Download Simbadol Technical Monograph

SIMBADOL™ (buprenorphine injection)
Technical Monograph
1
Give SIMBADOL today for 24-hour surgical
pain control­— even through the night
T he first and only buprenorphine
FDA approved for cats
emonstrated safety and efficacy in
D
more than 200 cats treated with SIMBADOL
Convenient 10 mL
multidose vial
Up to 3 once-daily subcutaneous doses
for a total of 72 hours of pain control
Dosing: 0.24 mg/kg
Concentration: 1.8 mg/mL
First dose is given
approximately 1 hour
before surgery
INDICATION: SIMBADOL is indicated for the control of postoperative pain associated with surgical procedures in cats.
IMPORTANT SAFETY INFORMATION
WARNINGS, PRECAUTIONS and CONTRAINDICATIONS: Due to serious human safety and abuse concerns,
including physical or psychological dependence, life-threatening respiratory depression and additive CNS
depressant effects, read the full prescribing information before using this drug, including the complete
Boxed Warning. Not for use in humans. Hospital staff should be trained in the handling of potent opioids
and should avoid accidental exposure. For subcutaneous (SQ) injectable use in cats. Opioid excitation has been
observed up to 8 hours after anesthetic recovery. Use with caution in cats with impaired hepatic function. SIMBADOL
has not been evaluated in breeding, pregnant, or lactating cats, in cats younger than 4 months of age or moribund cats.
Do not use in cats with known hypersensitivity to buprenorphine hydrochloride or any of the components of SIMBADOL,
or known intolerance to opioids.
See attached full Prescribing Information, including the complete Boxed
Warning for human safety and adverse reactions.
2
Table of Contents
Preface...................................................................................... 4
Target Animal Safety Study........................................................ 5
Clinical Efficacy (Soft Tissue)...................................................... 7
Clinical Efficacy (Orthopedic).................................................... 10
Blood Pressure Study............................................................... 13
Full Prescribing Information..................................................... 15
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SIMBADOL™ (buprenorphine injection)
Technical Monograph – Preface
According to the AVMA, at least one cat lives in 30% of all households in the United States. With an estimated population
of 74.1 million, cats are America’s number one pet, outnumbering dogs by over 4 million.1
Most cats will need an analgesic for acute pain at some time during their life
At some point in their life, most cats will be at risk of suffering from acute pain. Regardless of the cause, veterinarians have a duty
to prevent and treat pain. Historically, cats have been undertreated for pain because of some unique challenges they pose. Some
barriers to feline pain management include recognizing and assessing pain, a lack of species specific data, fear of adverse drug
effects, difficulty in administering drugs and a lack of products approved for use. The development of new pain assessment tools
based on the unique nuances of feline behavior2 makes assessment more objective and is increasing our awareness of pain in this
species. The approval by the FDA of SIMBADOL may help veterinarians break down some of the barriers to treatment and improve
our ability to provide the surgical pain control that cats deserve.
Opioids are integral to the management of acute pain
Opioids are the cornerstone of effective pain treatment in veterinary medicine.3 However, the timing of administration and duration
of action of opioids are important for pain treament.4 Opioids are often given as with other anesthetic premeds prior to surgery,
but their duration of action must continue past the completion of surgery and into the healing phase to provide satisfactory patient
comfort.5,6 Many of the concerns that have surrounded the use of opioids in cats in the past have been dispelled and we can now
include this class of drug in the top drawer of our feline tool box with confidence. Opioids have been widely studied in cats and we
continue to improve our understanding of its benefits.
SIMBADOL overcomes some of the challenges associated with medicating cats
Intravenous access is not always readily available and repeated intramuscular injections are painful and often resented by cats.
SIMBADOL is given subcutaneously, once-daily every 24 hours (with the first dose given approximately one hour before surgery),
allowing you to provide around the clock comfort to feline patients for up to 3 days.
SIMBADOL is the first FDA approved buprenorphine for cats. Veterinarians can use SIMBADOL with confidence, knowing that it has
proven clinical efficacy and a team of technical and veterinary professionals for support.
