I. GENERAL INFORMATION:
| NADA |
140-439 |
| Sponsor: |
Merck Sharp & Dohme Research Laboratories
Division of Merck & Co., Inc.
P.O. Box 2000
Rahway, NJ 07065-0914
|
| Generic Name: |
Ivermectin |
| Trade Name: |
EQVALAN Liquid |
| Marketing Status: |
Veterinary prescription drug |
II. Indications For Use:
For treatment and control of the following parasites or parasitic conditions in
horses:
Bots
Gastrophilus spp., oral and gastric stages
Large mouth stomach worms
Habronema muscae, adults
Neck threadworms
Onchocerca sp., microfilariae
Pinworms
Oxyuris equi, adults and fourth stage larvae
Ascarids
Parascaris equorum, adults
Lungworms
Dictyocaulus arnfieldi, adults and fourth stage larvae
Intestinal threadworms
Strongyloides westeri, adults and fourth stage larvae
Small strongyles - including those resistant to some benzimidazole class
compounds
Cyathostomum spp., adults and fourth stage larvae
Cylicocyclus spp., adults and fourth stage larvae
Cylicodontophorus spp., adults and fourth stage larvae
Cylicostephanus spp., adults and fourth stage larvae
Blood worms or large strongyles
Strongylus edentatus, adults and tissue stages
Strongylus equinus, adults
Strongylus vulgaris, adult and arterial larval stages
Triodontophorus spp., adults
Hair worms
Trichostrongylus axei, adults
Summer sores caused by Habronema and Draschia spp. cutaneous third stage
larvae
Dermatitis caused by neck threadworm microfilariae (Onchocerca sp.)
III. Dosage Form, Route of Administration and Recommended Dosage
EQVALAN liquid is formulated for administration by stomach tube or
as an oral drench. The recommended dosage is 200 micrograms of ivermectin per kilogram of body weight
(0.2 mg/kg or 91 mcg/lb). Each ml of EQVALAN liquid contains 10 mg of
ivermectin, sufficient to treat 110 lb (50 kg) of horse body weight;
10 ml will treat an 1100 lb (500 kg) horse.
IV. Effectiveness:
The New Animal Drug Application for ivermectin liquid for horses contains data
demonstrating that the product is the therapeutic equivalent of EQVALAN paste.
Therefore, the full spectrum of indications for use of EQVALAN paste (NADA
134-314) is applicable to EQVALAN liquid. The therapeutic equivalence demonstrated
in the controlled efficacy confirmation trial and the five field trials is supported
by the data from a bioavailability trial where the liquid and paste formulation
were compared.
Pivotal Studies
Controlled Efficacy Trial
One controlled efficacy confirmation trial was conducted by Dr. Joseph A. DiPietro
at the University of Illinois, Urbana, Illinois, using 15 horses that were given
induced ascarid infections. When the infections were 11 days old, horses were
randomly allocated to an unmedicated control group, or to treatment with ivermectin
liquid as an oral drench or with EQVALAN paste (5 horses per group). No Parascaris
equorum were found at necropsy, 14 days after treatment, in any ivermectin
liquid- or ivermectin paste-treated horse, while all 5 controls were infected with
an average of 1136 P. equorum. While the immature (migrating) ascarid is not
currently included as a claim in the indications for use of ivermectin, it is
known to be difficult to control.
Field Trials
Five field trials with 471 horses were conducted in the United States and
Canada, one each in Arkansas, Florida, Illinois, Texas and Saskatchewan. The
investigators are listed below:
Investigator Location/Address
Dr. Richard L. Asquith University of Florida,
Ocala, Florida
Dr. Roxanne Bell Univ. of Saskatchewan
Saskatoon, Saskatchewan,
Canada
Dr. Joseph A. DiPietro University of Illinois,
Urbana, Illinois
Dr. Ed S. Murray Spur, Texas
Dr. Mark Hubbard Springdale, Arkansas
All
471 horses (from 15 days old to 24 years old) in these 5 field trials
received ivermectin at use level: 250 horses received ivermectin liquid as a
drench, 117 horses received the liquid by stomach tube, and 104 horses got
EQVALAN Paste. These numbers include the horses used as concurrent untreated
controls and subsequently treated with ivermectin.
