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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 136-483 Filaribits® Plus Chewable Tablets - supplemental approval (January 18, 1989 )

Approval Date: January 18, 1989

I. GENERAL INFORMATION:

NADA 136-483
Sponsor: Norden Laboratories
Generic Name: diethylcarbamazine citrate and oxibendazole chewable tablets
Trade Name: Filaribits® Plus Chewable Tablets
Marketing Status: Prescription Drug - Accurate laboratory diagnosis for the presence of existing heartworm disease is required in the proper use of the product.
Effect of Supplement: Results in the addition of a label statement to provide for the removal and control of mature and immature stages of intestinal Toxocara canis (ascarid infection). Adequate data showing efficacy for the additional use has been submitted in the supplemental application which is the subject of this approval.

II. INDICATIONS FOR USE

FILARIBITS Plus are indicated for use in the prevention of infection with Dirofilaria immitis (heartworm disease), Ancylostoma caninum (hookworm infection), the removal and control of Trichuris vulpis (whipworm infection) and the removal and control of mature and immature stages of intestinal Toxocara canis (ascarid infection) in dogs. FILARIBITS Plus may be given to dogs of all ages, including bitches, throughout the reproductive period and following whelping.

III. DOSAGE FORM(S), ROUTE OF ADMINISTRATION AND RECOMMENDED DOSAGE

FILARIBITS Plus are chewable tablets that are palatable to most dogs. Tablets may be fed free-choice or placed on food. FILARIBITS Plus are scored for convenient adjustment of dosage.

For the Prevention of Heartworm Disease, Hookworm Infection and for the Removal and Control of Whipworms and Mature and Immature Stages of Intestinal Ascarids in Dogs

FILARIBITS Plus are given orally (once a day) at a dosage rate of 3 mg diethylcarbamazine citrate and 2.27 mg oxibendazole per pound of body weight. Young dogs may be started on the preventive program at two months of age. Administration of FILARIBITS Plus in heartworm or hookworm endemic areas should start prior to hookworm exposure and at least one month before the beginning of the mosquito season. FILARIBITS Plus administration should continue daily throughout the entire period of exposure to hookworms and two months past the mosquito season since there is little residual effect of the drugs. Continuous low level administration effectively prevents maturation of hookworms (A. caninum ) and recently inoculated heartworm larva (D. immitis ) into adults and provides for the removal and control of whipworms (T. vulpis ) and mature and immature stages of intestinal ascarids (T. canis ). If FILARIBITS Plus is discontinued because of seasonal heartworm problems, hookworm prevention or therapy and whipworm and ascarid removal and control should be continued.

IV. EFFECTIVENESS

A. LABORATORY STUDIES

The efficacy of FILARIBITS Plus in removing and controlling ascarids is reported in four critical laboratory efficacy studies involving a total of 42 dogs (Table I).

Critical laboratory studies were conducted by the following investigators:

M.L. Sharp, D.V.M.
Sharp Veterinary Research
P.O. Box 353
Vernon, TX 76384

John McCall, Ph.D.
TRS Labs, Inc.
295 Research Road
Athens, GA 30605

S.M. Kruckenberg, D.V.M., Ph.D.
Kruckenberg Drug Research
2851 Oregon
Manhattan, KS 66502

Critical laboratory studies were conducted using each animal as its own control. Efficacy of FILARIBITS Plus was determined using the formula:

No. Parasites Removed / No. Parasites Removed + No. Parasites Remaining x 100 = % Efficacy

Treated dogs showed 100% ascarid removal in all four studies, (Tables II, III, IV and V) after a 30 day treatment period.

B. CLINICAL (FIELD) STUDIES

In the clinical (field) trials, 68 dogs from eighteen veterinary practices in twelve states were studied. All dogs were infected with ascarids when entering the study. They received FILARIBITS Plus as the only deworming agent for an average of 73.5 days. Eleven ascarid infected dogs in a control group received a diethylcarbamazine citrate containing product (FILARIBITS) for an average of 71 days. Fecal examinations were conducted in all dogs before and at approximately 4 week intervals during the trials.

In pivotal studies seven (7) of the eighteen (18) investigators evaluated controls (FILARIBITS) as well as treated cases (FILARIBITS Plus). Using a Mantel-Haenszel test on data from the pivotal studies and evaluated at the first two fecal recheck examinations, the number of dogs cleared of ascarids is significantly greater (P<0.02) for the FILARIBITS Plus groups than the FILARIBITS groups. The results of the field trials are shown in Tables VI and VII.