Sheilah A. Robertson, BVMS (Hons), PhD,
DACVAA, DECVAA, DACAW, DECAWBM (WSEL),
Specialist in Welfare Science, Ethics and Law, MRCVS
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1 . U.S. pet ownership Statistics; avma.org. 2012 2. Brondani JT, Luna SP, Padovani CR. Refinement and initial validation of
a multidimensional composite scale for use in assessing acute postoperative pain in cats. Am J Vet Res. 2011;72(2):174183. 3. Grimm K, Tranquilli W, Lamont L, eds. Essentials of Small Animal Anesthesia and Analgesia; 2nd ed. Hoboken, NJ:
Wiley-Blackwell, 2011:99. 4. Lascelles BD, et al. Central sensitization as a result of surgical pain: investigation of the preemptive value of pethidine for ovariohysterectomy in the rat. Pain. 1995;62(2):201-212. 5. Woolf CJ. Central sensitization:
implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-15. 6. Gurney MA. Pharmacological options
for intra-operative and early postoperative analgesia: an update. JSAP. 2012;53,377-386.
Target Animal Safety Study†
Objective: To assess the safety of SIMBADOL™ (buprenorphine injection) when administered
subcutaneously (SQ) to young domestic shorthair cats under exaggerated use.
Study design: A total of 32 cats approximately 4 months old were randomized to 4 treatment groups with equal numbers of males
and females in each group. Once per day, cats were administered saline or SIMBADOL 0.24, 0.72, 1.20 mg/kg/day SQ for
9 consecutive days, representing control, 1X, 3X, and 5X the recommended dose. Cats were evaluated through behavioral responses to
injection, body weight, clinical observations, vital signs, electrocardiograms, food and water consumption, urination and defecation,
adverse event monitoring, injection site inspections, physical examinations, bleeding times, clinical pathology, necropsy, and histopathology.
Acclimation period
Study period
Observed 2x/day, conditioned to restraint ≥3x/week
Receipt
Telemetry
implanted
Study drug administered (AM) followed
by behavioral response to injection
Randomization
Study day:
-10
-2
0
1
BL Labs
Labs
PE
~2 weeks
Day -10
Vaccination status confirmed
Stool examination
Cats shaved
Injection sites marked
Eligibility assessed
Numbers assigned
Labs
-1
Day -9 to -2
C, F/W, V
2
PE
3
4
5
Labs
PE
6
PE
7
8
9
BL
Labs
PE
PE
Days -1 through 9:
Adverse event monitoring, C/PE, and V: twice daily except once on day 9
Body weight, F/W, and urination/defecation: daily
Injection site inspections at 1, 4, and 12 hours following dose administration on
study day 0; at 1 and 6 hours following dose administration during study days
1-8; on study day 9 at approximately the same time of day as the first inspection
on study day 8.
BL=bleeding time; C=clinical observations; F/W=food/water intake
Labs=CBC with differential, coagulation, chemistry, urinalysis
PE=detailed physical examination
V=heart and respiration rate, temperature, blood pressure, ECG
Treatment Groups
†
Multiple of Recommended Dose
Number of Cats
Test Article
0
4 males, 4 females
Sterile saline
1x
4 males, 4 females
0.24 mg/kg/day SIMBADOL
3x
4 males, 4 females
0.72 mg/kg/day SIMBADOL
5x
4 males, 4 females
1.20 mg/kg/day SIMBADOL
Data on file. SIMBADOL Target Animal Safety Study, 09-06-WR-D-TS-BP. Zoetis Inc.
5
Results: In this 9 day safety study, all 32 cats survived to study termination. SIMBADOL™ (buprenorphine injection)-related clinical
observations included difficulty in handling, lower incidence of urination, abnormal oral dryness, dilated pupils, and decreased
pupillary light reflex. The incidence of temperatures ≥103°F was higher in the SIMBADOL groups compared to the control group. The
highest temperature observed in the SIMBADOL group was 103.8°F in a 5X cat.
One 1X cat and one 3X cat experienced an episode of hyperactivity, difficulty in handling, slight disorientation, agitation, dilated
pupils (which were responsive to light), and respiratory sinus arrhythmia. One 1X cat (one episode) and one 3X cat (three episodes)
were reported with nystagmus. One 1X and one 3X cat were reported with decreased blink response (one episode). Three cats in the
5X group lost body weight (79 g or less) during the study which correlated with decreased food consumption. All other cats gained
weight during the study.
The incidence of “moderate responses” (minor vocalization or wincing and quick resolution) and “severe responses” (tried to bite
or scratch or had marked vocalization or persistent attention to the injection site) to injection was higher in the SIMBADOL groups
compared to the control group.
