This NADA provides for the use
of Veteeze® (diazepam) as a preanesthetic agent to reduce the quantity
of barbiturates required to induce anesthesia.
Effectiveness for the recommended
indication has been established on the basis of a laboratory dose titration
study and four well-controlled field trials validating in vivo activity
under clinical conditions.
Dose Titration Study - Pivotal
Study Number: C-88-1
Investigator:
William W. Muir, III, DVM, PhD
Columbus, Ohio
A blinded titration study was
conducted to determine the dose of Veteeze (diazepam) required as a preanesthetic
drug to reduce the amount of barbiturate required to achieve anesthesia in
dogs. The barbiturate, thiamylal sodium, was used to induce anesthesia, as
indicated by achieving endotracheal intubation, in dogs. The parameter measured
was the amount of thiamylal required to achieve intubation. Subsequent to
intubation, the dogs were maintained on Halothane. Diazepam dosage was evaluated
at 0 (placebo), 0.05, 0.1 and 0.2 mg/kg b.w., intravenously. Twenty-four (12
male, 12 female) mixed breed dogs weighing 15-25 kg were randomly assigned
to six replicates of a 4 x 4 Latin square. Every animal received each dose,
thus providing 24 dogs per treatment. Following a treatment cycle, all dogs
were rested for 3 weeks before the next treatment cycle was started. The quantity
of thiamylal required to achieve endotracheal intubation was measured. The
dogs were monitored for drug effect on respiration rate, heart rate and body
temperature, and any visible signs of drug effect, including depression, anger
or vocalization. Time to achieve extubation, and sternal and standing recovery
were noted.
Diazepam or placebo was injected
3-5 minutes prior to the anesthetic thiamylal sodium, which was administered
until endotracheal intubation was possible. The dose used was blinded to the
person administering the drug and making the observations.
Results:
0.2 mg group used 8.261 mg/kg
thiamylal (22% reduction)
0.1 mg group used 9.097 mg/kg thiamylal (14% reduction)
0.05 mg group used 9.293 mg/kg thiamylal (12% reduction)
Control group used 10.6 mg/kg thiamylal
Statistical analyses of the data
show that the intravenous administration of diazepam at 0.05, 0.1 and 0.2
mg/kg of body weight decreased (P < .05) the amount of thiamylal sodium
required to achieve intubation. It was further shown that the 0.2 mg/kg intravenous
dose of Veteeze reduced the amount of thiamylal required over that of the
0.05 and 0.1 mg/kg dose levels (P < .05).
No adverse reactions were observed.
No treatment differences were noted for respiratory rate, heart rate, body
temperature, demeanor or recovery time associated with the four treatment
levels.
Four clinical field studies,
comprising a placebo, 0.10 and 0.20 mg/kg bw groups, administered IV doses
of diazepam, were conducted to confirm that the dose of 0.2 mg was consistently
more effective than the 0.1 mg dose in reducing the amount of anesthetic required
for endotracheal intubation. Note clinical studies C-88-23, C-89-10, C-89-13
and C-89-14.
It is concluded that the 0.2
mg/kg of body weight dose of Veteeze administered by the intravenous route
is the appropriate dose to reduce the amount of a barbiturate required for
endotracheal intubation in dogs.
Clinical Studies - Pivotal
1. Study Number: C-88-23
Investigator:
Dr. Robert McLain
Addison, Illinois
A blinded, well-controlled study
was conducted in dogs to determine the amount of thiamylal required to induce
anesthesia following the intravenous use of Veteeze (diazepam) as a preanesthetic
agent. Ninety (90) dogs of various breeds, age and sex, which were surgical
candidates from routine hospital admissions, were randomly assigned by a computer-generated
schedule to treatments of 0.1, 0.2 mg/kg body weight of diazepam (as Veteeze
Injection) or sterile water placebo. Veteeze or the placebo was given 3 to
5 minutes prior to administration of thiamylal which was administered intravenously
until endotracheal intubation was possible. The amount of thiamylal required
for satisfactory endotracheal intubation was measured. Animals were monitored
for drug effect on heart rate, respiratory rate and levels of depression,
anger and aggression.
