A. Dose Establishment
No additional dose establishment work was required. The minimum target doses
of ivermectin (6 mcg/kg body weight) and pyrantel pamoate (5mg/kg) were established
previously. 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. The Freedom of Information
Summary for the Heartgard®-30 Plus chewables (Merck's NADA 140-971) application
can be referenced to support the dose of pyrantel pamoate against the developing
stages of hookworm (See FOI dated January 15, 1993).
B. Dose Confirmation
Two dose confirmation studies (Trials ASR #14326 and ASR #14543) were conducted
to evaluate the effectiveness of HEARTGARD™ Plus in the removal and control
of the adult hookworm, A. braziliense.
Trial ASR 14326 was conducted by Dr. John McCall at TRS Laboratories
in Athens, Georgia. The trial used nine male and nine female purpose-bred
beagles, 3.6 to 3.7 months old, and weighing 3.45 to 5.70 kg. Dogs were individually
caged and were inoculated orally with approximately 400 infective larvae (L3)
of A. braziliense 27 days before the day of treatment. Fecal flotation
examinations conducted on the day before treatment confirmed infection with
A. braziliense.
Pairs were formed by sex and body weight on the day before treatment; the
ninth pair consisted of the lightest male and the lightest female. Within
pairs, dogs were randomly allocated to an untreated control group or to treatment
with HEARTGARD™Plus once, according to label directions (i.e.,
dogs received ivermectin at the dosage of at least 6 mcg/kg and pyrantel as
pamoate salt at the dosage of at least 5 mg/kg).
The dogs were examined at necropsy on Day 7, and collected worms were identified,
counted and preserved. All nine control dogs had A. braziliense worms
(geometric mean = 275.4 worms; range = 104 to 384). One dog treated with HEARTGARD™
Plus had one female A. braziliense. The efficacy of HEARTGARD™
Plus was calculated as 99.97% relative to the control group geometric mean.
The difference between treatment groups was highly significant (p<0.001,
by a t-test for means with equal variances).
Trial ASR 14543 was conducted by Dr. Bruce Kunkle at the Merck Farm
in Fulton, Missouri. The trial used eight male and eight female beagles, approximately
6 months old, and weighing 9.3 to 14.4 kg. The animals were determined to
be free of helminths on Day -29 by a fecal flotation technique. Dogs were
individually caged and were inoculated orally with approximately 300 infective
larvae (L3) of A. braziliense 28 days before the day of treatment.
Fecal flotation examinations conducted on the day before treatment confirmed
the infection.
Within pairs formed by sex and body weight on the day before treatment,
dogs were randomly allocated to an untreated control group or to treatment
HEARTGARD™ Plus once, according to label directions.
Dogs were observed for retention of the dose. Three dogs vomited the chewable
or a portion thereof, and in each case, the chewable that had been vomited
was re-administered. Vomiting did not recur in animals who were administered
the chewables. This reaction is considered a response to tablet administration
and not treatment.
Dogs were examined at necropsy on Day 7, and collected worms were identified,
counted and preserved. All eight control dogs had A. braziliense worms
(geometric mean = 137.1 worms; range = 59 to 262). None of the dogs treated
with HEARTGARD™ Plus had hookworms. No adverse reactions to treatment
were reported. The difference between treatment groups was highly significant
(p<0.001, by a t-test for means with unequal variances). These studies
demonstrate 100% efficacy of HEARTGARD™ Plus against A. braziliense.
C. Clinical Field Trials
Five clinical trials were originally conducted under NADA 140-971 to confirm
the efficacy, safety and acceptability of the chewable formulation of HEARTGARD™
Plus (ivermectin/pyrantel) against heartworms, hookworms and ascarids of dogs.
Safety and efficacy data for hookworms was extracted to support the label
change for this supplement. Various breeds of dogs, 6 months to 14 years of
age, and ranging from 2.6 to 68 kg in body weight were used. Animals were
administered HEARTGARD™ Plus chewables at monthly intervals (5 months).
Fecal exams were conducted prior to each treatment and within one month following
the last treatment. Efficacy was demonstrated at 100% in each of the trials
(See table 1 below).