Respiratory rate, heart rate, and blood pressure were similar between all groups, including the control group.
SIMBADOL-related clinical pathology findings included an increase in creatine kinase values in the 3X and 5X groups and correlated
with subcutaneous inflammation at the injection sites.
Conclusion: This study demonstrated an adequate safety margin to support the use of 0.24 mg/kg
for the control of postoperative pain associated with surgical procedures in cats.
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Clinical Efficacy (Soft Tissue)‡
Objective: To evaluate the efficacy and safety of SIMBADOL™ (buprenorphine injection) for the
control of post-operative pain in cats undergoing soft tissue surgery.
Study design: This was a randomized, double-blind, placebo-controlled, parallel group study conducted at 19 sites in the
United States. Eligible cats were randomized to SIMBADOL 0.24 mg/kg (n = 109) or placebo (n = 112), which were administered SQ
approximately 1 hour before surgery and then every 24 hours for 2 more days. Protocol-specified premedication and anesthetic
procedures were limited to nonanalgesic agents to reduce variability and minimize effects confounding pain assessment. Cats
were assessed by trained professionals at baseline and during recovery up to 72 hours using a sedation, excitement, and pain
assessment system. Cats with inadequate pain control were removed from the study and administered rescue analgesia. The
primary efficacy end point was the rate of treatment success, defined as cats not requiring additional analgesia during the 72-hour
observation period. Adverse events (AEs) and safety parameters were monitored throughout the study.
Treatment period (72 hours)
SIMBADOL™ (buprenorphine injection)
0.24 mg/kg or placebo SQ
Randomization Rx 1
Rx 2
Induction
and surgery
Time point: (hours)
Rx 3
Recovery
Discharge
0
Presurgical
assessments
0.5
1
2
3
4
8
▼
▼
▼
▼
▼
C
▼ ▼
C C
12
24
28
32
48
52
56
72
▼* ▼
C* C
▼
C
▼* ▼
C* C
▼
C
▼
C
▼ (Baseline)
Postanesthetic recovery (hours)
Rescue Algorithm
The cat was withdrawn from the study and meloxicam 0.1 mg/kg SQ was
administered. Monitoring continued until the cat was considered comfortable.
* = Assessed immediately before drug administration
C = Clinical observations (vital signs, inspection of injection and
incision sites, appetite, urination, and defecation)
Rx = Study drug administration
▼ = Sedation, excitation, and pain assessment
If pain still evident after 1 hour, hydromorphone 0.3 mg/kg SQ was
administered as needed.
In cases of extreme pain, meloxicam 0.1 mg/kg SQ and hydromorphone
0.3 mg/kg SQ were administered concurrently.
If pain continued, the cat was treated per investigator judgment.
Sedation, Excitation, and Pain Assessment Methodology Utilized During Study
Parameter
Observation
Absent
Present
Level of discomfort
Comfortable
Mild
Moderate
Severe
Normal
Mild
Moderate
Severe
Degree of control
Well
Moderately
Poorly
Sedation and excitation
a
Pain Assessment
Behavior from a distance and
behavior during social interaction
Response to palpation
(surgical site)
Pain Assessment
Overall pain assessmentb
Does the cat need to be rescued?b
a
b
The assessor used clinical judgment to determine if the cat required rescue.
No specific score defined the need for rescue.
Euphoria was considered a sign of excitation
Not performed at baseline
‡
Data on file. Clinical Efficacy (Soft Tissue), 08-30-MC-D-CT-BP. Zoetis Inc.
7
Characteristics of Enrolled Cats
Placebo
N = 112*
SIMBADOL™ (buprenorphine injection),
(1.8 mg/mL) 0.24 mg/kg, N = 109
Neutered
28
33
Intact
6
4
Spayed
22
28
Intact
56
44
Characteristic
Gender, n
Male
Female
Age, years
Mean (SD)
4.1 (4.3)
5.0 (4.8)
2.5 (0.3 to 15)
2.0 (0.3 to 16)
3.7 (1.5)
4.2 (1.8)
Ovariohysterectomy
49
41
Lumpectomy
18
22
Perineal urethrostomy
10
7
Cystotomy
7
8
Enucleation
5
8
Herniorrhaphy
3
6
Blepharoplasty
5
3
Exploratory laparotomy
3
5
Other procedures (thyroidectomy, ear hematoma, etc.)
