I. GENERAL INFORMATION:
| NADA |
140-971 |
| Sponsor: |
Merck Research Laboratories
Division of Merck & Co., Inc.
P. O. Box 2000
Rahway, New Jersey 07065-0914 |
| Generic Name: |
Ivermectin
Pyrantel (as pamoate salt) |
| Trade Name: |
HEARTGARD-30® Plus |
| Marketing Status: |
Rx |
II. INDICATIONS FOR USE
For use in dogs:
Ivermectin (to prevent canine heartworm disease by eliminating the tissue
larval stages of Dirofilaria immitis for a month (30 days) after infection),
Pyrantel pamoate (for the treatment and control of adult Toxocara canis,
Toxascaris leonina, Ancylostoma caninum and Uncinaria stenocephala
.)
III. DOSAGE
| A. |
DOSAGE FORM |
Ivermectin and pyrantel (as pamoate salt) are formulated
in a meat-based chewable tablet. Three dosage strengths are available
for dogs of different weight classes. |
| B. |
ROUTE OF ADMINISTRATION |
HEARTGARD-30® Plus is administered orally at monthly
intervals during the mosquito (vector for D. immitis ) season.
|
| C. |
RECOMMENDED DOSAGES: |
HEARTGARD-30® Plus chewable tablets are administered
once monthly and provide a minimum of 6 mcg ivermectin per kg of body
weight (2.72 mcg/lb) and a minimum of 5 mg pyrantel per kg of body weight
(2.27 mg/lb) when given as follows: |
| |
|
|
(Eds. note: The following table consists of 3 columns.)
Ivermectin Pyrantel Dog Weight
68 mcg 57 mg 2.27 to 11 kg (5 to 25 lb)
136 mcg 114 mg 12 to 22 kg (26 to 50 lb)
272 mcg 227 mg 23 to 45 kg (51 to 100 lb)
Dogs heavier than 45 kg (100 lb) are administered the appropriate combination
of these chewable tablets.
IV. EFFECTIVENESS
Adequate data support the efficacy of ivermectin at a dose rate of 6 mcg/kg
body weight in preventing the development of heartworm larvae in dogs. The
New Animal Drug Application for HEARTGARD-30® Plus contains data demonstrating
that it is equivalent to HEARTGARD-30® Chewables with respect to ivermectin.
The Freedom of Information Summary for the HEARTGARD-30® Chewables (Merck's
NADA 140-886) application can be referenced to support the dose of ivermectin
against the developing stages of heartworm.
Data from three pivotal dose determination and three pivotal dose confirmation
trials, submitted to this combination NADA, demonstrate that the two new sources
of pyrantel used in the formulation (Farmos Group, Ltd and Cosmos S.p.A.),
at a dose rate of 5 mg/kg, are effective for the labeled indications for use.
Two pivotal dose confirmation studies with HEARTGARD-30® Plus were conducted
against D. immitis. The percent control in both studies was 100% indicating
that the pyrantel does not interfere with the efficacy of the ivermectin in
the combination. In the three pivotal dose confirmation studies against the
intestinal parasites, the efficacy of HEARTGARD-30® Plus was not statistically
different than that of pyrantel, indicating that the ivermectin does not interfere
with the efficacy of the pyrantel in the combination.
A. Bioequivalence Study
A bioequivalence trial (Table 1, Trial #12664) was conducted to show that
HEARTGARD- 30® Chewables (Merck's NADA 140-886) are bioequivalent to HEARTGARD-30®
Plus, with respect to ivermectin. The study used a two-period crossover design.
Eighteen non- pregnant female dogs received each of two treatments: HEARTGARD-30®
Chewables containing tritiated ivermectin to provide a dose rate of 6 mcg/kg
body weight, or HEARTGARD-30® Plus to provide the same dose of tritiated
ivermectin and pyrantel at 5 mg/kg body weight.
Blood was collected at various intervals after treatment on Day 0 (Period
I) and Day 28 (Period II). Plasma was assayed for radioactivity, and results
were calculated based on ng- equivalents of ivermectin per mL of plasma.
Statistical analysis of area under the curve (AUC), peak ivermectin concentration
(Cmax) and time to peak ivermectin concentration (Tmax) used an analysis of
variance for a 2- period crossover design. Plasma ivermectin concentration
data were analyzed using a repeated measures analysis of variance.