In corroborative studies eleven (11) of the eighteen (18) investigators evaluated the efficacy of FILARIBITS Plus. The results of these studies are shown in Table VI.

V. ANIMAL SAFETY

No adverse reactions or unusual observations associated with FILARIBITS Plus were reported by investigators conducting the critical laboratory trials.

Untoward reactions in the clinical trials were minimal in number as well as severity. Investigators in the clinical trials reported one or more of the following side effects in a total of 4 dogs: vomiting, diarrhea, anorexia, tenesmus and depression plus elevated serum alkaline phosphatase and white blood cell count levels. Safety was rated excellent or good in all of the dogs by the investigators.

Labeling contains a boxed warning that addresses the occasional association with hepatic toxicity including several fatalities. It also provides advice for monitoring of animals receiving the drug and the clinical/biochemical criteria which should be considered.

For additional information on target animal safety studies, refer to the Freedom of Information Summary filed for the original approval.

This supplement falls under Category II Supplements in which the safety data is unchanged and re-evaluation was not required. Federal Register, Vol. 42, No. 247, P. 64367-64371.

VI. HUMAN SAFETY:

Data on human food safety, pertaining to consumption of drug residues in food, were not required for the approval of this NADA. The drug is labeled to be used in dogs, which are non-food animals.

Human Safety considerations other than food safety. No identified hazards or characteristics of the drug were observed in a wide range of toxicological studies. No specific precautions over and above those normally used when handling drug substances are indicated.

VII. AGENCY CONCLUSIONS:

The data in support of this supplemental new animal drug application comply with the requirements of Section 512 of the Act and demonstrate that Filaribits-Plus (diethylcarbamazine citrate and oxibendazole) when used as directed is both safe and effective for the removal and control of mature and immature stages of intestinal Toxocara canis (ascarid infection) in dogs.

According to the Center's supplemental approval policy (42 FR 64367), this is a Category II change. The approval of this supplemental application had no adverse effect on the safety and effectiveness of this new animal drug because it provides solely for a claim of a new parasite species. Accordingly, this approval did not require a reevaluation of the safety and effectiveness data in the parent application.

The product is categorized as Rx because veterinary intervention is needed to diagnose heartworm, hookworm, whipworm and ascarid positive animals. Animals having heartworms and hookworms would have to be converted to a parasite negative status by the veterinarian prior to being placed on prophylactic therapy.

The Clinical Field Trials were conducted by the following investigators:

Dr. Horace Blalock                 Dr. Mike Groh
Highland Animal Hospital           Blue Springs Animal Hospital
2124 Highland                      1201 W. 40 Hwy.
Augusta, GA 30904                  Blue Springs, MO  64015
Dr. W. A. Bryant                   Dr. Gary Heinzle
Pulaski Veterinary Clinic          610 South Jeffers
Rt. 6                              North Platte, NE 69101
Waynesville, MO 65583
                                   Dr. John C. Leite
Dr. G. W. Buckaloo                 Animal Clinic of Westerville
Crysler Animal Hospital            153 S. Sunbury Road
12440 East New 40 Hwy.             Westerville, OH 43081
Independance, MO 64055
                                   Dr. Jim Maxted
Dr. Don Buller                     2 East Anson
Bethalto Animal Clinic             Marshaltown, IA 50158
132 Bethalto Blvd.
Bethalto, IL 62010                 Dr. Robert Neunzig
                                   Forrest Brook Animal Clinic
Dr. Vincent Castellano             3200 Union Road
Cobleskill Veterinary Clinic       Gasionia, NC 28052
Cobleskill, NY 12043
                                   Dr. James Snodgrass
Dr. Charles Conrad                 Baxter County Animal Clinic
Fort Plain Animal Hospital         200 Bomber Blvd.
Fort Plain, NY 13339               Mountain Home, AR 72653
Dr. Dean Frey                      Dr. Wm. W. Somerville
Frey Animal Clinic                 Rt. 2, Box 336
1823 16th Ave. S.W.                Hwy 163 W
Cedar Rapids, IA 52404             Clinton, IN 47842
Dr. Wm. Gengler                    Dr. John H. Thomas
Animal Hospital of Verona          P.O. Box 1521
203 W. Verona Ave.                 Martinsville, IN 46151
Verona, WI 53593
                                   Dr. George Wadley
Dr. Brooks K. Glass                Wadley Animal Clinic
1916 Manchester Exp.               Rt. 4, Box 166
Columbus, GA 31904                 Searcy, AR 72143

(Eds. note: The following table consists of 5 columns.)