11
9
Median (range)
Mean weight, kg (SD)
Type of Surgery, n
*Total of n ≠ 112 in the placebo group; 1 patient did not undergo surgery due to an adverse event.
Results:
Treatment success in
feline soft tissue surgery
(P = 0.005)
100
Treatment Success (%)
90
80
70
71%
60
44%
50
40
30
20
10
SIMBADOL
(n = 93)
8
Placebo
(n = 102)
Adverse Reactions in the Soft Tissue Field Study
SIMBADOL™ (buprenorphine injection) (N = 109)
Adverse Reaction
Control (N = 112)
During Surgery
After Surgery
During Surgeryb
After Surgery
c
Hypotension
39 (35.8%)
29 (26.6%)
33 (29.5%)
24 (21.4%)
d
Tachycardia
26 (23.9%)
29 (26.6%)
15 (13.4%)
20 (17.9%)
Hypothermia
(≤98.0°F)
30 (27.5%)
1 (0.9%)
31 (27.7%)
0
Hyperthermia
(≥103.0°F)
0
40 (36.7%)
0
19 (17.0%)
Hypertensione
a
b
7 (6.4%)
20 (18.3%)
9 (8.0%)
6 (5.4%)
Anorexia
0
18 (16.5%)
0
15 (13.4%)
Hyperactivity
0
10 (9.2%)
0
4 (3.6%)
Reduced Oxygen
Saturation of
Hemoglobin (pulse
oximetry ≤90%)
5 (4.6%)
1 (0.9%)
8 (7.1%)
0
Bradycardia
(≤90 beats/min)
2 (1.8%)
1 (0.9%)
1 (0.9%)
0
0
3 (2.8%)
0
2 (1.8%)
1 (0.9%)
0
1 (0.9%)
0
Hyperesthesia
0
1 (0.9%)
0
0
Blindness
0
1 (0.9%)
0
0
Apnea/Death
0
1 (0.9%)
0
0
Tachypnea
(≥72 breaths/min)
Arrhythmia
a. Cats may have experienced more than one type or occurrence of an adverse reaction. Cats experiencing the same reaction both during and after surgery are
presented in both time periods.
b. During surgery is the time from the administration of the anesthetic induction agent until discontinuation of the gas anesthetic.
c. Hypotension is defined as a mean blood pressure of ≤ 60 mmHg during surgery and ≤ 90 mmHg after surgery.
d. Tachycardia is defined as a heart rate ≥ 180 beats per minute during surgery and ≥ 200 beats per minute after surgery.
e. Hypertension is defined as a mean blood pressure of ≥ 120 mmHg during surgery and ≥ 160 mmHg after surgery.
One cat with apnea in the SIMBADOL™ (buprenorphine injection) group died from the adverse reaction. The cat underwent a
necropsy and a specific cause of death was not found, although other remarkable findings included metastatic neoplasia affecting
multiple systems. One cat in the SIMBADOL group was reported with presumptive post-anesthetic cortical blindness. This cat
received blood pressure intervention during the surgery for low blood pressure. The cat regained vision within 30 days after
surgery; however, the cat continued to have some visual and balance deficits. One cat in the SIMBADOL group was euthanized after
completion of the study due to pulmonary complications. The complications were considered likely related to the severity of the cat’s
injuries prior to surgery.
Conclusions: Administration of SIMBADOL at a dose of 0.24 mg/kg once daily for three days was
effective and considered safe for the control of postoperative pain associated with soft tissue surgery
in cats.
9
Clinical Efficacy (Orthopedic)§
Objective: To evaluate the efficacy and safety of SIMBADOL™ (buprenorphine injection) for the
control of postoperative pain in cats undergoing onychectomy.
Study design: This was a randomized, double-blind, placebo-controlled, parallel group study conducted at 19 sites in the
United States. After meeting eligibility criteria, client-owned cats undergoing onychectomy with or without spay or castration were
randomized and received SIMBADOL 0.24 mg/kg (n = 115) or placebo (n = 114). Study drug was administered SQ approximately
1 hour before surgery and again at 24 and 48 hours. Nonanalgesic agents were used for premedication and anesthesia to
minimize confounding factors. A sedation, excitement, and pain assessment system was used by trained professionals at baseline
and at specific time points up to 72 hours after recovery from anesthesia. Cats considered to have insufficient pain control
were removed from the study and given rescue analgesia. The primary end point was the treatment success rate, the number of cats
completing the study without rescue at 72 hours. Safety parameters and adverse events (AEs) were recorded and summarized.