These trials were run under practical field conditions with the market
formulation of EQVALAN liquid to assess the acceptability of the product in
horses when administered as an oral drench or by nasogastric intubation, and to
confirm its efficacy (by fecal egg counts) when given at 1 ml per 50 kg of body
weight (i.e., at 200 mcg/kg).
All of the trials were conducted similarly. Horses had natural infections of
internal parasites and no anthelmintics were used on trial animals for at least
six weeks before the trial start date. An acclimation period of at least 7
days was provided at each site. Feed, water and housing were given according
to the usual practices at each property.
At each U.S. trial location, replicates of four horses were formed based on order
of presentation or based on pretreatment fecal egg count. All horses in a
replicate were housed, managed, and handled similarly. Within each replicate,
1 horse was assigned to be an unmedicated control, 1 horse was assigned to
receive ivermectin liquid by nasogastric tube, and 2 horses were assigned to
receive ivermectin liquid as a drench. The Canadian field trial differed from
the 4 U.S. trials in that one each of the 4 horses in a replicate was randomly
assigned to an unmedicated control group or to treatment with ivermectin liquid
as a drench or by stomach tube, or to treatment with EQVALAN paste.
The assigned ivermectin liquid treatments were administered on Day 0, at the
rate of 1 ml per 50 kg of horse body weight (200 mcg of ivermectin/kg). Horses
were weighed, or had their weights estimated (by girth tape), within a few days
prior to Day 0. Ivermectin liquid was administered undiluted. For each
horse in the tubing group, at least 200 ml of clean water was flushed through
the tubing equipment in situ immediately after the administration of ivermectin
liquid.
Fecal samples were collected from 471 horses, and examined for parasite eggs on
or before Day 0, and most horses were sampled again on Day 13 or 14. At the
time of the second sampling, control horses were treated with ivermectin liquid
as a drench or with EQVALAN paste. Almost all of these horses had fecal
samples taken one more time, usually 2 weeks later, except for the 29
controls in the Canadian field trial.
Fecal samples were generally examined by a modified McMaster procedure. Most
samples with a count of 100 or fewer eggs per gram of feces (EPG count) were
examined again with a direct flotation technique. Eggs were classified and
recorded by type as Parascaris equorum, Strongyloides westeri , or
strongylids.
For each trial, total EPG counts (i.e., total counts of all types of nematode
eggs per horse) were analyzed for differences among treatment groups on Day 13
or 14 using Friedman's test, a nonparametric chi-square test for randomized
block designs. Two treatment contrasts were of interest: control vs.
ivermectin liquid by stomach tube, and control vs. ivermectin liquid as a
drench. In each trial both contrasts were significant at P<.01.
Natural parasitic infections were confirmed for 441 of the animals on or before
the trial start day. On Day 13 or 14, eggs of parasitic nematodes were found
in the feces of 107 of 114 sampled untreated controls, while only 14 of 301
sampled horses that received ivermectin liquid had strongyle type eggs in their
feces, and none of 29 horses given EQVALAN paste had parasite eggs. Of the 14
ivermectin liquid-treated horses with positive counts two weeks after
treatment, only 2 had counts detectable by the modified McMaster procedure
(50 and 300 epg); the others had eggs observed only on the more sensitive
direct flotation. Fourteen or 16 days after the controls were treated with
ivermectin, strongyle-type eggs were found in the feces of 4 of 41 horses
that received ivermectin liquid as a drench, and on 4 of 40 horses that got
EQVALAN paste. Included in these trials were 58 horses positive for ascarid
eggs prior to treatment with ivermectin liquid (29 tubed, 29 drenched) but
negative 14 days after treatment, and 26 horses with Strongyloides westeri eggs
prior to treatment (8 tubed, 18 drenched) but with none 14 days after
treatment).
