. ROUTE OF ADMINISTRATION oral
C. RECOMMENDED DOSAGES:

Five (5) mg fenbendazole/kg body weight (2.27 mg/lb) administered orally with the complete feed as a single dose. The labels carry adequate directions for administration. Safe-Guard (TM) Type A Medicated Article will be manufactured using two concentrations (4% and 20%) of fenbendazole.

The treatment level for the free choice vitamin/mineral mixes (Type C Feed) is a dose of 5 mg fenbendazole/kg body weight given over a 3 to 6 day treatment period.

The container for the Safe-Guard (TM) 4% product is a 25 lb. paper bag. The container for the Safe-Guard (TM) (fenbendazole) 20% Premix will be a 25 cardboard box.

IV. EFFECTIVENESS

A. Type A Medicated Article (premix) blended into complete feed (Type C Feed)

This NADA relies on adequate well controlled studies showing the anthelmintic efficacy of fenbendazole in cattle included in the approved NADA 128-620 (Fenbendazole Suspension 10%, 48 FR 42809, September 20, 1983). One study was conducted in cattle to demonstrate that the premix (Type A Medicated Article) has comparable efficacy to the 10% suspension formulation when used at the same dose of 5 mg fenbendazole/kg body weight. Four parasites indicated on the label were tested. The suspension, premix and pellets are equally efficacious with respect to those parasites, as indicated by the two confirmatory studies which provide data to support and confirm the claim of efficacy.

Comparable efficacy was demonstrated in these pivotal studies:

Study #123-A, Comparison Study Fenbendazole Suspension 10% versus Premix, Top Dress Pellets made from Premix and Untreated Controls.

M. Blagburn, Auburn University, Auburn, Alabama

Forty-four cattle naturally infected with gastrointestinal nematodes were identified and assigned to four groups of eleven cattle each. One group remained unmedicated, one group was given a single dose of fenbendazole suspension at a dose level of 5 mg/kg and one group each premix or top dress pellets made from premix at the same dose. Sufficient numbers of parasites were recovered from the control animals at postmortem to evaluate and compare the effect of the three formulations on the following species based on biological and medical expertise:

(Eds. note: The following table consists of 4 columns.)

                        --------------% Reduction-------------------
                     Premix          Pellets          Suspension
H. contortus             100                100                   100
O. ostertagi             100                99.8                  99.8
C. punctata              99.9               99.9                  99.9
O. radiatum              100                100                   100

Study #4-N, Evaluation of Market Formulations (Premix, and Top Dress Pellets made from Premix) of Fenbendazole Against Cattle Helminths.

A. Todd, University of Wisconsin, Madison, WI

Thirty cattle experimentally infected with gastrointestinal nematodes and lungworms were assigned to three groups of ten cattle each. One group remained unmedicated, one group was given as a group treatment a single dose of fenbendazole premix at a dose level of 5 mg/kg body weight and one group fenbendazole top dress pellets at the same dose. Sufficient numbers of parasites were recovered from the control animals at postmortem to evaluate the effect of the two formulations on the following species based on biological and medical expertise:

                      -------% Reduction-------
                   Premix            Pellets
H. contortus           70.9                 100
O. ostertagi           99.3                 100
C. oncophora           99.3                 100
D. viviparus           99.0                 100
  
N. helvetianus         92.5                 70.9

Study #4-T, Evaluation of Market Formulations (Premix and Top Dress Pellets made from Premix) of Fenbendazole Against Cattle Helminths.

A. Todd,University of Wisconsin, Madison, WI

This study was designed to further evaluate the efficacy of fenbendazole premix and pellets on Haemonchus contortus and Nematodirus helvetianus which were not as much affected as usual in the previous study (#4-N).

Thirty cattle were experimentally infected with a mixed inoculum of infective cattle trichostrongylid larvae. The inoculum contained approximately 47% Haemonchus larvae. Each animal received also 1,000 Nematodiruslarvae. The cattle were assigned to 3 groups of 10 animals each. One group remained unmedicated, one group was given as a group treatment, a single dose of fenbendazole premix at a dose level of 5 mg/kg body weight and one group fenbendazole pellets at the same dose. Sufficient numbers of parasites were recovered from the control animals at postmortem to evaluate the effect of the two formulations on the following species based on biological and medical expertise:

                      -------% Reduction------- 
                   Premix            Pellets
H. contortus           100                  100
O. ostertagi           99.9                 99.1
C. oncophora           99.9                 99.2
N. helvetianus         100                  100

All studies proved that fenbendazole premix and pellets made from premix have an efficacy comparable to that of the 10% suspension. The results were analyzed statistically using a nonparametric procedure. The analysis confirmed the comparable efficacy.

