NADA 136-483

Approval Date: January 18, 1989

Freedom of Information Summary
NADA 136-483

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 +       x  100  =  % Efficacy
No. Parasites Remaining  
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.

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.