All horses treated with ivermectin liquid were closely monitored immediately
after treatment and observed daily for 13 or 14 days. Also, the oral cavities
of all horses receiving ivermectin liquid as an oral drench were examined for
abnormalities.
No adverse reactions attributed to ivermectin treatment were reported for any
horse. One mare had colic 11 days after treatment and 1 gelding was
euthanized on Day 14 suffering from an acute central nervous system disorder;
necropsy revealed severe multifocal encephalomalacia consistent with
septicemia. No abnormalities were found in the oral cavity of any horse given
ivermectin liquid as a drench.
Supporting Data
Bioavailability
A bioavailability trial was conducted by Dr. Richard L. Asquith at the
University of Florida, Ocala, Florida, utilizing 13 healthy pregnant mares. One
horse was randomly selected to be an unmedicated control whose plasma was used
to verify the absence of ivermectin. Pairs of horses were formed based on
breed, body condition and weight. Within pairs, one horse received EQVALAN
paste orally at 200 mcg/kg and the other received ivermectin liquid by
nasogastric intubation at 200 mcg/kg. Blood samples were collected from each
mare prior to treatment and at appropriate intervals following treatment.
Plasma samples were assayed for ivermectin. Area under the plasma time curve
(AUC) was computed for each animal. The natural logarithm transformation was
found to help homogeneity of variance for AUC; plasma concentration data and
time-to-peak were not transformed. Peak plasma value, log (AUC), and
time-to-peak were analyzed, with and without a rank transformation, using
analysis of variance for a repeated measures design, to investigate whether the
treatment profiles were similar. The conclusions were the same whether or not
the rank transformation was used.
All plasma samples for the control horse and all pretreatment samples were free
of ivermectin. Ivermectin liquid had a higher and earlier peak plasma
ivermectin concentration than EQVALAN paste. The differences between
formulations were confined to the first 24 hours after dosing (see Figure 1).
After that time, the profiles of the two formulations were almost identical and
the difference in area under the plasma time curves was only 12%. Ivermectin
liquid provides equivalent parasite exposure to ivermectin and, therefore,
equivalent efficacy against the same spectrum of equine parasites as the
paste.
Conclusion
The therapeutic equivalence of ivermectin liquid to EQVALAN paste was confirmed
in one controlled efficacy confirmation comparison trial and in 5 field trials.
The efficacy was demonstrated as a drench or by nasogastric tube.
EQVALAN liquid has the same indications for treatment and control of parasites
and parasitic conditions as has EQVALAN paste.
V. Safety in the Target Animal
Pivotal Studies
NADA 134-314 and 127-443
The safety of ivermectin in horses has been established in trials included in
previous submissions (EQVALAN paste; NADA 134-314 and EQVALAN injection; NADA
127-443). Information on these studies is included in the Freedom of
Information Summaries for these previously approved products.
Breeding Animal Safety - Horses
Two teratology trials were conducted in which mares were given ivermectin paste
at 600 mcg/kg six times at two-week intervals during the period of
organogenesis. Two additional trials were conducted where mares were treated
six or seven times with ivermectin injection at 600 mcg/kg at two months of
pregnancy. A stallion breeding safety trial was also conducted in which
stallions received a single treatment of ivermectin injection at 600 mcg/kg.
No adverse effects on reproduction were seen in these trials and it was
concluded that ivermectin may be used safely in breeding stallions and in
pregnant mares. These trials are more fully described in the Freedom of
Information Summary for EQVALAN paste.
Supporting Data
Ivermectin liquid for horses has been tested in a tolerance trial conducted
using repeated administrations at 3 and 5 times use level. The clinical
field trials discussed in the previous section also demonstrated safety and
acceptability of ivermectin liquid under commonly experienced field
conditions.
Tolerance
The tolerance trial was conducted by Dr. Joseph A. DiPietro, University of
Illinois, Urbana, IL, in young foals because they are considered to be the most
sensitive age of horse based on studies with EQVALAN paste. Young foals were
given repeated doses of ivermectin liquid at 0, 3 or 5 times use
level, i.e., at 0, 600 or 1000 mcg/kg. This trial was conducted using 18
standardbred foals that were from 24 to 92 days old on Day 0.