Well documented clinical studies were conducted in the United States according to a uniform protocol which was only slightly modified to accomodate local management conditions. Groups of cattle with a worm infection, as determined by egg counts in their feces, were selected. Approximately the same number of animals were treated with 5 mg fenbendazole/kg body weight or left untreated as controls. Worm eggs in fecal samples were counted before and after treatment, the animals were visually observed for side effects.

Three investigators studied fenbendazole premix 20% and top dress pellets (0.5%) made from premix in 3 different states. They treated cattle of various breeds (242 with premix, 243 with pellets) and compared their observations to those in 242 untreated control animals, investigators, location and numbers of animals in the trials are tabulated on the following page.

(Eds. note: The following table consists of 7 columns.)

F.O.I. Summary Clinical Trials

                                     -------------Total Number of Animals--------------
                                                                        
                                                     +*                         +*  
            Investigator/                       Before/After               Before/After
Study #     Location                 Treated     Treatment     Controls     Treatment
1684-47-82    Bechtol          Premix        100            80/6            100             80/58
              Canyon, TX       Pellets       101            81/1
1684-14-81    O'Kelley         Premix         42            41/0             42             40/37
              Terre Haute, IN  Pellets        42            41/1
1684-37-81    Horton           Premix        100            79/10           100             81/95
              Wellington, CO   Pellets       100            90/1 
*) + = cattle with nematode eggs in their feces.

The clinical studies confirm the results of the critical studies by eliminating or reducing local egg counts in virtually all treated cattle.

The recommended treatment was found to be both safe and practical under field conditions.

B. Vitamin/Mineral mix (Type C Feed)

For this vitamin/mineral supplement approval, the critical efficacy study was conducted in the feed block medium to show the consumption and efficacy of a 3-10 day feeding of the total dose of 5 mg/kg body weight for fenbendazole.

  1. Dose Confirmation.

    This cold-press free-choice protein feedblock was approved as a supplemental filing to NADA 139-189 by letter dated May 9, 1989. The cold-pressed Medicated Feed block study was conducted by B. Blagburn, Auburn University, Auburn, Alabama (Submitted in NADA 139-189; Fenbendazole medicated feedblocks).

    Thirty calves with natural infections were divided into three groups of ten each. Group 1 served as an unmedicated control, group 2 had access to the medicated blocks for three days, and group 3 had access to the medicated blocks for ten days. Both medicated groups consumed approximately 5 mg/kg, with the following results:

    (Eds. note: The following table consists of 3 columns.)

                          -----------Eggs Per Gram (EPG)-----------
                       
                       Average (Range)           Average (Range)
    Group              Pretreat - EPG            Posttreat - EPG
    1  Control                  1,207                          1,620
                           (100 to 3,900)                  (0 to 6,600)
    2  Medicated-3 days         1,880                            0
                           (400 to 6,200)
    3  Medicated-10 days        1,240                            0
                           (300 to 2,800)
    % Reduction of Worms Reported at Necropsy
                      Medicated   Medicated
    Parasite           3 days      10 days
    H. contortus           100%          100%
    O. ostertagi            99           100
    C. punctata            100           100
    C. oncophora           100           100
    Trich. axei            100           100
    Oesoph. radiatum       100           100
    B. phlebotomum         100           100
    
  2. Clinical Trials:

    For this vitamin/mineral 20% protein supplement, the clinical trials were conducted by adding the fenbendazole premix (Type A Article) to vitamin/mineral Free Choice feeds (Type C feeds) to confirm and verify dosage consumption and efficacy under field-use conditions. These studies were conducted as follows:

    Two hundred sixty-eight (268) cattle were used in these three studies. The three treatments were control, 3-day fenbendazole treatment and 6-day fenbendazole treatment. These three clinical trials were conducted using fenbendazole at 5 mg/kg administered to cattle in medicated vitamin/mineral mixes. The reduction in numbers of eggs per gram (EPG) of local material before and after treatment were evaluated from these trials. The data from the trials were combined and gave the following averages:

    (Eds. note: The following table consists of 3 columns.)

    Group EPG % Reduction Control 126 0 3-day treat 24 81% 6-day treat 13 89% These clinical trials were conducted by:

    Dr. D. Bliss
    MidAmerica Agricultural Research Inc.
    3705 Sequoia Trail
    Verona, WI 53593

    Dr. Jorgen Hanson
    Virginia Tech
    Blacksburg, VA 24061

    Dr. Gary Rohwer
    Bar Diamond Ranch
    Parma, ID 83650

    Conclusion/Recommendation

    The results from these three clinical trials (eggs per gram of fecal matter) using medicated vitamin/mineral mixes were approximately 85% reduction, and the necropsy results (worm counts) from the medicated block confirmation trial were approximately 99% reduction. These data are acceptable and support the claim that the medicated vitamin/mineral mixes are efficacious when consumed at the recommended levels.

