The Supplemental New Animal Drug Application for milbemycin oxime tablets
contains adequate and well-controlled studies which demonstrate efficacy in
removing and controlling roundworm and whipworm infections in dogs.
A. Dose Establishment
Controlled studies were undertaken to confirm the effectiveness of milbemycin
oxime tablets against adult intestinal stages of roundworm (Toxocara canis
) and whipworm (Trichuris vulpis ). These additional claims are
added to the existing indications for heartworm prevention and hookworm control.
One confirmation study was completed for each parasite.
At necropsy, the entire gastrointestinal tract was removed from each dog.
The contents of the tract were removed, sieved, and parasites were recovered
and identified. The opened tracts were examined carefully for remaining parasites
which were recovered and identified. Additionally, the small intestine was
incubated in saline for recovery of embedded parasites which also were counted
and identified.
Percent efficacy was calculated using the formula:
Mean Number of Parasites Mean Number of Parasites
in Control Animals - in Treated Animals
----------------------------------------------------------- X 100% Efficacy
Mean Number of Parasites
in Control Animals
The studies are identified in Table 1 and the results are summarized in Table
2. These studies confirmed the effectiveness of milbemycin oxime tablets at
a minimum dose of 0.5 mg/kg body weight for the removal and control of adult
roundworm and whipworm parasites.
- (1) Pivotal Roundworm (T. canis ) Dose Confirmation Study
- Study No. MR-147-01-89
- Purpose: Dose confirmation
- Investigator: Dr. Dwight Bowman
Ithaca, New York
- Type of study: experimental infections
- Animals: 28 beagles entered into study (20 completed study),
2-4 months of age, one treatment group of 14 dogs (10 completed the
study). See Table 2.
- Dosage form: milbemycin oxime tablets
- Route of administration: oral
- Controls: 14 dogs administered placebo tablets composed of
excipients. Ten dogs completed the study (see Table 2)
- Doses tested: 0.5 mg/kg body weight minimum dose
- Frequency and interval of treatment: one treatment
- Study duration: Initial part of study (16 dogs), 44 day study
duration (37 days postinfection, 7 days post-treatment). Extended protocol
(11 dogs), 73 day study duration (66 days post-infection, 7 days post-treatment.
- Results: 99.5% efficacy
- (2) Non-Pivotal, Supportive Roundworm (Toxocara canis ) Dose
Confirmation Study
- Purpose: preliminary efficacy determination
- Investigator: Drs. D. Bowman and R. Grieve
Madison, Wisconsin
- Type of Study: experimental infection
- Animals: 15 ascarid-free beagles 10 weeks of age
- Dosage form: milbemycin oxime tablets
- Route of administration: oral
- Controls: group of 5 dogs administered placebo tablets composed
of excipients
- Doses tested: two groups of 5 dogs received 5.68 mg (0.27-0.39
mg/kg) and 34.08 mg (1.32 - 2.30 mg/kg), respectively
- Frequency and interval of treatment: one treatment
- Study duration: 75 days (70 days post-infection, 5 days post-treatment)
- Results: 100% efficacy in both milbemycin oxime treated groups
- (3) Pivotal Whipworm (T. vulpis ) Dose Confirmation Study
- Study No. MW-147-01-88
- Purpose: dose confirmation
- Investigator: Drs. B. Blagburn and C. Hendrix
Auburn, Alabama
- Type of study: natural infections
- Animals: 24 random source mature dogs of various breeds screened
for whipworm infection; one treatment group composed of 12 dogs.
- Dosage form: milbemycin oxime tablets
- Route of administration: oral
- Controls: group of 12 dogs administered placebo tablets
- Doses tested: 0.5 mg/kg body weight minimum dose
- Frequency and interval of treatment: one treatment
- Study duration: 7 days
- Results: 97.1% efficacy
B. Well-Controlled Clinical Field Trial
Study No. MT-147-00-89
A multi-location, well-controlled clinical field trial employing essentially
identical study protocols was conducted during 1989-90.
The overall objective was to evaluate the safety and efficacy of milbemycin
oxime for the removal and control of roundworms and whipworms when used under
typical veterinary practice conditions. The study employed six individual
veterinary hospitals or clinics in the following states: Alabama, California,
Florida, and Texas.