TABLE I Summary of Filaribits® Plus Efficacy in Removal of Ascarid Infections in Laboratory Studies

                                                      % Efficacy         
                                                    Dogs Cleared at      
                Type of        Study      --------Approximately 30 Days-------
Investigator     Study       --Number--   Toxocara canis    Toxascaris leonina
Sharp              Critical       85-030-0302       (9/9) 100%
Sharp              Critical       86-001-0102      (16/16) 100%
Kruckenberg        Critical       86-115-0102       (9/9) 100%             (2/2) 100%
McCall             Critical       86-116-0102       (8/8) 100%

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

TABLE II The Effectiveness of Filaribits® Plus in Removing Ascarids from Dogs (Sharp 85-030-0302)

                      Ascarids Passed/Ascarids Retained
Dog Number        T. canis (Mature)   T. canis (Immature)
     
   655                   6/0
   731                  16/0
   688                  10/0
   735                  23/0                     5/0
   714                  12/0                     2/0
   627                  12/0                     5/0
   700                  37/0
   617                                           2/0
   696                  13/0                     2/0
                       -----                    ----
  9 Dogs               129/0                    16/0

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

TABLE III The Effectiveness of Filaribits® Plus in Removing Ascarids from Dogs Weighing Less Than 20 Pounds (Sharp 86-001-0102)

                ------Ascarids Passed/Ascarids Retained-----
Dog Number      T. canis (Mature)      T. canis (Immature)
   729                    10/0                         10/0
   764                     7/0
   792                                                  7/0
   794                                                  8/0
   796                                                  7/0
   798                                                  6/0
   800                                                 11/0
   802                                                  8/0
   768                    10/0                         52/0
   770                     2/0                         21/0
   816                    15/0
   822                    23/0                         55/0
   824                    28/0                         85/0
   826                     9/0                          1/0
   828                     4/0
   830                    19/0
   ---                   -----                        -----
 16 Dogs                 127/0                        271/0

(Eds. note: The following table consists of 2 columns.)

TABLE IV The Effectiveness of Filaribits® Plus in Removing Ascarids from Dogs (Kruckenberg 86-115-0102)

                                 Mature Ascarids Passed/
Dog Number                      Mature Ascarids Retained
          
     1                                            5/0
     5                                           32/0
     6                                          237/0
     7                                            6/0
     8                                            9/0
    11                                            1/0
    12                                           19/0
    13                                           3/0
    15                                           23/0
    16                                           17/0
    17                                           16/0
  -------                                       -----
  11 Dogs                                       368/0

(Eds. note: The following table consists of 2 columns.)

TABLE V Effectiveness of Filaribits® Plus in Removing Ascarids from Dogs (McCall 86-116-0102)

                                 Mature Ascarids Passed/
Dog Number                      Mature Ascarids Retained
           
   173                                           28/0
   174                                           30/0
   175                                           22/0
   177                                           33/0
   178                                           10/0
   180                                            4/0
   225                                           20/0
   226                                           21/0
 ------                                         -----
 8 Dogs                                         168/0

(Eds. note: The following table consists of 9 columns.)

TABLE VI Effect Of Filaribits® Plus On The Removal And Control Of Ascarid Infections In Dogs

                                                            No. of Dogs
                                                 Average    Positive for    ----------% Ascarid Infection Cleared----------
Investigator/                   No.    Number    Days On    Ascarids                         (Fecal Check)
Location          Treatment    Dogs    Breeds     Test      Initially         Recheck 1        Recheck 2        Recheck 3
                                                                            Av. 30.1 days    Av. 65.7 days    Av. 87.2 days 
________________________________________________________________________________________________________________________________________________ 
Buller/IL                T1           2      1 + mixed      57            2                100% (2/2)          100% (1/1)          100% (1/1)     
Conrad/MY                T1           3      2 + mixed      71            3                100% (3/3)          100% (3/3)          100% (1/1)
Gengler/WI               T1           4      2              70            4                100% (4/4)          100% (4/4)    
Leite/OH                 T1           3      2 + Mixed      64            3                100% (3/3)          100% (3/3)          100% (1/1)
Maxted/IA                T1           6      4 + Mixed      72            6                100% (6/6)          100% (6/6)          100% (2/2)
Snodgrass/AR             T1          10      2 + Mixed      92           10                100% (10/10)        100% (10/10)        100% (10/10)
Sommerville/IN           T1           4      2 + Mixed      85            4                100% (3/3)*         100% (4/4)          100% (4/4)
 