Confidence intervals (90%) were constructed for the true mean values for
HEARTGARD-30® Plus.
HEARTGARD-30® Plus was equivalent to the HEARTGARD-30® Chewable
formulation with respect to the bioavailability of ivermectin. The AUC and
Cmax were not statistically significantly different for the two formulations
(p>.20). Confidence intervals confirmed that the AUC and Cmax for HEARTGARD-30®
Plus fell within 10% and 15%, respectively, of the HEARTGARD-30® Chewable
formulation. The Tmax was longer by about 2.5 hours for HEARTGARD-30®
Plus, but since the formulation is intended for monthly use, this difference
is of no clinical significance.
B. Dose Selection
1. Pivotal Dose Determination Studies
Three well controlled dose determination trials (Table 1, Trial #'s 12665,
12489, and 12444) were conducted against induced and/or natural infections
of ascarids and/or hookworms using pyrantel formulated in the vehicle for
HEARTGARD-30® Plus. Trial #12665 was conducted against induced infections
of Ancylostoma caninum, Uncinaria stenocephala, Toxocara canis , and
Toxascaris leonina ; Trial #12489 against natural infections of T.
canis , and Trial #12444 against natural infections of T. canis
and induced infections of A. caninum . Four dogs within each replicate
were randomly allocated to one of four treatments and dosed orally with vehicle
only or with pyrantel at a dose rate of 2.5, 5 or 10 mg/kg body weight. Treatments
were tailored to the weight of the individual animal. Dogs were individually
penned following treatment. At necropsy 7 days after treatment, nematodes
were recovered from the intestinal tract, counted, and identified according
to species and stage of development. The total fecal output from each dog
was collected daily on approximately Days -1 to 7, and nematode eggs and worms
recovered were counted at specific time points.
Geometric mean parasite counts at necropsy were calculated for each group
for each parasite using log (count +1). In combining data on a single parasite
from 2 or more trials, overall treatment group geometric means were calculated
as the geometric mean of the trial geometric means, weighting trials equally.
The transformed adult T. canis counts were analyzed using an analysis
of variance and contrasts to explore dose-response models.
The following table shows the percent efficacy against adult T. canis,
T. leonina, A. caninum and U. stenocephala from the three trials:
(Eds. note: The following table consists of 4 columns.)
2.5 mg/kg 5.0 mg/kg 10 mg/kg
T. canis 70.0 94.2 90.7
T. leonina 85.6 92.0 97.6
A. caninum 88.6 93.8 93.3
U. stenocephala 100 93.5 98.7
For all parasites, counts in the control group were statistically significantly
higher than those in the pyrantel groups (p<.01). In most of the studies,
there were no statistically significant differences between pyrantel treated
groups. However, for T. canis, T. leonina , and A. caninum ,
the 2.5 mg/kg dose groups had less than the required 90% efficacy. Based on
the results of these studies, a dose of 5.0 mg/kg was selected as effective.
Table 2 shows the percent efficacy of the selected pyrantel dose (5 mg/kg)
in the individual trials.
2. Pivotal Dose Confirmation Trials
Two well controlled studies (Table 1, #'s 12589 and 12590) were conducted
to demonstrate the efficacy of HEARTGARD-30® Plus against the developing
stages of heartworms, and three separate studies (Table 1, #'s 12591, 12592
and 13095) confirmed the efficacy against hookworms and/or ascarids. All trials
used the proposed market formulation of HEARTGARD-30® Plus or single component
chewable tablets based on the HEARTGARD-30® Plus vehicle.
a. Heartworm
Two studies (Table 1, #'s 12589 and 12590) were conducted using induced
infections of Dirofilaria immitis . Each study used 32 heartworm-free
Beagles (16 of each sex). These studies evaluated the components of the combination
as well as the combination product. Eight replicates of 4 dogs each were formed,
based on sex and weight. Within replicates of 4 dogs each were formed, based
on sex and weight. Within replicates, dogs were randomly allocated to one
of four treatments: (1) vehicle, (2) ivermectin, (3) pyrantel, or (4) HEARTGARD-30®
Plus. Ivermectin and pyrantel were administered at 6 mcg/kg and 5 mg/kg body
weight, respectively. All treatments were incorporated into the vehicle of
the proposed commercial formulation, tailored to the weight of each animal
and given once orally.