The specific trial objectives were achieved by comparing the relative effectiveness
of milbemycin oxime formulated tablets, administered monthly, to Filaribits
Plus chewable tablets (Norden Laboratories) administered daily.
Patients were selected for inclusion in the study from animals presented
to the hospital or clinic for routine immunizations, physical examinations,
heartworm examinations, etc. Dogs of various breeds, ages, weights and of
either sex, were entered into the study. Animals were evaluated for nematode
infections by standard fecal egg flotation procedures. When appropriate infections
(roundworm, whipworm) were discovered, animals were assigned to treatment
group A (milbemycin oxime) or treatment group X (Filaribits Plus, Norden Laboratories)
according to a computer-generated randomization table. Each investigator was
provided with his own unique randomization table. Fecal egg flotation counts
were scored on the case report form according to the following format:
(Eds. note: The following table consists of 2 columns.)
Eggs Found Score
0 epg 0
1-5 epg + 1
6-20 epg + 2
> 20 epg + 3
Dogs also received the clinic's standard physical examination. Supplies of milbemycin
oxime (treatment A) were supplied to the investigator by the sponsor in three
tablet sizes. Treatment was administered three times at thirty day intervals.
The practical dosing regimen was as follows:
(Eds. note: The following table consists of 2 columns.)
Body Weight Milbemycin oxime
0-10 lbs. 1 Brown tablet
11-25 lbs. 1 Green tablet
26-50 lbs. 1 Yellow tablet
51-100 lbs. 2 Yellow tablets
> 100 lbs. Appropriate tablet mix
The reference drug, Filaribits Plus® chewable tablets (Norden Laboratories),
was provided by each investigator and administered according to label directions.
Test subjects receiving either treatment A or treatment X were returned to the
clinic for follow-up examinations according to the following schedule:
- At 7-10 days following the initial treatment, a fecal sample was returned
for evaluation of adult worm removal by each treatment, TA and TX.
- Thirty days after initial treatment, each TA dog returned to the clinic
for fecal examination and the second TA treatment. TX dogs received daily
treatments, and also returned on day 30 for follow-up fecal examination.
- If the fecal examination at day 30 for a TA dog was positive, another
fecal examination was required on day 37-40. For TX dogs, this fecal was
not required.
- Sixty days after initial treatment, each TA dog returned to the clinic
for fecal examination and the final TA treatment. TX dogs received their
final fecal and physical examination on day 60.
- If the day 60 fecal examination was negative for TA dogs, they received
a final physical examination on day 60. If the day 60 fecal was positive,
the TA dog returned at day 67-70 for final fecal and physical examinations.
Results:
A total of 231 patients were enrolled in the field trial, 115 in treatment
group A (milbemycin oxime) and 116 in treatment group X (Filaribits Plus,
Norden Laboratories). Of the 231 patients initially enrolled, 220 (95.28%)
successfully completed the study regime. Approximately 77 (33.3%) of the study
patients were puppies (6 months or less) and 16 (6.92%) were 10 years old
or greater. The study population breakdown by weight was as follows:
0-10 lbs. - 23.5%
11-25 lbs. - 24.3%
26-50 lbs. - 18.3%
> 50 lbs. - 33.9%
Thirty-four different breeds of dogs were represented as well as a large selection
of mixed breeds. See Table 3.
The 220 patients successfully completing the study regime generated 329
cases of roundworm and whipworm infections. Many patients had dual infections.
Treatment group A (milbemycin oxime) results were as follows: 84 cases of
roundworm successfully cured, 98.8%, 7 days after the initial treatment, 100%
by study completion (60 days); 85 cases of whipworm successfully cured 96.5%,
7 days after the initial treatment, 100% by study completion (60 days). See
Table 4. INTERCEPTOR® was used safely in animals receiving frequently
used veterinary products such as vaccines, anthelmintics, antibiotics, steroids,
flea collars, shampoos, and dips.
Treatment group X (Filaribits Plus) results were as follows: 90 cases of
roundworm successfully cured 76.7% after 7 days of treatment, 95.6% by study
conclusion after 60 days of treatment, 70 cases of whipworm clinically controlled,
62.9% after 7 days of treatment, 82.9% by study conclusion, after 60 days
of treatment. See Table 4.