Results were as follows:
(Eds. note: The following
table consists of 4 columns.)
Thiamylal Reduction Following Diazepam Administration - 90 Dog Study
Diazepam Thiamylal % Reduction of
No. of Dogs (mg/kg b.w.) (mg/kg b.w.) Thiamylal vs. Control
30 0.2 7.77 28
30 0.1 8.8 18.6
30 0.0 10.81 -
No adverse reactions or behavioral
changes were noted during the course of the study. It is concluded that Veteeze
(diazepam) as a preanesthetic agent is effective at the dose of 0.2 mg/kg bw
in reducing the amount of barbiturate required for endotracheal intubation.
2. Study Number: C-89-10
Investigator:
Dr. Michael Aronsohn
Boston, Massachusetts
A blinded, well-controlled study
was conducted in 90 dogs following the same study protocol as described in
the previous summary (C-88-23).
Results were as follows comparing
controls to 0.1 and 0.2 mg/kg diazepam treated groups:
(Eds. note: The following
table consists of 4 columns.)
Thiamylal Reduction Following Diazepam Administration - 90 Dog Study
Diazepam Thiamylal % Reduction of
No. of Dogs (mg/kg b.w.) (mg/kg b.w.) Thiamylal vs. Control
30 0.2 12.95 12.3
30 0.1 13.7 7.2
30 0.0 14.76 -
Adverse reactions were recorded
for 7 dogs; three in each of the treatment groups and one in the placebo group.
The reactions reported were not life-threatening and are generally expected
reactions noted in dogs undergoing surgical procedures. Reactions reported varied
from hyperexcitability, nausea, vomiting or retching and excessive salivation.
These occurred post-operatively in all dogs. No adverse reactions were reported
in the other three studies. It is concluded that Veteeze (diazepam) as a preanesthetic
agent is effective at the dose of 0.2 mg/kg bw in reducing the amount of barbiturate
required for endotracheal intubation.
3. Study Number: C-89-13
Investigator:
Dr. Robert Gordon
Oakland, New Jersey
A blinded, well-controlled study
was conducted in 30 dogs following the same study protocol as described for
studies C-89-23 and C-89-10.
Results were as follows:
(Eds. note: The following
table consists of 4 columns.)
Thiamylal Reduction Following Diazepam Administration - 30 Dog Study
Diazepam Thiamylal % Reduction of
No. of Dogs (mg/kg b.w.) (mg/kg b.w.) Thiamylal vs. Control
10 0.2 8.16 24
10 0.1 9.95 7
10 0.0 10.70 -
No adverse reactions or behavioral
changes were noted during the course of the study. It is concluded that Veteeze
(diazepam) as a preanesthetic agent is effective as the dose of 0.2 mg/kg bw
in reducing the amount of barbiturate required for endotracheal intubation.
4. Study Number: C-89-14
Investigator:
Dr. Thomas Mulligan
San Diego, California
A blinded, well-controlled study
was conducted in 28 dogs following the same study protocol as described for
the previous studies, C-88-23, C-89-10, and C-89-13.
Results were as follows:
(Eds. note: The following
table consists of 4 columns.)
Thiamylal Reduction Following Diazepam Administration - 28 Dog Study
Diazepam Thiamylal % Reduction of
No. of Dogs (mg/kg b.w.) (mg/kg b.w.) Thiamylal vs. Control
10 0.2 9.89 22
9 0.1 11.97 6
9 0.0 12.73 -
No adverse reactions or behavioral
changes were noted during the course of the study. It is concluded that Veteeze
(diazepam) as a preanesthetic agent is effective at the dose of 0.2 mg/kg bw
in reducing the amount of barbiturate required for endotracheal intubation.
Statistical analyses of the pooled
data from the four studies showed that the average 20% reduction in thiamylal
use is significant (P < .017).
(Eds. note: The following
table consists of 5 columns.)