Dogs were infected with D. immitis larvae and treated 30 days later.
Approximately 5 to 6 months after challenge with heartworm larvae, dogs were
euthanized and examined for the presence of heartworms. HEARTGARD-30®
Plus was shown to be 100% effective against 30-day-old larvae of D. immitis
. All animals in the control and pyrantel groups were infected.
b. Intestinal Parasites
Three well controlled trials (Table 1, #'s 12591, 12592, and 13095) were
conducted using induced parasitic infections of Ancylostoma caninum, Uncinaria
stenocephala, and Toxascaris leonina and natural infections of Toxocara canis
and Ancylostoma caninum. Ivermectin and pyrantel were given at 6 mcg and 5
mg/kg body weight, respectively. Trial #12591 included 36 dogs with natural
T. canis and A. caninum infections. Trial #12592 included 32
dogs with induced infections of T. leonina, A. caninum , and U.
stenocephala . In these efficacy studies, dogs within each of 8 replicates
were randomly allocated to receive (1) vehicle, (2) ivermectin, (3) pyrantel
or (4) HEARTGARD-30® Plus in the proposed market formulation. The remaining
dose confirmation study (# 13095) was conducted with 16 dogs to demonstrate
the efficacy of HEARTGARD-30® Plus against induced infections of the two
hookworm species. Dogs within 8 replicates were randomly allocated to receive
(1) vehicle or (2) HEARTGARD-30® Plus.
In all trials, dogs were treated orally once on Day 0 and necropsied on
Day 7 at which time worms in the intestinal tract were collected, counted
and identified according to species and stage of development. Geometric mean
counts at necropsy were calculated for each group for each parasite, using
log (count +1). Overall treatment group means weighted trials equally.
Efficacy of pyrantel at 5 mg/kg against adult T. canis, T. leonina, A.
caninum , and U. stenocephala is presented in Table 2. In each
case, the mean worm count for HEARTGARD-30® Plus was significantly lower
(p<.01) than the control mean. In the component efficacy studies, the efficacy
of HEARTGARD-30® Plus was generally significantly higher (p<.02) than
the ivermectin-treated group, but not significantly different from the pyrantel-treated
group within individual studies (p>.20).
In study #12591, one dog in group 3 and one dog in group 4 died from parvovirus
during the terminal part of the study (days 5 to 7). The reduction in efficacy
against T. canis seen in this study (<90%) was possibly due to a
change in intestinal transit time associated with the infection.
3. Corroborative Dose Confirmation Trials
a. Heartworm
One controlled study (Table 1, #12767) was conducted using an induced infection
of Dirofilaria immitis in 32 heartworm-free Beagles (16 of each sex). The
dogs were formed into 8 replicates of 4 dogs each by weight and sex. Within
replicates, dogs were randomly allocated to one of four treatments- (1) vehicle,
(2) HEARTGARD-30® Plus, (3) pyrantel, or (4) HEARTGARD-30® Plus and
pyrantel (due to improper labeling instructions, dogs in the second treatment
group received a combination chewable tablet instead of an ivermectin chewable
tablet alone and dogs in the fourth treatment group received a combination
chewable tablet and a pyrantel chewable tablet instead of the combination
chewable tablet alone). All treatments were given orally 30 days after infection
with D. immitis . Five months after challenge with heartworm larvae,
dogs were euthanized and examined for the presence of heartworms. HEARTGARD-30®
Plus was shown to be 100% effective against 30-day old larvae of D. immitis
. All animals in the control and pyrantel groups were infected.
b. Intestinal Parasites
One controlled study (Table 1, #12765) was conducted in 36 dogs using natural
infections of Toxocara canis and Ancylostoma caninum while a
second study (Table 1, #12766) was conducted in 32 dogs using induced infections
of Toxascaris leonina, Uncinaria stenocephala and Ancylostoma caninum
. The dogs in both studies were dosed as in the corroborative heartworm
study due to the same labeling error. The percent control of HEARTGARD-30®
Plus was 91.6% against T. canis , 97.6% against T. leonina ,
and 100% against U. stenocephala . The A. caninum infections
did not take in either study. Two dogs in group 2 died from parvovirus infection
2 to 4 days following treatment.