C. Non-Pivotal Field Trials Conducted in Canada
Three trials were conducted in Canada during 1988-89 which evaluated and
corroborated the efficacy of milbemycin oxime for the treatment of intestinal
nematodes in dogs. Dogs diagnosed with intestinal nematode infections were
treated with a single dose of milbemycin oxime at > 0.5 mg/kg body weight.
The identical four tablet formulations used in U.S. trials were administered
to dogs in these trials. All dogs were reexamined by fecal flotation 7-10
days following treatment.
- Trial 1
- Investigator/locations: Dr. Barbara Cameron
Ostrander Vet Clinic
Tillsonberg, Ontario
Dr. Tony Braithwaite
Kingsville Animal Clinic
Kingsville, Ontario
Dr. Irene Moore
Southridge Animal Clinic
Morpeth, Ontario
- Results: Twenty-four (24) dogs were treated with milbemycin
oxime, 9 dogs with roundworms, 11 dogs with hookworms and 4 dogs with
whipworm infections. All dogs, except one dog with roundworms had negative
fecal examinations 7-10 days after treatment.
- Trial 2
- Investigators/location: Drs. Alain Villeneuva and Susie Lemay
University of Montreal
Veterinary Teaching Hospital
St. Hyacinthe, Quebec
Drs. Micheline Marcotte and Danielle Jolly
Varennes, Quebec
Drs. Diane Fraud and N. Plourde
Rosemere, Quebec
- Results: Twenty (20) dogs with T. canis , 15 dogs with
A. caninum and 4 dogs with T. vulpis infections were treated
and reexamined during the trial. Fecal egg counts from these dogs were
reduced by more than 98% for all three parasites following treatment
with milbemycin oxime.
- Trial 3
- Principal Investigator: Dr. Owen Slocombe
University of Guelph
Guelph, Ontario
- Locations: University of Guelph
Guelph, Ontario
Braemar Collie Kennels
Moorefield, Ontario
Kelvingrove Kennels
Guelph, Ontario
Roymark Kennels
Brucedale, Ontario
Taybro Kennels
Orton, Ontario
Toronto-North York Hunt Club
Aurora, Ontario
Walter Klausnitzer Kennels
Kenilworth, Ontario
- Results: Fourteen (14) dogs with T. canis , 20 dogs
with A. caninum and 15 dogs with T. vulpis infections
were treated with milbemycin oxime and re-examined during the trials.
Fecal egg counts from these dogs were reduced by more than 96% for T.
canis , 98% for A. caninum and 99% for T. vulpis following
treatment with milbemycin oxime.
Conclusion - Effectiveness
Based upon data generated in laboratory studies and clinical field trials,
it can be concluded that milbemycin oxime tablets, at the labeled rate of
0.5 mg/kg, are safe and effective for the removal and control of adult roundworm
(T. canis ) and whipworm (T. vulpis ) parasites in dogs.
The data in support of this supplemental NADA complies with the requirements
of Section 512 of the Act and Section 514.111 of the implementing regulations.
It demonstrates that INTERCEPTOR® (milbemycin oxime) tablets when used
under the labeled conditions of use is safe and effective.
According to the Center's supplemental approval policy (42 FR 6436) this
is a Category II change. This supplement provides for the addition of claims
to include the removal and control of roundworms (Toxocara canis )
and whipworms (Trichuris vulpis ). The approval of the supplemental
application has no adverse effect on the safety and effectiveness of the new
animal drug. Accordingly, this approval did not require a reevaluation of
the safety and effectiveness data in the parent application.
For this supplement, the drug is restricted to use by or on the order of
a licensed veterinarian because professional expertise and proper diagnosis
are required to determine the existence of roundworm and/or whipworm infection.
In addition, professional expertise is required to determine the existence
of heartworm and/or hookworm infection, and to then properly treat existing
heartworm infection prior to starting treatment with INTERCEPTOR® (milbemycin
oxime) Tablets in a prevention program, and for the control of hookworm infection
(original approval).
Under Section 512(c)(2)(F)(iii) of the Generic Animal Drug and Patent Term
Restoration Act of 1988, this supplemental new animal drug application qualifies
for three years of marketing exclusivity because new clinical or field investigations
conducted by the sponsor were essential to the approval of this supplemental
NADA.
(Eds. note: The following table consists of 4 columns.)