Treatment period (72 hours)
SIMBADOL™ (buprenorphine injection)
0.24 mg/kg or placebo SQ
Randomization
Rx 1
Rx 2
Induction
and surgery
Time point: (hours)
Rx 3
Discharge
Recovery
0
Presurgical
assessments
0.5
1
2
3
4
8
▼
▼
▼
▼
▼
C
▼ ▼
C C
12
24
28
32
48
52
56
72
▼* ▼
C* C
▼
C
▼* ▼
C* C
▼
C
▼
C
▼ (Baseline)
Postanesthetic recovery (hours)
* = Assessed immediately before drug administration
C = Clinical observations (vital signs, inspection of injection and
incision sites, appetite, urination, and defecation)
Rx = Study drug administration
▼ = Sedation, excitation, and pain assessment
Rescue Algorithm
The cat was withdrawn from the study and meloxicam 0.1 mg/kg SQ was
administered. Monitoring continued until the cat was considered comfortable.
If pain still evident after 1 hour, hydromorphone 0.3 mg/kg SQ was
administered as needed.
In cases of extreme pain, meloxicam 0.1 mg/kg SQ and hydromorphone
0.3 mg/kg SQ were administered concurrently.
If pain continued, the cat was treated per investigator judgment.
Sedation, Excitation, and Pain Assessment Methodology Utilized During Study
Parameter
Observation
Absent
Present
Level of discomfort
Comfortable
Mild
Moderate
Severe
Normal
Mild
Moderate
Severe
Degree of control
Well
Moderately
Poorly
Sedation and excitation
a
Pain Assessment
Behavior from a distance and
behavior during social interaction
Response to palpation
(surgical site)
Pain Assessment
Overall pain assessmentb
Does the cat need to be rescued?b
a
b
10
The assessor used clinical judgment to determine if the cat required rescue.
No specific score defined the need for rescue.
Euphoria was considered a sign of excitation
Not performed at baseline
§
Data on File. Clinical Efficacy (Orthopedic), 08-31-MC-D-CT-BP. Zoetis Inc.
Characteristics of Enrolled Cats
Placebo
N = 114
SIMBADOL™ (buprenorphine injection)
(1.8 mg/mL) 0.24 mg/kg, N = 115
Neutered
36
37
Intact
19
17
Spayed
29
35
Intact
30
26
Characteristic
Gender, n
Male
Female
Age, years
Mean (SD)
Median (range)
Mean weight, kg (SD)
1.9 (1.9)
1.8 (1.8)
1.0 (0.3 to 8)
1.0 (0.3 to 10)
4.2 (1.4)
4.0 (1.3)
Results:
Treatment success in
feline orthopedic surgery†
(P = 0.002)
100
Treatment Success (%)
90
80
70
60
61%
50
32%
40
n=33
30
20
10
SIMBADOL
(n = 105)
Placebo
(n = 102)
†Orthopedic surgical procedures included onychectomy, onychectomy
and castration, or onychectomy and ovariohysterectomy.
11
Adverse Reactions in the Orthopedic Field Study
SIMBADOL™ (buprenorphine injection) (N = 115)
Adverse Reaction
Control (N = 114)
During Surgery
After Surgery
During Surgeryb
After Surgery
c
29 (25.2%)
44 (38.3%)
15 (13.2%)
24 (21.1%)
Hypotension
29 (25.2%)
22 (19.1%)
27 (23.7%)
16 (14.0%)
Hyperthermia
(≥103.0°F)
1 (0.9%)
51 (44.3%)
0
14 (12.3%)
a
Tachycardia
d
Anorexia
b
0
22 (19.1%)
0
20 (17.5%)
Hypertensione
3 (2.6%)
20 (17.4%)
8 (7.0%)
12 (10.5%)
Hypothermia
(≤98.0°F)
8 (7.0%)
0
16 (14.0%)
0
Hyperactivity
0
16 (13.9%)
0
7 (6.1%)
3 (2.6%)
0
3 (2.6%)
1 (0.9%)
Tachypnea
(≥72 breaths/min)
0
2 (1.8%)
1 (0.9%)
4 (3.5%)
Reduced Oxygen
Saturation of
Hemoglobin (pulse
oximetry ≤90%)
3 (2.6%)
0
3 (2.6%)
0
Arrhythmia
0
1 (0.9%)
1 (0.9%)
0
Blindness
0
1 (0.9%)
0
1 (0.9%)
Ataxia
0
1 (0.9%)
0
0
1 (0.9%)
0
0
0
Bradycardia
(≤90 beats/min)
Apnea/Death
a. Cats may have experienced more than one type or occurrence of an adverse reaction. Cats experiencing the same reaction both during and after surgery are
presented in both time periods.