C. Clinical Field Trials
Eight clinical field trials (see Table 1) were conducted with 8 investigators
in 6 geographic locations using client-owned dogs to establish the safety,
efficacy and acceptability of HEARTGARD-30® Plus under field use conditions.
Dogs were maintained in their normal environments and were subject to concomitant
therapy generally administered to dogs under veterinary care. Prior to being
placed on trial, dogs > 6 months old were shown to be heartworm-free by
means of a microfilariae test (Knott or Difil®, EVSCO). Fecal examinations
for intestinal tract nematodes were conducted prior to treatment and at various
intervals during the trials.
For each 3 dogs that received HEARTGARD-30® Plus, 1 dog (control group)
received HEARTGARD-30® swallow tablets and pyrantel pamoate (NEMEX®/Pfizer,
U.S. or PYR-A-PAM 2/Rotar FIB, London). All medications were given monthly
for 5 to 7 months. HEARTGARD-30® Plus was dosed to provide ivermectin
at a minimum of 6 mcg/kg body weight and pyrantel at a minimum of 5 mg/kg
body weight. In the positive control group, pyrantel and ivermectin were dosed
according to the manufacturers' recommendations.
Owners recorded acceptability of the combination chewable tablet and any
concurrent therapy, reactions or observations during the trial. No owner had
more than 4 dogs on trial. Clinical trial reports were compiled from owner's
and investigator's recorded observations.
A summary of the eight field trials conducted is shown in Table 3. In all,
323 animals were treated with HEARTGARD-30® Plus, and 107 were included
in the control group. The trials included 280 female and 150 male dogs aged
6 months to 14 years and weighing from 1.6 to 68 kg. These animals represented
122 breeds, varieties or types, including Collies or Collie crosses.
Although approximately 85-90% of the dogs in the field trials received all
scheduled monthly doses, fifty-five dogs did not complete the trials because
of lack of owner compliance (#30), death/illness due to unrelated causes (#14),
or loss of dog or contact with owner (#11).
HEARTGARD-30® Plus was shown to be effective for the treatment and control
of hookworms and ascarids under field use conditions. No hookworm eggs were
detected in 94.7% of dogs and no ascarid eggs were detected in 99.0% of dogs.
HEARTGARD-30® Plus also was shown to be completely effective in preventing
the development of D. immitis . HEARTGARD-30® Plus was consumed
with an overall acceptability of 97%. Four dogs accepted the chewable tablet
after it was broken or crumbled, 2 needed more than 1 attempt before they
would accept it, 2 accepted the chewable tablet with some hesitation, and
2 were force-fed.
A number of vaccines, antibiotics, flea control preparations (dips, collars,
mists, shampoos, etc.), steroids, vitamins, cestocides, antiinflammatories,
anesthetics, tranquilizers, ophthalmic medications and hormone preparations
were administered during the course of the studies. No adverse reactions occurred
with the concomitant use of these products, demonstrating the safety of HEARTGARD-30®
Plus when used under field conditions concurrent with commonly used veterinary
products.
A number of clinical observations were recorded for both treatment groups
during the trial. The incidence of vomiting and diarrhea, the most commonly
observed clinical conditions, was low (1.1% of administered doses).
D. Controlled Clinical Acceptability
The acceptability of 18 to 24-month-old HEARTGARD-30® Plus chewable
tablets was compared to that of < 3-month-old chewable tablets (Table 1,
#13713). Each of 60 dogs received one of each age chewable tablet with an
interval of 14 days. Acceptability was evaluated by the owners as 1: Dog accepted
the chewable tablet or 2: Rejected. The average acceptability score for both
groups (new and older HEARTGARD-30® Plus chewable tablets) was 1.0. The
acceptability of the 18 to 24-month-old and the < 3-month- old chewable
tablets was equivalent.
E. Conclusions from Drug Effectiveness Studies
The results of these efficacy trials demonstrate that HEARTGARD-30®
Plus prevents the development of D. immitis larvae and is effective
for the treatment and control of infections of A. caninum, U. stenocephala,
T. canis and T. leonina . Results of clinical trials confirm that
HEARTGARD-30® Plus is safe and effective for use under field conditions
in the presence of concomitant standard veterinary therapy. HEARTGARD-30®
Plus was consumed with an overall acceptability of 97% in the clinical field
trials.
