Summary of 
FDA Information:
 
  

Approval Date: July 3, 1989 

Freedom of 
Information Summary
NADA 140-886

I. GENERAL INFORMATION: 

NADA 140-886 
Sponsor:  Merck Sharp & Dohme Research Laboratories 
Division of 
Merck & Co., Inc. 
P.O. Box 2000 
Rahway, New Jersey 07065-0914
 
Generic Name: Ivermectin  
Trade Name: HEARTGARD-30 Chewables  
Marketing Status: Rx  

  

II. INDICATIONS FOR USE


For use in dogs to prevent canine heartworm disease by eliminating the tissue stage of 
heartworm larvae (Dirofilaria immitis ) up to a month after infection.

III. DOSAGE 


A. DOSAGE FORM The ingredients of 
HEARTGARD-30 Chewables are formulated into 
palatable, meat based chewable cubes.
Three dosage sizes are available for 
dogs of 
different weight classes.  
B. ROUTE OF ADMINISTRATION HEARTGARD-30 Chewables are orally administered at monthly intervals during the period of 
the year when 
mosquitoes (vectors), potentially carrying heartworm larvae, are active.  
C. RECOMMENDED DOSAGES: HEARTGARD-30 Chewables supply a minimum of 
6.0 mcg ivermectin per kg (2.72 mcg/lb) of 
body weight when 
given at the 
following recommended dose levels:  
      

  

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

  





   Dog           Chewables         Ivermectin  
  Weight         Per  Month         Content  

Up to 25 lb            1                  68 mcg  
26 to 50 lb            1                 136 mcg  
51 to 100 lb           1                 272 mcg 


Give dogs heavier than 100 lb the appropriate 
combination of 
these sizes. 


IV. EFFECTIVENESS

The New Animal Drug Application for 
ivermectin chewables contains data demonstrating that the 
product is the pharmacological equivalent of 
HEARTGARD-30 tablets and 
thus is also effective in the 
prevention of 
canine heartworm disease when 
given monthly at dose levels of 
at least 6 mcg of 
ivermectin per kg of 
body weight. 
For additional information on efficacy studies for 
ivermectin in dogs refer to the Freedom of 
Information Summary, NADA 138-412 (52 FR 11041, 11042, 4/7/87). 

Bioavailability 

A bioavailability trial was 
conducted at Research Triangle Institute in Research Triangle Park, North Carolina. Sixteen non-pregnant adult female Beagles, with no history of 
a tendency to vomit, were 
selected for 
the trial. All dogs received one ivermectin chewable and 
one ivermectin tablet in a two-period crossover design. Radio-labeled ivermectin was 
used in both formulations. Treatments were 
separated by 42 days. No other medications were 
given. 

Dogs were 
dosed orally and 
were 
carefully observed for 
emesis for 
4 hours after each dosing. All dogs accepted and 
retained both the chewable and 
tablet formulations. Ivermectin was 
given at 6 mcg/kg, the 
lowest level that would be administered following label directions. 

Blood samples (5 ml) were 
taken from 
each dog at Hour -24, and 

following each treatment at Hours 1,2,3,4,6,10,and 24, and 

at Days 2,3,5,7,10, and 

14 (i.e., Hours 48, 72, 120, 168, 240 and 
336).
Three additional blood samples (at Hours 8, 12 and 
15) were 
collected following the second treatment to define more precisely the radioactivity peak. Blood was 
centrifuged and 
plasma samples were 
frozen immediately for 
subsequent assay. 

Two or 
3 aliquots from 
each plasma sample were 
analyzed for 
total radioactivity in a scintillation spectrometer.
The recovery of 
tritium from 
tritiated ivermectin was 
ð97%. Radioactivity counts per minute were 
converted to ivermectin ng-eq/g plasma using the specific activity of 
[3H]-ivermectin standards. Statistical analysis of 
area under 
the curve and 
of the 
natural logarithm of 
peak ivermectin concentration used an ANOVA for 
a two-period crossover design; plasma ivermectin concentration data were 
transformed using natural logarithms and 
analyzed using a repeated measures ANOVA.
There were 
no significant Period or 
Sequence (i.e., Period x Formulation) effects for 
any variable analyzed.
The bioavailability of 
the two formulations was 
similar although not identical. Area under 
the curve was 
22% greater for 
the chewable formulation than for 
the tablet (pÐ0.03); peak ivermectin plasma concentration was 
comparable for 
both formulations (p ð.05). Mean time-to-peak ivermectin plasma concentration was 
longer for 
the chewable formulation than for 
the tablet, but for 
both formulation, peak plasma concentrations were 
reached by 10 hours for 
15 of 
the 16 dogs. Considering these results, a medical determination was 
made that the 
chewable formulation would provide comparable efficacy to the tablet. 

Conclusion 

Ivermectin has been shown to be effective in preventing heartworm disease in dogs at dose levels of 
6 mcg/kg and 
higher. HEARTGARD-30 tablets are a dosage form of 
ivermectin which 
has been approved for 
use in this regard (NADA 138-412). Because the tablet and 
chewable dosage forms have been shown to be pharmacokinetically similar and 
the chewables are as bioavailable to dogs as the tablets, HEARTGARD-30 Chewables are effective in preventing canine heartworm disease with a minimum monthly dose of 
6 mcg ivermectin/kg body weight. 

V. ANIMAL SAFETY 

For additional information on safety studies for 
ivermectin in dogs refer to the Freedom of 
Information Summary, NADA 138-412. 