Ed. note: The following table has 5 columns.
TABLE 1
Investigator Trial # No. of Animals No. of Animals % Efficacy
/ Location (+) Before (-) After The
Treatment Final Treatment
Acre/ FL #12779 4 4 100%
Coleman/ FL #12780 4 4 100%
Currin/ NC #12781 7 7 100%
Weiner/ GA #12906 2 1 100%(1)
Lange/ TN #12907 3 3 100%
Total 20 19
(1) One of two animals diagnosed with hookworms prior to study
initiation died prior to conducting the final fecal exam. The efficacy of
Heartgard-30® plus for the remaining animal (1) was 100%.
D. Supportive Clinical Field Trials
Three clinical trials were conducted following the approval of the NADA
to confirm the efficacy, safety and acceptability of the chewable formulation
of HEARTGARD™ Plus (ivermectin/pyrantel) against heartworms, hookworms
and ascarids of dogs. Safety and efficacy data for hookworms was extracted
to support the label change for this supplement. Various breeds of dogs, 1
month to 13 years of age, and ranging from 3 to 70 kg in body weight were
used. Animals were administered HEARTGARD™ plus chewables at monthly
intervals (#13628: 9 months, #13647 and #13648: 3 months). Fecal exams were
conducted prior to the start of the trial for each trial. Additional fecals
were conducted at 5 months after the first treatment and at 0 to 28 days after
the final treatment (#13628) or on the day of treatment to 39 days following
the last treatment (#13647 and #13648). Each animal was observed up to eight
hours following each dose of HEARTGARD™ Plus. There were 15 reported
cases of diarrhea and 8 reported cases of vomiting which occurred within 24
hours of tablet administration. While these reported cases of vomiting and
diarrhea were considered treatment related, both are already listed in the
adverse reactions section of the approved product label. The average efficacy
of the trials was demonstrated to be 92% (See table 2 below).
TABLE 2
Investigator Trial # No. of Animals No. of Animals (-)
/ Location (+) Before After The Final
Treatment Treatment
Labarthe/ #13628 32 26
Brazil
McArthur/ GA #13647 26 25
Clekis/SC #13648 24 24
Conclusion: Based upon the 100% efficacy demonstrated in the dose confirmation
studies (2), the 100% efficacy in the clinical field trials (5), and the supportive
clinical field trials (3), this data is adequate to support the expansion
of the hookworm claim (A. braziliense). The enrolled clinical field
trial cases are applicable to this additional hookworm claim based on the
inability to distinguish hookworm species based on egg size. There are overlapping
sizes among hookworm species and practitioners do not distinguish to differentiate
species under typical veterinary clinical settings.
The data in support of this supplemental NADA application complies with
the requirements of Section 512 of the Act and Section 514.111 of the implementing
regulations. It demonstrates that HEARTGARD™ Plus, when used under the
labeled conditions of use, is safe and effective.
According to the Center's supplemental approval policy (21 CFR 514.106),
this is a category II change. This supplement provides for an additional claim
for the removal and control of the adult hookworm, A. braziliense.
This approval relied upon the safety and effectiveness data in the parent
application and evaluation of new efficacy data submitted in the supplemental
application.
Under section 512(c)(2)(F)(iii) of the Federal Food, Drug, and Cosmetic
Act (FF DCA), this approval qualifies for THREE years of marketing exclusivity
beginning on the date of approval because the supplemental application contains
reports of new clinical or field investigations (other than bioequivalence
studies) essential to the approval of the application and conducted or sponsored
by the applicant. The three years of marketing exclusivity applies only to
the additional adult hookworm claim (A. braziliense) for which the
supplemental application was approved. This exclusivity period will expire
three years from the date of the approval letter.
The drug is restricted to use by or on the order of a licensed veterinarian
because professional expertise is required to determine the existence of hookworm
and/or roundworm infection. In addition, professional expertise is required
to determine the existence of heartworm infection, and then properly treat
existing heartworm infection prior to starting treatment with HEARTGARD-30Plus
in a prevention program.