V. ANIMAL SAFETY
In target animal and clinical safety studies, ivermectin has been shown
to have a wide margin of safety in dogs at the recommended heartworm-preventive
dose. This is supported by field use of the product in several countries worldwide.
The bioequivalence study (Table 1, # 12664) demonstrated that HEARTGARD-30®
Plus and HEARTGARD-30® Chewables are equivalent with respect to ivermectin.
This allows reference to the ivermectin safety data presented in the Freedom
of Information Summary for HEARTGARD-30® Chewables (Merck's NADA 140-886).
Two pivotal safety studies (Tablet 1, #'s 12666 and 12932) and one corroborative
safety study (#12663) were conducted to determine the safety in the target
animal of the two new sources of pyrantel (Farmos Group, Ltd and Cosmos S.p.A.)
used in the HEARTGARD-30® Plus formulation. These included pup tolerance
(#12932), reproductive safety (#12666) and repeated treatment studies (#12663).
The results of these trials confirm that HEARTGARD-30® Plus is safe for
use in most classes of dogs including breeding animals and pups six weeks
of age and older.
A. Pup Safety
A study was conducted in Beagles, aged 38-49 days, to demonstrate safety
in pups. Thirty-two pups were treated at 1, 3 or 5X the target dose of HEARTGARD-30®
Plus given on 3 successive days and repeated 3 times within a 30-day period.
Replicates of 4 pups from each of 8 litters were formed.
Within replicates, dogs were randomly allocated to 4 treatment groups: vehicle,
ivermectin/pyrantel (1X use level, i.e., 6 mcg ivermectin and 5 mg pyrantel/kg
body weight, respectively), ivermectin/pyrantel (3X use level, i.e., 18 mcg
ivermectin and 15 mg pyrantel/kg body weight, respectively), or ivermectin/pyrantel
(5X use level, i.e., 30 mcg ivermectin and 25 mg pyrantel/kg body weight,
respectively). Treatments, based on body weights obtained on Days -3, 11 and
25, were given on Days 0, 1, 2, 14, 15, 16, 28, 29 and 30. Hematology, serum
chemistry, fecal analyses and clinical observations were performed. All animals
in the control and high-dose groups were necropsied on Day 35 or 36, and tissues
were examined for gross and microscopic pathology.
Clinical pathology and physical examination data were analyzed by analysis
of variance or covariance for a repeated measures design.
Initial and terminal physical examinations did not reveal any treatment
related effects. Some dehydration was observed in animals of all groups and
was considered to be related to weaning and adapting to solid feed and individual
housing. Random vomiting was reported in all groups and was usually of one
day duration.
Clinical pathology results indicated changes in the treated animals in the
following parameters: calcium, creatinine, MCHC, phosphorus and WBC. There
were also treatment effects seen in eosinophils, platelets, prothrombin time,
albumin, BUN, protein, potassium and phosphorus. None of these differences
were considered to be biologically or clinically significant. There were no
changes in temperature, weight gain or changes in heart rate and no differences
between groups in fecal bilirubin, occult blood or microscopic examinations.
On necropsy there were no treatment related lesions. Occasional incidental
findings in control and treated animals included agonal congestion in lymph
nodes and thymus, splenic capsule scars, focal areas of pneumonia and normal
but small thyroid lobes. On histopathology there were no drug related microscopic
lesions observed in the tissues examined. Microscopic findings were either
agonal or typical of common background findings in dogs of this age and breed.
B. Reproductive Safety
A trial (Table 1, #12666) was conducted to evaluate safety of HEARTGARD-30®
Plus in breeding male and female dogs.
Thirty-six bitches were paired by weight and randomly allocated to one of
two treatment groups within pairs. Sixteen males, selected on the basis of
a normal semen analysis, were paired based on pretreatment sperm counts and
were randomly allocated within pairs to treatment. Treatment consisted of
either HEARTGARD-30® Plus at 3X the target use level (a total of 18 mcg
ivermectin and 15 mg pyrantel/kg body weight) or vehicle chewable tablet administered
orally. Males were dosed weekly through Day 63, then daily from Day 68 through
breeding. Females received 8 to 14 weekly doses prior to breeding, then were
dosed daily through the first half of pregnancy and weekly for the remainder
of gestation through weaning.