Table 1: Identification of Investigators and Locations for Milbemycin Oxime
Dose Confirmation and Clinical Field Trial Studies
Trial Number Investigator Location/Address Type of Trial
MW-147-01-88 Drs. B. Blagburn Auburn Dose
and C. Hendrix University confirmation
Auburn, AL
MR-147-01-89 Dr. D. Bowman Cornell Dose
University, confirmation
Ithaca, New York
COL-MT-147-00-89 Dr. J. Colley Opelika Animal Field trial
Hospital
Opelika, AL
LEG-MT-147-00-89 Dr. W. Legg Lewisville North Field trial
Animal Clinic
Lewisville, TX
STO-MT-147-00-89 Dr. K. Stocks San Joaquin Field trial
Animal Clinic,
Fresno, CA
UTG-MT-147-00-89 Dr. H. Utgard Dade Animal Field trial
Hospital,
North Miami, FL
(Eds. note: The following table consists of 6 columns.)
Table 2: Summary of Milbemycin Oxime Dose Confirmation Studies
for Removal of Adult Roundworms and Whipworms in Dogs
Treatment No. of Dogs No. of Dogs Range of Total Percent
Treated With Worm Worms Efficacy
Worms Counts Found
Roundworm Removal-Pivotal
Control 10* 10 5-60 193
0.5 mg/kg 10* 1 0-1 1 99.5%
Roundworm Removal-Non-Pivotal
Control 5 5 2-19 52
0.27-0.39 mg/kg 5 0 0 0 100%
1.32-2.30 mg/kg 5 0 0 0 100%
Whipworm Removal-Pivotal
Control 12 12 3-278 860
0.5 mg/kg 12 3 0-13 25 97.1%
* number of dogs actually completing the study
(Eds. note: The following table consists of 2 columns.)
Table 3: Milbemycin Oxime Case Studies - MT-147-00-89
Number of Animals by Breed
Number of Animals Breed
1 Akita
1 Alaskan Malamute
6 Australian Cattle Dog
4 Beagle
5 Chihuahua
2 Chow Chow
9 Cocker Spaniel
2 Collie (smooth, rough)
3 Dachshund
1 Dalmatian
10 Doberman Pinscher
2 English Setter
2 English Springer Spaniel
18 German Shepherd Dog
7 Golden Retriever
4 Great Dane
1 Irish Setter
1 Keeshond
19 Labrador Retriever
3 Lhasa Apso
2 Mastiff
6 Miniature Schnauzer
2 Misc. Hounds
1 Misc. Non-Sporting Breeds
5 Misc. Toy Breeds
68 Mixed Breed
11 Pointer
1 Pomeranian
2 Poodle
2 Rhodesian Ridgeback
8 Rottweiler
4 Staffordshire Bull Terrier (Pit Bull)
1 Standard Schnauzer
3 Toy Poodle
3 Yorkshire Terrier
220 Total
(Eds. note: The following table consists of 5 columns.)
Table 4: Effects of Milbemycin Oxime on Removal and Control of Adult Roundworm
and Whipworm Infections in Dogs During Clinical Field Trials
Number of Dogs Roundworm Whipworm
Investigator/ Completing Infections/ Infections/
Location Treatment Study 1 Number Cured 2 Number Cured
Colley/ Milbemycin oxime 25 22/22 23/23
Alabama Filaribits Plus(TM) 24 23/20 22/103
Legg/ Milbemycin oxime 15 5/5 10/10
Texas Filaribits Plus(TM) 14 3/3 11/11
Stocks/ Milbemycin oxime 9 9/9 0/0
California Filaribits Plus(TM) 8 8/8 0/0
Utgard/ Milbemycin oxime 62 48/48 52/52
Florida Filaribits Plus(TM) 63 56/55 37/37
Totals Milbemycin oxime 111 84/84 = 100% 85/85 = 100%
Filaribits Plus(TM) 109 90/86 = 96% 70/58 = 83%
1 Number of dogs is fewer than total number of infections
because some dogs had multiple infections;
i.e.; 133 A treatment dogs, 193 A treatment parasite cases.
2 "Cured" means no eggs or proglottids found at final fecal examination.
3 Clinical control was achieved in all cases but low number of eggs
were found at final fecal examination for 12 dogs. This is a
hyperendemic whipworm area.