b. During surgery is the time from the administration of the anesthetic induction agent until discontinuation of the gas anesthetic.
c. Tachycardia is defined as a heart rate ≥ 180 beats per minute during surgery and ≥ 200 beats per minute after surgery.
d. Hypotension is defined as a mean blood pressure of ≤ 60 mmHg during surgery and ≤ 90 mmHg after surgery.
e. Hypertension is defined as a mean blood pressure of ≥ 120 mmHg during surgery and ≥ 160 mmHg after surgery.
One cat with apnea in the SIMBADOL™ (buprenorphine injection) group died from the adverse reaction. The cat experienced apnea
during endotracheal intubation. The cat was healthy and a specific cause of death was not found. A cat in the SIMBADOL group and
one cat in the placebo control group were reported with presumptive post-anesthetic cortical blindness. The cat in the SIMBADOL
group received blood pressure intervention during surgery for low blood pressure. The cat in the SIMBADOL group regained vision
within 7 days after surgery and the cat in the placebo control group regained vision within 84 days after surgery.
Conclusions: Administration of SIMBADOL at a dose of 0.24 mg/kg once daily for three days was
effective and considered safe for the control of postoperative pain associated with orthopedic surgery
in cats.
12
Blood Pressure Study||
Objective: To determine the effect of SIMBADOL™ (buprenorphine injection) on arterial blood pressure
during a surgical procedure in cats.
Study design: This prospective, single-center, randomized, blinded, active control study was conducted in 16 healthy domestic
cats ≥ 4 months of age (4 males + 4 females per group). Cats were randomized to receive either a single dose of SIMBADOL
0.24 mg/kg SQ or 0.3 mg/kg meloxicam SQ, which were administered 1 hour prior to anesthetic induction. A 1-hour exploratory
laparotomy was performed. Blood pressure, heart rate, respiration rate, body temperature, electrocardiograms, end tidal carbon
dioxide, and oxygen saturation were measured at protocol-specified time points during the study. Cats were also evaluated through
physical examinations, body weights, clinical pathology, urinalysis, adverse events, and clinical observations.
Acclimation period*
Day 0
Day 1 (Study period)
Day -18 to Day -1
Rx
Induction
and surgery
Released
Extubation
Time point: hours
0.5
(Baseline assessments)
~1 hour
*Minimum 14 days
~1 hour
Physiologic
variables
recorded every
5 minutes
2
4
8
Time postextubation (hours)
Treatment Groups
Treatment Group
Number of Cats
Test Article
Route
Dose Concentration (mg/mL)
1
4 males, 4 females
SIMBADOL 0.24 mg/kg
SQ
1.8
2
4 males, 4 females
Meloxicam 0.3 mg/kg
SQ
5.0
Data on File. Blood Pressure Study, 10-41-SN-D-GLP-BP. Zoetis Inc.
||
13
Results: All 16 animals were clinically healthy for the duration of the study. There were no differences between treatment
groups in mean blood pressure during the study. During the surgery and postoperatively, heart rate was higher for the
SIMBADOL™ (buprenorphine injection) group. During surgery, the incidence of heart rates ≥ 180 beats/minute was higher in the
SIMBADOL group compared to the control group. Post-operatively, the incidence of heart rates ≥ 200 beats/minute was higher
in the SIMBADOL group compared to the control group. During surgery, respiration rate was significantly lower (p<0.10) for the
SIMBADOL group. Post-operatively, body temperature was higher for the SIMBADOL group. Four cats in the SIMBADOL group had
temperatures ≥ 103°F post-operatively compared to none in the control group. The highest temperature observed in the SIMBADOL
group was 104.3°F. Electrocardiograms were qualitatively normal in all cats. During surgery, one cat in the SIMBADOL group had
hemoglobin saturation less than 90% (88% at one point in time).