Semen analysis and body weights were evaluated weekly during the trial.
Physical examinations were performed prior to treatment and at the conclusion
of the trial. Each treatment group of studs was assigned to a breeding sequence,
and bitches were allocated to the appropriate stud based on onset of estrus.
Each bitch had two breeding opportunities. Breeding began on the final day
of semen collection (Day 85).
Fertility, whelping and weaning indices were calculated, and pups that were
born dead or died during the course of the study were necropsied. Data on
semen characteristics; stud, bitch and pup weights; proportion of pups weaned
and percent with abnormalities were analyzed with the appropriate analysis
of variance or covariance. Litter size was analyzed using an exact randomization
procedure.
HEARTGARD-30® Plus, given orally at 3X the target dose through one reproductive
cycle, was found to have no effect on semen evaluations in terms of total
sperm count, speed of progression, motility or pH. Sperm morphology and semen
color in both test and vehicle treatment groups were normal.
The following table shows the breeding indices from both groups:
(Eds. note: The following table consists of 4 columns.)
#WHELPED/#BRED MEAN LITTER WEANING
(CONCEPTION RATE) SIZE PERCENT
Vehicle 8/12 (66.7%) 6.0 91.1%
Heartgard-30 11/12 (91.7% 5.5 84.2%
Plus
Four puppies in the vehicle-treated group died due to the following: 1 from
an umbilical infection, 1 was crushed, 1 was rejected by the dam, and 1 was
unable to nurse due to a cleft palate. Ten puppies died in the HEARTGARD-30®
Plus-treated group due to the following: 4 were crushed, 1 was rejected, 1 was
euthanized due to a congenital deformity, and 4 did not nurse. The treatment
groups were not significantly different for litter size at birth or weaning
(p>1.0). Congenital abnormalities were seen in 7 of 48 pups born in the vehicle
control group (cleft palate, anasarca, runt, open fontanel, prognathia, harelip,
and flat chest) and 5 of 61 pups born in the group treated at 3X HEARTGARD-30®
Plus (missing kidney, gastroschisis, open fontanel, persistent pupillary membrane
and kinked tail). The treatment groups were not significantly different for
percent of pups with abnormalities (p>2.0). Types and incidence of malformations
seen were not markedly different from those in the breeding colony and therefore
were not attributed to treatment.
C. Corroborative Repeated Treatment Study
A study (Table 1, # 12663) was conducted to evaluate the toxic potential
of repeated oral treatment with ivermectin alone or in combination with 2
levels of pyrantel. Six replicates of 4 Beagles each were allocated to 4 treatment
groups-(1) vehicle only, (2) ivermectin (6 mcg/kg), (3) ivermectin/pyrantel
(6 mcg and 5 mg/kg, respectively), and (4) ivermectin/2X pyrantel (6 mcg/kg
ivermectin, 10 mg/kg pyrantel). All medications were administered daily for
5 consecutive days. Dogs were evaluated by a physical examination prior to
the study and by general observations through Day 4 and again on Day 7. On
Days 0, 1, 4, and 7 blood was drawn and urine collected for CBC, serum chemistry,
and urine analysis. At the end of the trial on Day 7, 3 dogs treated with
ivermectin/2X pyrantel were euthanized, necropsied and examined for any gross
or histopathologic changes.
Ivermectin alone or in the presence of up to 2 times the target dose of
pyrantel did not cause any drug-related adverse physical or clinical signs
in this study. There were no gross lesions at necropsy or histomorphologic
changes on light microscopic examination of tissues following necropsy.
D. Target Animal Safety Conclusions
HEARTGARD-30® Plus has a wide margin of safety when administered repeatedly
at elevated doses to dogs including 6-week-old pups and breeding studs and
bitches.
VI. HUMAN SAFETY:
Human safety: Data on human safety, pertaining to consumption of drug residues
in food, were not required for approval of this NADA. This drug is labeled
for use in dogs, which are non-food animals.
Human safety relative to possession, handling, and administration: Labeling
contains adequate caution/warning statements.