Study Placebo 0.1 mg/kg 0.2 mg/kg Decrease from placebo
1 10.8 8.8 7.8 -3.0 (27.8%)
2 14.8 13.7 12.9 -1.9 (12.8%)
3 10.7 10.0 8.2 -2.5 (23.4%)
4 12.7 12.0 9.9 -2.8 (22%)
Pooled 12.3 11.0 9.7 -2.6 (21%)
A summary of the amount of thiamylal
used within various age groups are presented in Table 1. The results consistently
showed that there was no treatment effect on the physiological variables, leading
to the conclusion that Veteeze has no effect on body temperature, heart rate
or respiratory rate. Only one significant difference (change in depression score
to an increase in the 0.2 mg group) was observed and no treatment effect was
observed on anger or vocalization. A summary of the distribution of ages, and
of the procedures performed, by center, are presented in Tables 2 and 3, respectively.
(Eds. note: The following table consists of 7 columns.)
TABLE 1
Four Center Summary
Thiamylal Usage By Treatment (Veteeze vs Placebo) and by Age
--------VETEEZE-------- --------PLACEBO--------
SUMMARY BY # DOGS THIAMYLAL % Reduction # DOGS THIAMYLAL % Increase
AGE from amount over amount
of thiamylal of thiamylal
used in used in
Placebo Veteeze
Group Group
All Dogs 80 10.0 mg/kg (-20.0) 80 12.5 mg/kg (+25.0)
avg. avg.
2 years & 37 11.2 mg/kg (-17.8) 33 13.3 mg/kg (+18.7)
under avg. avg.
3 to 6 years 17 10.0 mg/kg (-20.6) 17 12.6 mg/kg (+12.6)
of age avg. avg.
Over 6 years 25 8.6 mg/kg (-23.7) 25 11.3 mg/kg (+31.4)
of age avg. avg.
Under 6 years 54 10.8 mg/kg (-17.6) 50 13.1 mg/kg (+21.3)
of age avg. avg.
(Eds. note: The following table
consists of 11 columns.)
TABLE 2
SUMMARY
Age Distribution by Center
NEW JERSEY CALIFORNIA ILLINOIS MASSACHUSETTS TOTAL*
AGE V P V P V P V P V P
Under 1 3 4 5 2 4 12 6
2 3 3 2 3 8 7 13 16 26 29
3 2 2 2 1 1 5 2 10 5
4 1 2 1 1 2 1 1 4 5
5 1 5 1 2 5
6 1 2 4 1 1 2 7
7 1 3 2 1 4 3
8 2 1 3 2 1 2 5 6
9 2 1 3 4 6 4
10 4 4 0
11 2 0 2
12 1 1 1 2 1
13 * 1 2 1 2 2
older
TOTAL* 10 10 10 9 29 28 30 28 79 75
*May not total exact numbers used in study(s), information was missing from some case reports.
(Eds. note: The following table
consists of 11 columns.)
TABLE 3
SUMMARY
Procedure Distribution by Center
NEW JERSEY CALIFORNIA ILLINOIS MASSACHUSETTS TOTAL*
V P V P V P V P V P
Spay 2 3 1 3 6 9 17 12 26 27
Dental 2 6 4 7 6 1 4 16 14
Castration 3 4 5 5 8 4 16 13
Orthopedics 2 1 2 6 4 7
Tumor 2 5 4 2 5 8
X-Ray 1 2 2 3 1 3 6
Other 2 1 3 3 2 2 1 10 4
TOTAL* 10 10 10 9 30 30 30 30 80 79
*May not total exact numbers used in study(s), information was missing from some case reports.
Four-week Intravenous
Toxicity Study in Dogs with Diazepam Solutions
Investigator:
B. Schlappi
Hoffmann-La Roche Inc.
Toxicology Department
Basle, Switzerland
The purpose of the study was
to compare the tolerance in dogs to commercial injectable diazepam that:
(1) had been stored under optimal conditions; (2) had been heat stressed;
or (3) contained added principal degradation products.
Four dogs (2 male, 2 female)
were assigned to each treatment group and were injected intravenously with
1 mL Veteeze (5 mg diazepam)/kg daily for a period of 30 days.