7 Investigators      TOTALS AND      32     13 separate     73           32                100% (31/31)        100% (31/31)        100% (19/19)
7 States              WEIGHTED              breeds and      
                      AVERAGES              mixed breeds 
  
Blalock/GA               T2           7      2 + mixed      42            7                100% (7/7)          100% (2/2)      
Bryant/MO                T2           2      1 + mixed      90            2                100% (2/2)          100% (2/2)          100% (2/2)     
Buckaloo/MO              T2           9      2 + mixed      74            9                100% (9/9)          100% (9/9)          100% (1/1)
Castellano/NY            T2           1      1              80            1                100% (1/1)          100% (1/1)          100% (1/1)
Frey/IA                  T2           2      2              55            2                100% (2/2)          100% (1/1)          100% (1/1)
Glass/GA                 T2           3      3              59            3                100% (3/3)          100% (3/3)
Heinzle/NE               T2           2      2              82            2                100% (2/2)          100% (2/2)          100% (1/1)
Morrow/NM                T2           3      3              79            3                100% (3/3)          100% (3/3)
Meunzig/NC               T2           3      2 + Mixed      90            3                100% (3/3)          100% (3/3)          100% (3/3)
Thomas/IN                T2           1      1              92            1                100% (1/1)          100% (1/1)          100% (1/1)
Wadley/AR                T2           3      Mixed          77            3                 67% (2/3)          100% (3/3)          100% (2/2)
 
11 Investigators     TOTALS AND      36     14 separate     74.5         36                 97% (35/36)        100% (30/30)        100% (12/12)
9  States             WEIGHTED              breeds and
                      AVERAGES              mixed breeds

T1 = FILARIBITS Plus (Treatment also included evaluation of control (FILARIBITS) cases. (See Table VII.)

T2 = FILARIBITS Plus

*No Fecal Sample Available for Dog No.0521 This Fecal Check.

(Eds. note: The following table consists of 9 columns.)

TABLE VII Effect Of Filaribits® Plus On The Removal And Control Of Ascarid  Infections In Dogs

                                                            No. of Dogs
                                                 Average    Positive for    ----------% Ascarid Infection Cleared----------
Investigator/                   No.     No.      Days On    Ascarids                         (Fecal Check)
Location          Treatment    Dogs    Breeds     Test      Initially         Recheck 1        Recheck 2        Recheck 3   
                                                                            Av. 31.6 days    Av. 61.7 days    Av. 87.8 days 
________________________________________________________________________________________________________________________________________________ 
Buller/IL            FILARIBITS       1         1           78            1                 O% (0/1)            O% (0/1)            0% (0/1)
Conrad/NY            FILARIBITS       1        Mixed        48            1               100% (1/1)
Gengler/WI           FILARIBITS       2       1 + Mixed     55            2                 0% (0/2)           50% (1/2)
Leite/OH             FILARIBITS       1        Mixed        54            1               100% (1/1)          100% (1/1)
Maxted/IA            FILARIBITS       2         2           65            2               100% (2/2)           50% (1/2)
Snodgrass/AR         FILARIBITS       3       1 + Mixed     92            3               100% (3/3)          100% (3/3)          100% (3/3)
Somerville/IN        FILARIBITS       1        Mixed        85            1               100% (1/1)          100% (1/1)          100% (1/1)
  
7 Investigators      TOTALS AND      11      5 separate     71           11              72.7% (8/11)          70% (7/10)          80% (4/5)
7 States             WEIGHTED                breeds and                                                               
                     AVERAGES                mixed breeds

VIII. LABELING (Attached)

  1. Package insert Filaribits® Plus
  2. Filaribits® Plus 180 mg/136 mg Bottle labels: 50, 100, and 200 tablets
  3. Filaribits® Plus 60 mg/45 mg Bottle labels: 100 and 200 tablets

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.