VII. AGENCY CONCLUSIONS:
The data submitted in support of this NADA comply with the requirements
of Section 512 of the Act and 21 CFR 514.111 of the regulations. It demonstrates
that HEARTGARD-30® Plus Chewable tablets, when used under the labeled
conditions of use, are safe and effective.
Section 512(c)(2)(F)(ii) of the Federal Food, Drug and Cosmetic Act provides
a three year period of exclusivity to this original new animal drug application
because new clinical or field investigations (other than bioequivalence or
residue studies) essential to this approval were conducted or sponsored by
the applicant.
Compliance with 21 CFR 514.1 (b)(8)(v) and the Center's Drug Combination
Guideline:
HEARTGARD-30® Plus is a 2-way combination of ivermectin and pyrantel
pamoate. The sponsor conducted adequate and well controlled safety and effectiveness
studies, including dose determination and field studies, that demonstrate
the source of pyrantel pamoate used in the formulation of HEARTGARD-30®
Plus is safe and effective for the labeled indications for use.
The sponsor also conducted 2 pivotal dose confirmation studies with HEARTGARD-30®
Plus against D. immitis . The percent control in both studies was 100%
indicating that the pyrantel does not interfere with the efficacy of the ivermectin
in the combination. In three pivotal dose confirmation studies against the
intestinal parasites, the efficacy of HEARTGARD-30® Plus was not statistically
different than that of the pyrantel, indicating that the ivermectin does not
interfere with the efficacy of the pyrantel in the combination.
The data submitted in the NADA demonstrate that the combination of ivermectin
and pyrantel is superior to ivermectin alone or pyrantel alone for the labeled
indications for use.
The drug is restricted to use by or on the order of a licensed veterinarian
as knowledge of veterinary parasitology is needed for the safe use, monitoring
and detection of possible adverse reactions with this drug.
(Eds. note: The following table consists of 4 columns.)
TABLE 1: IDENTIFICATION OF INVESTIGATORS AND TRIAL LOCATION
FOR HEARTGARD-30® Plus EFFECTIVENESS, SAFETY AND CLINICAL TRIALS
Trial Investigator Location Objective
12664 Dr. R. Jeffcoat Research Triangle Institute Bioequivalence
Dr. E. Cheung Research Triangle Park, NC
12665 Dr. S. Rubin Univ of Saskatchewan Dose determination, pyrantel
Dr. L. Polley Saskatchewan, Canada
12489 Dr. D. Jacobs Royal Veterinary College Dose determination, pyrantel
Hertsfordshire, U.K.
12444 Dr. F. Horchner University of Berlin Dose determination, pyrantel
Berlin, Germany
12589 Dr. J. McCall TRS Laboratories Dose confirmation
Athens, GA Heartworms
12590 Dr. K. Acre Acre Farm Dose confirmation
Eustis, FL Heartworms
12591 Dr. E. Robertson Univ of Georgia Dose confirmation
Athens, GA Intestinal parasites
12592 Dr. E. Robertson Univ of Georgia Dose confirmation
Athens, GA Intestinal parasites
13095 Dr. G. Schad Univ of Pennsylvania Dose confirmation
Philadelphia, PA Intestinal parasites
12767 Dr. K. Todd Univ of Illinois Corroborative Dose confirmation
Dr. A. Paul Urbana, IL Heartworms
12765 Dr. K. Todd Univ of Illinois Corroborative Dose confirmation
Dr. A. Paul Urbana, IL Intestinal parasites
12766 Dr. K. Todd Univ. of Illinois Corroborative Dose confirmation
Dr. A. Paul Urbana, IL Intestinal parasites
12774 Dr. R. Blakely Central Hospital for Animals Controlled clinical/efficacy/
Carterville, IL field safety/acceptability
12779 Dr. K. Acre Howell Branch Animal Hosp. Controlled clinical/efficacy/
Winter Park, FL field safety/acceptability
12780 Dr. M. Coleman Suburban Animal Hospital Controlled clinical/efficacy/
Gainesville, FL field safety/acceptability
12781 Dr. S. T. Currin Mayfair Animal Hospital Controlled clinical/efficacy/
Cary, NC field safety/acceptability
12782 Dr. A. Ellis River Cove Animal Hospital Controlled clinical/efficacy/
Williston, VT field safety/acceptability
12829 Dr. J. Hugenbois Beattie Animal Hospital Controlled clinical/efficacy/
Brantford, Ontario, Canada field safety/acceptability
12906 Dr. D. Weiner Dogwood Hospital for Animals Controlled clinical/efficacy
Atlanta, GA field safety/acceptability
12907 Dr. R. Lange Lange Animal Hospital Controlled clinical/efficacy
Dr. R. Lange Knoxville, TN field safety/acceptability
13713 Dr. R. L. Sifferman Grant Avenue Pet Hospital Controlled clinical/acceptability
Springfield, MO
12666 Dr. M. Gilman Hazelton-LRE Reproductive safety
Kalamazoo, MI
12932 Dr. M. Gilman Hazelton-LRE Pup safety
Kalamazoo, MI
12663 Dr. A. D'ver White Eagle Labs Repeated treatment tolerance
Doylestown, PA (Corroborative)
(Eds. note: The following table consists of 5 columns.)
