Summary of
FDA Information:
Approval Date: December 17, 1992
Freedom of
Information Summary
NADA 140-848
I. GENERAL INFORMATION:
NADA 140-848
Sponsor: Hoffman-La Roche Inc.
Nutley, NJ 07110
Generic Name: diazepam
Trade Name: VeteezeŽ Injection
Marketing Status: Rx (Schedule IV of
Controlled Substances)
II. INDICATIONS FOR USE
As a preanesthetic agent to reduce the amount barbiturate required for
short duration anesthesia in dogs.
III. DOSAGE
A. DOSAGE FORM VeteezeŽ Injection 5 mg diazepam/mL, 10-mL multiple use vial.
B. ROUTE OF ADMINISTRATION Intravenous injection.
C. RECOMMENDED DOSAGES: A single intravenous dose of
0.2 mg diazepam/kg body weight, 3-5 minutes before inducing anesthesia with a short acting barbiturate.
IV. ANIMAL EFFICACY
This NADA provides for
the use of
VeteezeŽ (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.
V. ANIMAL SAFETY
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.
VI. HUMAN SAFETY:
Data on human safety, pertaining to consumption of
drug residues in food, were
not required for
approval of this NADA.
The drug is to be labeled for
use in dogs, which
are non-food animals.
VII. AGENCY CONCLUSION
The data submitted in support of
this NADA comply with the requirements of
section 512 of
the Act and
section 514.111 of
the regulations. It demonstrates that VeteezeŽ (diazepam) Injection, when
used under
the labeled conditions of
use, is safe and
effective.
Section 512(c) (2) (F) (i) of
the Federal Food, Drug and
Cosmetic Act provides a five year period of
exclusivity to this original new animal drug which
has not been approved in any other application.
The Agency has carefully considered the potential environmental effects of
this action and
has concluded that the
action will not
have a significant impact on the human environment and
that an environmental impact statement is not required.
A Finding of
No Significant Impact for
this action has been prepared.
The drug is restricted to use by or
on the order of
a licensed veterinarian as knowledge of
veterinary anesthesia is needed for
the safe use, monitoring and
detection of
possible adverse reactions with this drug.
VIII. LABELLING
1. VeteezeŽ package label
2. VeteezeŽ carton label
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
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