Mean arterial blood pressure over time
200
180
Buprenorphine
Meloxicam
Blood pressure (mm Hg)
160
140
120
100
80
60
40
Indirect
20
Direct
Indirect
0
BL
PI
0
5
10
15
20
BL=baseline PI=prior to induction
25
30
35
40
45
Minutes
50
55
60
65
70
75
80
85
90 <0.5 2
Endotracheal extubation
4
Hours
Time
Conclusions: Results of this study support the safe use of SIMBADOL in cats undergoing anesthesia
and surgery.
14
8
Full Prescribing Information
15
INDICATION:
4131-04-01
SIMBADOL is indicated for the control of postoperative pain associated
with surgical procedures in cats.
DOSAGE AND ADMINISTRATION:
The dosage of SIMBADOL is 0.24 mg/kg (0.11 mg/lb) administered
subcutaneously once daily, for up to 3 days. Administer the first dose
approximately 1 hour prior to surgery.
For Use in Cats Only
Simbadol
TM
(buprenorphine injection)
1.8 mg/mL
For subcutaneous use in cats
Opioid Analgesic
Do not dispense SIMBADOL for administration at home by the pet owner
(see Human Safety).
CONTRAINDICATIONS:
SIMBADOL is contraindicated in cats with known hypersensitivity to
buprenorphine hydrochloride or any of the components of SIMBADOL,
or known intolerance to opioids.
CAUTION:
Federal law restricts this drug to use by or on the order of a licensed
veterinarian.
WARNINGS:
HUMAN SAFETY WARNING
For subcutaneous (SQ) injectable use in cats.
Abuse Potential
Human Safety:
Not for use in humans. Keep out of reach of children.
SIMBADOL contains buprenorphine (1.8 mg/mL), an opioid agonist
and Schedule III controlled substance with an abuse potential
similar to other Schedule III opioids. Buprenorphine has certain
opioid properties that in humans may lead to dependence of the
morphine type. Abuse of buprenorphine may lead to physical
dependence or psychological dependence. The risk of abuse by
humans should be considered when storing, administering, and
disposing of SIMBADOL. Persons at increased risk for opioid
abuse include those with a personal or family history of substance
abuse (including drug or alcohol abuse or addiction) or mental
illness (suicidal depression).
Adult Human User Safety while handling SIMBADOL in the hospital:
Mucous membrane or eye contact during administration:
Direct contact of SIMBADOL with the eyes, oral or other mucous
membranes could result in absorption of buprenorphine and the potential
for adverse reactions. If accidental eye, oral or other mucous membrane
contact is made during administration, flush the area with water and contact
a physician.
Skin contact during administration:
If human skin is accidentally exposed to SIMBADOL, wash the exposed
areas with soap and water and contact a physician. Accidental exposure
could result in absorption of buprenorphine and the potential for adverse
reactions.
Life-Threatening Respiratory Depression
Respiratory depression, including fatal cases, may occur with
abuse of SIMBADOL.
Additive CNS Depressant Effects
SIMBADOL has additive CNS depressant effects when used with
alcohol, other opioids, or illicit drugs that cause central nervous
system depression.
Drug Abuse, Addiction, and Diversion of Opioids:
Controlled Substance:
SIMBADOL contains buprenorphine, a mu opioid partial agonist and
Schedule III controlled substance with an abuse potential similar to other
Schedule III opioids. SIMBADOL can be abused and is subject to misuse,
abuse, addiction, and criminal diversion. SIMBADOL should be handled
appropriately to minimize the risk of diversion, including restriction of access,
the use of accounting procedures, and proper disposal methods, as
appropriate to the clinical setting and as required by law.
Accidental Exposure
Because of the potential for adverse reactions associated with
accidental injection, SIMBADOL should only be administered by
veterinarians or veterinary technicians who are trained in the
handling of potent opioids.
See Human Safety for detailed information.
DESCRIPTION:
Abuse:
Abuse of SIMBADOL poses a hazard of overdose and death. This risk
is increased with concurrent abuse of alcohol and other substances
including other opioids and benzodiazepines. Buprenorphine has been
diverted for non-medical use into illicit channels of distribution. All people
handling opioids require careful monitoring for signs of abuse. Drug abuse
is the intentional non-therapeutic use of a prescription drug for its rewarding
psychological or physiological effects. Abuse of opioids can occur in the
absence of true addiction.