TABLE 2: EFFICACY OF PYRANTEL (5 MG/KG) IN
HEARTGARD-30® PLUS FORMULATION AGAINST NATURAL
AND/OR INDUCED INFECTIONS OF INTESTINAL TRACT NEMATODES
Number % Efficacy Trial Treatment
of compared to control #
Parasite dogs treated
Toxocara canis 6 97.5 12444 pyrantel*
6 91.9 12489 pyrantel
8 88.3 12591 iver/pyrantel**
8 80.1 12591 pyrantel
Toxascaris leonina 8 100.0 12592 iver/pyrantel
8 95.9 12592 pyrantel
7 92.0 12665 pyrantel
Ancylostoma caninum 8 100.0 12592 iver/pyrantel
8 >99.0 13095 iver/pyrantel
7 >99.0 12665 pyrantel
8 96.8 12592 pyrantel
6 92.8 12444 pyrantel
8 89.9 12591 pyrantel
8 86.3 12591 iver/pyrantel
Uncinaria stenocephala 8 >99.0 12592 iver/pyrantel
8 >99.0 13095 iver/pyrantel
8 96.3 12592 pyrantel
7 93.4 12665 pyrantel
* pyrantel pamoate at 5 mg/kg in the HEARTGARD-30® Plus vehicle
** pyrantel pamoate at 5 mg/kg with 6 mcg/kg in the HEARTGARD-30® Plus formulation
intended for market
(Eds. note: The following table consists of 11 columns.)
TABLE 3: SUMMARY OF FIELD TRIALS WITH HEARTGARD-30 Plus
Trial Female Male Total # Owners Age Weight HG-30/N* HG-30+** Site Investigator
12774 44 20 64 45 6 ms-13 y 4-68 kg 16 48 Carterville, Il. R. S. Blakely
12779 34 17 51 29 9 ms-13 y 2.7-68 kg 13 38 Winter Park, Fl. K. E. Acre
12780 33 19 52 30 6 ms-14 y 2.6-46 kg 13 39 Gainesville, Fl. M. W. Coleman
12781 37 15 52 32 1 - 13 y 1.6-54 kg 13 39 Cary, N.C. S. T. Currin
12782 37 15 52 39 6 ms-14 y 6.4-49 kg 13 39 Williston, Vt. A. J. Ellis
12829 29 27 56 37 1 - 12 y 2.4-39 kg 14 42 Brantford, Ontario, J.W. Hugenbois
Canada
12906 36 16 52 35 1 - 13 y 4.1-47 kg 13 39 Atlanta, Georgia D. Weiner
12907 30 21 51 28 7 ms-12 y 4.0-43 kg 12 39 Knoxville, Tn R. L. Lange
Total: 280 150 430 275 107 323
*HEARTGARD-30 tablets and NEMEX/Pfiser Inc. US or HEARTGARD-30 tablets and PYR-A-PAM 2/Rotar FIB London
Trial #12829 was the only one in which PYR-A-PAM 2 was used
**HEARTGARD-30 Plus
VIII. LABELING (Attached)
a. Veterinarian's insert
b. Package insert
c. 5 to 25 lb body weight (shipping carton, outer and inner drug cartons)
d. 26 to 50 lb body weight (shipping carton, outer and inner drug cartons)
e. 51 to 100 lb body weight (shipping carton, outer and inner drug cartons)
Copies of these labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855