The foals were kept on pasture and received a dietary supplement. Well water
was available. Replicates of 3 foals were formed based on sex and
pretreatment weight. Within replicates, foals were randomly allocated to
receive a water treatment (placebo control), or ivermectin liquid as a drench
at 600 or at 1000 mcg/kg. Assigned treatments were administered on Days 0,
14 and 28 to each foal. The dose for each foal was calculated based on the
weight obtained 2 days prior to each of the 3 treatment administrations.
Procedures were followed during dosing to ensure that the drug was retained.
Thorough physical examinations were made of each foal before treatment and on
Day 35; clinical observations were made daily. The foals were closely monitored
and examined for toxic signs for several days following each treatment. If any
one of the observations in the examination for primary toxic signs was other
than "normal", a more detailed examination for secondary toxic signs was
conducted.
None of the 6 foals given 3 exposures to 5 times the use level of
ivermectin liquid had adverse reactions or toxic signs.
Those reactions which were considered not related to ivermectin treatment at 3
times use level included respiratory infections, a submandibular lymph node
enlargement and diarrhea. Reactions similar to these were observed in the control
foals.
Two of the foals given ivermectin liquid at 3 times use level had front
limb lameness after their third exposure to the drug. The cause of this
lameness could not be determined. In both foals, all signs resolved
completely.
Laboratory Animals - Teratology
Ivermectin has been shown to be teratogenic in rats, rabbits, and mice at or
near maternotoxic dose levels. At these high doses, evidence of a teratogenic
effect is limited to cleft palate that occurs at a low frequency in all three
species and clubbing of the forepaws which occurs only in rabbit fetuses. Mice
are the most sensitive species to the effects of ivermectin with
maternotoxicity at a dose of 200 mcg/kg/day and teratogenicity at 400
mcg/kg/day. In rabbits 6000 mcg/kg/day was maternotoxic and teratogenic, and
teratogenicity was also evident at a dose of 3000 mcg/kg/day. The threshold for
both maternotoxicity and teratogenicity in rats was 10,000 mcg/kg/day.
Breeding Animal Safety - Other Domestic Animals
The Freedom of Information Summaries for IVOMEC injection for cattle, IVOMEC
injection for swine, IVOMEC paste for cattle and HEARTGARD 30 Tablets for dogs
describe various breeding safety studies in the respective target animals. In
each of these species ivermectin has been found safe for use in breeding
animals.
Conclusions
There are insufficient data to determine safety of ivermectin liquid in foals
less than 4 months old.
Demonstration of the safety and acceptability of ivermectin liquid in horses
was found in the 5 field trials conducted using 471 horses. Ivermectin
liquid was given once, at use level, to 367 of these horses (250 were drenched,
117 were tubed). No adverse reactions attributable to ivermectin liquid were
observed. Both routes of administration were satisfactory.
The safety seen in these trials was expected, based on the previously reported
safety trials where high levels of ivermectin, up to 12 mg/kg (12,000 mcg/kg),
were administered to horses by intramuscular injection or orally. These
studies demonstrate that EQVALAN liquid is safe for use in horses, including
breeding animals.
VI. Human Safety
As labeled the drug poses no hazard to human safety pertaining to drug
residues, because it is labeled "not for use in horses intended for food". The
labeling contains adequate caution statements and instructions for the safe use
of EQVALAN liquid by experts (veterinarians).
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. It
demonstrates EQVALAN (ivermectin) liquid when used under its labeled conditions
of use is safe and effective.
Because the route and techniques for administration (nasogastric intubation and
drenching) require the expertise of a veterinarian, EQVALAN (ivermectin) liquid
is labeled for prescription use even though the efficacy of the product covers
all the economically important parasites of the horse.
VIII. Labeling
1. EQVALAN® (ivermectin) Oral Liquid for Horses package label
2. EQVALAN® (ivermectin) Oral Liquid for Horses package insert
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