    The results from the clinical trials with medicated vitamin/mineral mixes for cattle and the trial with the medicated feed block, all providing fenbendazole for free choice consumption at 5 mg/kg body weight for periods of three to six days are acceptable to support the same efficacy claims as approved for the Type A Medicated Article (NADA 137-600) and the medicated feed block (NADA 139-189).

V. ANIMAL SAFETY

This NADA relies on safety studies included in the approved NADA 128-620 (Fenbendazole Suspension 10%, 48 FR 42809, September 20, 1983), that indicated the maximum tolerance dose is greater than 2000 mg fenbendazole/kg body weight.

No visible adverse reactions were observed in any of the laboratory efficacy or clinical field trials conducted with fenbendazole premix and pellets in cattle.

VI. HUMAN SAFETY:

  1. Safe Concentration of Residues
    The safe concentration for total fenbendazole residues in the uncooked edible tissues of cattle were established, based upon toxicology studies submitted under NADA 128-620 as 5 ppm in muscle, 10 ppm in liver, 15 ppm in kidney and 20 ppm in fat.
  2. Metabolism Studies
    Under NADA 128-620 metabolism studies in cattle were conducted to select a marker substance and target tissue for fenbendazole. Cattle liver is the target tissue with parent fenbendazole being the marker substance. The tolerance (Rm) is 0.8 ppm parent fenbendazole for cattle receiving a single oral dose of 10 mg fenbendazole/kg BW, i.e. when total fenbendazole residues are 10 ppm in liver, there is 0.8 ppm parent fenbendazole as determined by the regulatory method. Acceptable comparative metabolism studies were described under NADA 128-620.
  3. Regulatory Method
    Under NADA 128-620, the method was developed for the determination of parent fenbendazole at the tolerance of 0.8 ppm concentration and above in cattle liver.
  4. Withdrawal Time
    This supplemental NADA provides for no change in the oral dose of 5 mg fenbendazole/kg BW. The supplemental NADA provides for a change in a 3-day medicated feed program to a 3 to 6-day medicated feed program. The levels of drug and metabolites in tissues at zero-hour withdrawal time are inversely related to the duration of time for administration of the 5 mg/kg BW. The smaller daily dosage is continuously metabolized, excreted, and eliminated by the target animal species. We have assigned the longest withdrawal time for fenbendazole, 13 days after the last day of the 3 to 6-day medicated feed program.
  5. Safety to Handler
    Under NADA 128-620, studies were conducted which demonstrated that the drug would have no ill effects on persons handling it if the drug is used according to label recommendations.

VII. AGENCY CONCLUSIONS

The data submitted in this supplemental NADA satisfy the requirements of section 512 of the Act and demonstrate that 4% and 20% fenbendazole premix (Type A Medicated Article) for cattle when used under its proposed conditions of use, is safe and effective for its labeled conditions. The premix will be used to manufacture vitamin/mineral supplements (Type C feed) to be fed free choice to cattle in a 3 to 6 day feeding for removal and control of parasites.

The data submitted consisted of a Dose Confirmation trial using the feed blocks medium which demonstrated that a 3-day or a 10-day feeding of a total dose of 5 mg/kg body weight of fenbendazole is effective in reduction of worms reported at necropsy of approximately 100%.

Clinical trials were conducted using various medicated free choice vitamin/mineral mixes in 3-day and 6-day treatment. Fenbendazole was administered in the feeds at a total dose of 5 mg/kg body weight with a resultant reduction in EPG (eggs per gram) of fecal material of approximately 85%. This is adequate to demonstrate the safety and effectiveness of the treatments for cattle.

This was a Category II supplemental application that required no reevaluation of human food safety data. The change in duration with no increase in the dose of 5 mg fenbendazole/kg BW decreases the concentration at zero hour withdrawal time without a change in the qualitative composition of the residues being unlikely. Additional residue depletion data were not required for approval of this supplemental NADA as it poses no increased human risk from exposure to residues of fenbendazole. This Type C free choice vitamin-mineral mix will be labeled with a 13 day withdrawal time, the longest withdrawal time for a fenbendazole medicated feed use. Currently, fenbendazole premix, feedblocks, paste and suspension are marketed for use in cattle.

Fenbendazole has previously been approved over the counter for control of the same parasites at the same dosage level. The agency is not aware of any information suggesting that the over the counter status of the drug should be changed. The changes made in this supplemental application (different duration of dosing and administration through a vitamin/mineral mix) are of the kind that can be followed by the lay person.

VIII. LABELING (Attached)

  1. 50 lb. Bag label, 10,000 g/ton Fenbendazole
  2. 50 lb. Bag label, 3,800 g/ton Fenbendazole

Copies of these 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.