A. Pivotal Studies
1. Cross-reference to the existing FOI Summary for Droncit Injectable Cestocide
(NADA 111-607, 46 FR 10464, February 3, 1981).
The original FOI summaries contain the details of the dose titration, dose
confirmation and clinical field studies which established the dose and effectiveness
of those products in dogs (and cats). The laboratory studies demonstrated
at the recommended dose a complete (100%) elimination of the various common
cestode species claimed on the label. Clinical field studies likewise established
the effectiveness of praziquantel against the cestodes.
B. Pivotal - Well-Controlled Laboratory Efficacy Studies
1. Efficacy of Praziquantel (Droncit) Against Echinococcus multilocularis
in Dogs
K.R. Kazacos
West Lafayette, IN
A controlled anthelmintic trial was conducted on 24 dogs according to CVM's
Canine/Feline Anthelmintic Guidelines. All were adults of various mixed breeds,
equal sex, ranging from 29 to 50 lbs. (13.2 to 22.7 kg) body weight. The dogs
were randomly divided into 3 groups of 12. Twelve dogs were dosed according
to the approved label (range = 4.8-7.0 mg/kg body weight) with the marketed
5.68% injectable solution, given intramuscularly. The remaining 12 dogs were
untreated controls. Blinding of those doing the evaluations was used to minimize
any potential bias.
The test animals, prior to treatment evaluation, were each experimentally
infected with Echinococcus multilocularis. This was done by feeding
each dog an estimated minimum of 100,000 protoscolices harvested from infected
gerbils. Because of the risk of a potentially fatal infection to those conducting
the study, dosing was accomplished at 21 days after administering the protoscolices
and necropsy was at 28 days. Diagnosis was by postmortem counting of E.
multilocularis parasites. Also, each dog was observed at least twice daily
from infection through necropsy for any indication of abnormal reactions or
side effects.
All 12 control dogs were infected with an average of 41,492 adult E.
multilocularis. By comparison, all treated dogs (12 with the injectable
solution), were completely negative for E. multilocularis (and as well
for other cestodes), i.e. 100% elimination. No adverse clinical signs or reactions
related to either the experimental infection or praziquantel treatment were
observed.
Praziquantel was effective and safe in treating E. multilocularis
infections in dogs.
2. Efficacy of Praziquantel (Droncit) Against Immature Echinococcus multilocularis
Infections in Dogs
K.R. Kazacos
West Lafayette, IN
This was an 8-dog controlled anthelmintic trial conducted according to CVM's
Canine/Feline Anthelmintic Guidelines. All were adults of various mixed breeds,
equal sex, ranging from 34 to 52 lbs. (15.4 to 23.6 kg). The dogs were randomly
divided into 4 groups of 2 dogs. Groups 1 through 3 were evaluated at 1,
7 and 14 days after experimental inoculation with a minimum of 100,000 protoscolices
per dog. Group 4, infected the same, was evaluated following parasite maturation,
for egg shedding in the feces. Blinding of those doing the evaluations was
used to minimize any potential bias.
Treated dogs received the label recommended dose (range 5.0 - 5.8 mg/kg
body weight) of the currently marketed Droncit formulation. They received
intramuscular doses of the injectable solution. The treated dogs were all
compared with the same number of untreated controls. There was one exception
in Group 4. The 2 control dogs were held, by design, after necropsy of the
treated dogs. At the conclusion of the egg monitoring interval, following
all egg count comparisons, those dogs were also treated. The purpose was to
observe the impact of praziquantel on more mature infections.
Evaluations in this study included the impact of praziquantel on immature
and mature E. multilocularis infections. Groups 1 through 3 were compared
with untreated controls for actual parasite counts. No parasite count comparisons
were possible in Group 4, as all these dogs were eventually treated with praziquantel
after evaluation of patent infections and egg shedding patterns. All animals
were observed at least twice daily from infection through necropsy for evidence
of adverse effects or reactions.
The untreated controls averaged 46,317 E. multilocularis per dog;
all were infected. All treated dogs had no E. multilocularis at necropsy,
i.e. 100% elimination. Treatment of mature infections produced a spike in
egg counts that lasted for up to 60 hours depending on the dog's fecal habits.
The peak counts in the treated dogs were many times less than the dog allowed
to continue shedding without treatment. No adverse effects or reactions were
observed.
Praziquantel was effective and safe for the treatment of immature E.
multilocularis infections in dogs.
C. Pivotal Clinical Field Trial
NOTE: It is not necessary to conduct a clinical field trial utilizing the
5.68% Injectable Solution, as the 10 year clinical field trial (referenced
below) with the 34 mg tablet formulation exceeds CVM's normal requirements.
This field trial was of 10 years duration and provided adequate safety and
effectiveness information on the drug when used monthly on a repeated basis.
For this reason and because of the difficulty in definitive diagnosis of Echinococcus
multilocularis and the zoonotic health implications, another clinical
field trial utilizing the injectable formulation is not necessary.