Group 1: Control group (sterile
saline)
Group 2: Injectable diazepam (fresh or optimally stored)
Group 3: Injectable diazepam (not optimally stored - heat stressed)
Group 4: Injectable diazepam (degradation products added)
Monitoring activities included
daily weighing and observations, hematology, serum chemistries, urinalysis,
ophthalmologic exams, ECG, autopsies and histology.
In all three groups treated
with injectable diazepam, the same type and degree of findings were noted,
principally:
A minimal increase in bilirubin
(control mean 0.08, treated groups 0.11 mg/100 ml), cholesterol (control
mean 126, treated groups 208 mg/100 ml) and ALT (SGPT-control 21, treated
groups 28)
A moderate to marked increase
of alkaline phosphatase. Dogs in control group levels were 111 and group
2 had increased levels up to 416 U/L
Increased liver weights were observed
in the treated groups. On an absolute basis the mean liver weight of the control
dogs was 325 gms vs 434 for the medicated dogs. Adjusting for differences
in average body weights of each group, the relative increase (i.e. gms liver/kg
body weight) was approximately 15%.
Intracanalicular cholestatsis was
observed more often in the treated groups.
Ataxic gait and sedation were
observed for approximately three hours after injection, mainly during the
first experimental week. An increase in appetite was also observed in treated
animals. From day 16 of the study onward, subcutaneous injections were necessary
in some of the dogs in groups 1, 2, and 3 because of hardening of the vessels
from continuous intravenous injections. Hematology, urinalysis, ophthalmology
and ECG findings were within normal limits.
This 30-day dosing at 25 times
the approved level confirms the safety of the preanesthetic dose of 0.2
mg a.i./kg b.w. of injectable diazepam in the dog (a.i. means active ingredient).
Acute Toxicity Studies for
Injectable Diazepam and the Diazepam Vehicle in Dogs
Investigator:
D. Hane
Hoffman-La Roche Inc.
Toxicology Department
Nutley, New Jersey
The purpose of the study was
to evaluate and compare the acute toxicity of injectable diazepam and of
the diazepam vehicle in dogs.
Sixteen beagle dogs, (two of
each sex per test group), received four intravenous injections of diazepam
(2 mg a.i./mL) or the vehicle given at 2-3 day intervals.
All dogs survived the 0.15,
0.5, 1.5, and 5 mL/kg intravenous doses of injectable diazepam (2 mg a.i./mL),
equivalent to 0.3, 1.0, 3.0, and 10 mg/kg of the active ingredient, or 0.15,
0.5, 1.5, and 5 mL/kg doses of the vehicle. Transient ataxia and general
decrease in motor activity occurred following administration of diazepam.
Emesis occurred in one dog each at 0.5, 1.5, and 5 mL/kg doses of diazepam
and at the highest dose, 5 mL/kg, of the vehicle. A transient decrease in
motor activity occurred in one dog receiving 5 mL/kg of the vehicle. Increases
occurred in serum glutamic pyruvic transaminase (control/baseline of 31
IU/L to 46 IU/L in the 10 mg/kg group) and alkaline phosphatase values (control/baseline
of 67 IU/L to 334 IU/L in the 10 mg/kg group) of diazepam-treated animals
compared to their own baseline values and compared to vehicle-treated controls.
Other changes (urea nitrogen predose of 12 mg/dL to 16 mg/dL in the 10 mg/kg
group) in serum clinical chemistry values of both diazepam- and vehicle-dosed
dogs were not considered biologically significant. In the dogs receiving
vehicle intravenously, salivation, licking, emesis and decreased motor activity
occurred following the 1.5 and 5 ml/kg doses. An increase in glucose values
was noted at 8 and 15 days after the final dose of vehicle (glucose from
110 mg/dL in the control to 124 mg/dL in the 10.0 mg/kg group and in the
vehicle group).
The final administration of
diazepam was 50 times (10 mg/kg body weight I.V.) the preanesthetic dosage
of 0.2 mg/kg body weight I.V. All dogs survived the doses and the 15-day
observation period following the four incremental administrations of injectable
diazepam or vehicle, which affirms the safety of Veteeze in dogs.
Acute Toxicity of Diazepam
Injectable in Dogs
Investigators:
W. Pool
D. Suckow
Hoffman-La Roche Inc.