Field Trials 

The acceptability and 
safety of 
the chewable formulation were 
tested in four similar controlled field trials.
The investigators are listed below: 

  


Investigator                       Location 

Dr. Mark W. Coleman                Gainesville, Florida  
Dr. Kenneth E. Acre                Winter Park, Florida  
Dr. John W. Huigenbos              Ontario, Canada  
Dr. Robert S. Blakely              Canterville, Illinois

Three hundred eighty-four client-owned dogs were 
enrolled in these trials.
The dogs were 
maintained at home and 
their usual routines were 
maintained including treatment with a wide variety of 
commonly used animal health products.
The owners administered the assigned trial medications, made observations, and 

kept records.
The investigators examined the dogs at the 
start of 
the trial and 
provided routine veterinary care. In two of 
the trials, dogs were 
brought back to the clinics for 
follow-up examinations after 4 to 6 months. Of the 384 dogs, 255 received monthly treatment with ivermectin chewables according to the recommended dosage schedule. Control dogs received monthly treatment with HEARTGARD-30 tablets, or 
daily treatment with Filaribits® and 
monthly placebo (ALPO Beef Bites(TM)). Most of 
the dogs received 3 to 6 doses of 
monthly trial medication. 
All dogs (except pups too young to require testing) were 
initially confirmed to be negative for 
heartworm, and 

all dogs brought back to the clinics for 
re-examination (in 2 trials) after 4 to 6 months were 
negative for 
heartworm. Test methods used were 
a Modified Knott or 
Difil-Test® (Evsco) and 
an antigen test.
The age range of 
dogs included in the 
trials was 
from 4 weeks to 14 years old and 
included 21 pups 14 weeks old or 
younger.
There were 
83 breeds, varieties or 
types of 
dogs, and 

170 owners participated. One bitch whelped and 
another was 
bred and 
whelped while on HEARTGARD-30 Chewable treatment. Fifteen dogs did not complete the field trials for 
reasons unrelated to treatment. 

No adverse reactions were 
attributed to treatment with ivermectin chewables.
The most common observations were 
vomiting and 
diarrhea, and 

these were 
observed with lower incidence among dogs receiving ivermectin chewables than among those in either control group. One dog consumed 16 X 272 mcg ivermectin chewables at one time (resulting in a dose of 
152 mcg/kg) and 
no untoward signs were 
observed. 

Other observations included dermatoses of 
various etiologies.
Three dogs on ivermectin chewables and 
three dogs on HEARTGARD-30 tablets were 
lethargic or 
sluggish. Two dogs were 
bitten by snakes and 
one of 
these dogs died; two dogs were 
hit by cars and 
one died.
A number of 
other unrelated observations were 
recorded, including: nephritis, cystitis, tachycardia, weight loss, coughing, protein losing enteropathy, tracheobronchitis, heart murmur, lump on shoulder, Sarcoptes infestation, chronic hip pain, sprained shoulder, throat infection, chewing on hip, and 

pharyngeal abscess. 

More than 97% of 
the dogs on study 
accepted all doses of 
the ivermectin chewables. Owners of 
the 6 dogs which 
rejected the chewable on one or 
more occasions generally dosed their dogs by putting the ivermectin chewable in the 
dog's mouth as they would a swallow tablet. Comparative acceptability scores were 
best for 
dogs receiving the ivermectin chewables. 

Palatability 

In order to demonstrate the palatability and 
acceptability of 
the chewable formulation, a total of 
91 dogs were 
used in a trial. Dogs were 
offered one chewable containing 85 to 112 mcg of 
ivermectin; owners were 
not given special instructions on how to administer the chewable, but rather, offered the chewable "free choice". Acceptance or 
rejection of 
the product, as well as any reactions, was 
recorded by owners who also made their own comments on the formulation. 

More than 93% of 
the trial dogs consumed their ivermectin chewable when 
offered, 5 did not consume it and 
1 ate half. No adverse reactions were 
observed after administration of 
the chewables. Comments concerning acceptability were 
generally very favorable. Twenty-four owners (26 dogs) remarked that their dogs were 
usually finicky, fussy, or 
hard to medicate but accepted the ivermectin chewable. Many breeds were 
included in the 
trial; the smallest dogs were 
two, 9-week old pups weighing 2.7 lb and 
3 lb, respectively. 

Conclusion 

The safety and 
efficacy of 
ivermectin in dogs have been established in trials included in a previous submission (HEARTRGARD-30 tablets, NADA 138-412). Information on these studies is included in the 
Freedom of 
Information Summary for 
this previously approved product. 

Demonstration of 
the safety and 
acceptability of 
ivermectin chewables in dogs was 
found in the 
4 field trials conducted using 384 dogs. Ivermectin chewables were 
given monthly, according to the recommended label direction, to 255 of 
these dogs; most dogs received 3 to 6 doses. No adverse reactions attributable to ivermectin were 
observed. 

VI. HUMAN SAFETY: 


Data on human safety, pertaining to consumption of 
drug residue residues in food, were 
not required for 
approval of this NADA.
This product is labeled as a prescription drug for 
use only on dogs which 
are non-food animals. 

Human safety relative to possession, handling, and 

administration: 

Labeling contains adequate caution statement. 

Labeling states: Keep this and 
all drugs out of 
reach of 
children. 

VII. AGENCY CONCLUSIONS: 


The data submitted in support of 
this NADA comply with the requirements of 
Section 512 of 
the Act and 
Section 514.111 of 
the implementing regulations.
The data demonstrated that HEARTGARD-30 Chewables when 
used under 
the labeled conditions of 
use are safe and 
effective.
The drug is restricted to use by or 
on the order of 
a licensed veterinarian because all dogs should be tested and 
treated for 
existing heartworm infection prior to starting treatment with HEARTGARD in a prevention program.

VIII. LABELING (Attached) 

Copies of 
applicable labels may be obtained by writing to the: 



Freedom of 
Information Office 
Center for 
Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855