A Program to Reduce the Risk of Infection by Echinococcus multilocularis:
The Use of Praziquantel to Control the Cestode in a Village in the Hyperendemic
Region of Alaska
R.L. Rausch, J.F. Wilson and P.M. Schantz
Anchorage, AK
St. Lawrence Island in Alaska was the site of a 10-year clinical anthelmintic
evaluation of the marketed tablet formulation of praziquantel. No treatments
were given for the first 3 years during which the population of the larval
stage of E. multilocularis was monitored in voles captured from the
town of Savoonga. An estimated 80-90 dogs from Savoonga were dosed on a monthly
basis for 7 consecutive years following the initial monitoring. The dogs were
Huskies and other miscellaneous breeds of both sexes including a wide range
of ages and weights. All dogs were dosed orally according to the established
label recommendations.
This island is part of a hyperendemic region for E. multilocularis.
The complete life cycle of the parasite occurs on the island. E. multilocularis
is passed between the Northern Voles and both wild (e.g. foxes) and domestic
(e.g. dogs) canids. Humans, through contact with the canid hosts, occasionally
contract the disease. The purpose of the study was to monitor the infection
rate of the parasite in the voles once yearly. Humans are an accidental host,
taking the place of the vole.
Monitoring the impact of praziquantel through the vole infection rate was
considered by the investigators as a good measure of the exposure rate encountered
by humans. Voles from the town were considered as being exposed to praziquantel-treated
canids. Those captured outside the town were controls as they were exposed,
primarily, to feces from untreated canids. This was a practical method for
evaluating clinical response in a natural clinical setting. Diagnosis, therefore,
was based on positive identification of the parasite in voles.
Over the first 3 years with no treatment, 29% of the voles in Savoonga were
identified with E. multilocularis. By the third year of praziquantel
dosing, the vole infection rate in Savoonga had dropped to 1%. Over the 7-year
period of dosing, the average reduction in the vole infection rate was 83%.
This translates to a similar reduction in the risk of a human infection. There
were no reported adverse effects identified by the investigators following
praziquantel dosing.
Praziquantel was safe for repeat administration over an extended period
of multiple dosing. The beneficial impact of treatment was clear. The drug
was safe and effective in the treatment and control of natural E. multilocularis
infections in a clinical setting.
D. Corroborative Studies (Published Articles/Abstracts)
1. Cross-reference to the existing FOI Summary for Vercom (febantel/praziquantel)
Paste (NADA 133-953, 50 FR 19167, May 7,1985).
Laboratory and clinical data gathered by the sponsor confirms the activity
of praziquantel against cestode parasites, i.e. 100% elimination.
2. Efficacy of Praziquantel Against Immature Echinococcus multilocularis
in Dogs and Cats
F.L. Andersen, J.R. Crellin and D.D. Cox
Provo, UT
This was a controlled anthelmintic study involving experimentally induced
E. multilocularis infections derived from cystic material in cotton
rats. The eighteen dogs were each equally divided between an unmedicated control
group and a treated group, given an intramuscular dose of the injectable solution.
This study, originally included with NADA 111-607, was to demonstrate the
effect of a 5 mg/kg dose of praziquantel, in the injectable form intended
for market, against E. multilocularis. The dogs consisted of purebred
and mixed breeds of both sexes and different ages, ranging from 7 to 50 lbs.
(3.2 to 22.7 kg) body weight.
Diagnosis was based on the identification of the parasite during necropsy.
Treatments were given 21 days after infection and necropsy of all animals
was 28 days after infection.
At necropsy, all 9 control dogs were infected. All dogs treated with praziquantel
were negative for E. multilocularis, i.e. 100% elimination. Signs of
toxicosis were not observed in any animals.
The injectable formulation of praziquantel was effective and safe for the
elimination of E. multilocularis in dogs.
3. Efficacy of a Combined Paste Formulation of Praziquantel/Febantel Against
Immature Echinococcus granulosus and Immature Echinococcus multilocularis
F.L. Andersen, J.A. Short and H.D. McCurdy
Provo, UT
A controlled anthelmintic study was conducted on 12 dogs using experimentally
induced infections of E. multilocularis. The dogs were of multiple
breeds and ages, of both sexes, ranging from 19 to 62 lbs. (8.4 to 28.2 kg)
body weight. The dogs were given 25,000 E. multilocularis protoscolices
from cotton rats. The dogs were divided into two groups of six. All treated
dogs were dosed orally for three consecutive days beginning on day 21 after
infection according to the label recommended dosages using the formulation
intended for market. All were necropsied 28 days after infection. Diagnosis
was based on the identification of the Echinococcus spp. collected
from the intestinal tract.
All E. multilocularis infected controls were positive at necropsy
for their respective parasite. All treated dogs with both Echinococcus
parasites were negative, i.e. 100% elimination. No adverse side effects
were reported from any of the treated animals. Praziquantel, combined with
febantel in a paste formulation, was effective and safe when used for the
elimination of E. multilocularis in dogs.