Toxicology Department
Nutley, New Jersey
The purpose of the study was
to determine the drug tolerance of diazepam administered intravenously to
dogs. Three dogs each (weighing 8-11 kg) were injected with either 5, 10,
or 20 mg diazepam/kg b.w. as a single dose.
Diazepam at 5 and 10 mg/kg
I.V. produced ataxia and sedation, while 20 mg/kg I.V. produced hypnosis
for 30-60 minutes. All dogs survived and were considered normal by 48 hours
postdosing.
Three out of three dogs surviving
a dose 100 times (i.e., 20 mg/kg b.w., I.V.) the preanesthetic dose of diazepam
(0.2 mg/kg b.w., I.V.) reaffirms the safety of diazepam in dogs.
Toxicity of Diazepam in
Dogs by Repeated Intravenous Doses
Investigator:
R. E. Bagdon
Hoffman-La Roche Inc.
Pharmacology Department
Nutley, New Jersey
The purpose of the study was
to evaluate the tolerance of dogs to repeated injections of diazepam (5
mg a.i./mL) with doses of 10 mg diazepam intravenously 5 days/week for four
weeks. A control group received 2 mL I.V. of the vehicle. Four dogs (2 male,
2 female) were assigned to each group. The average starting weight of the
dogs was 8.36 kg (6.7-10.2 kg). The group given 10 mg diazepam I.V. received
the equivalent of 1.1 mg of diazepam per kg of body weight.
Group 1, four dogs were administered
10 mg in 2 ml diazepam I.V. for five days for four weeks. Group 2 Controls,
two dogs were administered 2 ml of vehicle I.V. for 5 days for four weeks.
In group 1, dogs given 10 mg
of diazepam I.V., transient ataxia was observed, but they were normal within
one hour after the drug was given. Sedation was not observed in these animals.
In the control group dogs given
the vehicle, no toxic effects were observed.
The results of the hematology,
serum chemistries and urinalyses carried out before treatment and during
the 2nd and 4th experimental weeks were within the normal range.
In both the control and diazepam
treated animals, the injection sites were firm, with local fibrosis and
occasional foci of necrotic tissue and hemorrhage. Thickening of the veins
used for I.V. administration and localized irritation of the tissues surrounding
the injection sites occurred in both control and treated animals.
Following sacrifice of animals
in both groups, the animals were observed for gross pathological changes
and apart from localized irritation at the sites of injection, no evidence
of gross pathology was seen in the animals. The localized irritation did
not differ significantly between control and diazepam-treated animals, indicating
that these localized effects were produced by the injection per se.
Administration of injectable
diazepam to dogs did not result in toxic manifestations; no changes in blood
counts, liver, kidney and pancreatic function were observed. No histopathological
changes, other than irritation at the injection sites, were noted.
These findings, after 20 intravenous
doses of 5 times the single preanesthetic dose of 0.2 mg/kg b.w. during
a four week period, confirm the safety of diazepam in the dog.
Toxicity of Diazepam in
Dogs by Repeated Daily 10X Doses
Investigator:
R. E. Bagdon
Hoffman-La Roche Inc.
Pharmacology Department
Nutley, New Jersey
The tolerance of four dogs
to 4 mL of either injectable diazepam (5 mg a.i./mL) administered as 10
intravenous or intramuscular injections over a period of two weeks was determined
in this study. Based on an average body weight of 10.2 kg, each dog received
10 doses of 2 mg/kg b.w. each. Following intravenous administration, both
animals displayed marked muscle relaxation, loss of righting reflex and
ataxia, which disappeared approximately 30 minutes post-dosing.
Hematology and blood chemistry
values before treatment and following the 10th injection remained within
normal ranges. Gross and histopathologic examination of organs and tissues
in the I.V. group were within normal limits when compared to controls.
The results of this study in
which the animals received 10 intravenous doses of 2 mg/kg b.w. during a
period of two weeks, i.e., each dose equivalent to 10 times the preanesthetic
dosage of 0.2 mg/kg b.w., confirms the safety of diazepam in the dog.