SIMBADOL is a clear, colorless to slightly yellow, sterile, injectable solution
intended for subcutaneous administration for use in cats. Each milliliter
of SIMBADOL contains 1.8 mg buprenorphine (equivalent to 1.94 mg
buprenorphine hydrochloride), 50 mg anhydrous dextrose, 1.8 mg
methylparaben, 0.2 mg propylparaben, 0.2 mg sodium acetate trihydrate,
0.5 mg glacial acetic acid, 100.0 mg anhydrous ethanol, water for injection,
and hydrochloric acid and/or sodium hydroxide to adjust pH.
Buprenorphine belongs to the opioid class of drugs and is a narcotic
under the Controlled Substances Act due to its chemical derivation from
thebaine. Buprenorphine hydrochloride is a weakly acidic, white or off-white
crystalline powder with limited solubility
in water. Chemically, it is
17-(cyclopropylmethyl)-α(1,1-dimethylethyl)-4, 5-epoxy18,19-dihydro-3-hydroxy6-methoxy-α-methyl-6,
14-ethenomorphinan-7-methanol,
hydrochloride [5α, 7α(S)].
Buprenorphine hydrochloride has the
molecular formula of C29H41NO4•HCl,
the molecular weight of 504.09, and
the following structural formula:
Storage and Discard:
SIMBADOL is a Class III opioid. Store in a locked, substantially constructed
cabinet according to DEA and local controlled substance guidelines. Discard
broached vials after 28 days. Any unused or expired vials must be destroyed
by a DEA registered reverse distributor; for further information, contact your
local DEA field office or call Abbott Animal Health at 1-888-299-7416.
Information for physician:
SIMBADOL injectable solution is a mu opioid partial agonist (1.8 mg
buprenorphine/mL). In the case of an emergency, provide the physician
with the package insert. Naloxone may not be effective in reversing
respiratory depression produced by buprenorphine. The onset of naloxone
effect may be delayed by 30 minutes or more. Doxapram hydrochloride
has also been used as a respiratory stimulant.
1
PRECAUTIONS:
Adverse Reactions in the Orthopedic Field Study
Hyperactivity (opioid excitation) has been observed up to 8 hours after
anesthetic recovery (see ADVERSE REACTIONS).
SIMBADOL (N = 115)
Adverse
Reactiona
Safety has not been evaluated in moribund cats (i.e., those not expected to
live more than 24 hours with or without surgery). Use in such cases should
be based on the risk-benefit assessment of the veterinarian.
Tachycardiac
Hypotension
Use with caution in cats with impaired hepatic function.
Hyperthermia
(≥103.0°F)
The use of SIMBADOL has not been evaluated in breeding, pregnant, or
lactating cats, or in cats younger than 4 months of age.
Anorexia
ADVERSE REACTIONS:
Hypertension
In two controlled field studies, a total of 450 male and female cats 4 months
to 16 years old, weighing between 2.6 – 20.0 lb were included in the field
safety analysis. In one study, cats underwent a soft tissue surgical procedure
(soft tissue). In the other study, cats underwent onychectomy, onychectomy
and castration, or onychectomy and ovariohysterectomy (orthopedic). The
following tables (one table for each study) show the number of cats exhibiting
each observation.
e
Hypothermia
(≤98.0°F)
Hyperactivity
Bradycardia
(≤90 beats/min)
Tachypnea
(≥72 breaths/min)
Adverse Reactions in the Soft Tissue Field Study
SIMBADOL (N = 109)
d
Reduced Oxygen
Saturation of
Hemoglobin (pulse
oximetry ≤90%)
Control (N = 112)
Control (N = 114)
During
Surgeryb
After
Surgery
During
Surgeryb
After
Surgery
29 (25.2%)
44 (38.3%)
15 (13.2%)
24 (21.1%)
29 (25.2%)
22 (19.1%)
27 (23.7%)
16 (14.0%)
1 (0.9%)
51 (44.3%)
0
14 (12.3%)
0
22 (19.1%)
0
20 (17.5%)
3 (2.6%)
20 (17.4%)
8 (7.0%)
12 (10.5%)
8 (7.0%)
0
16 (14.0%)
0
0
16 (13.9%)
0
7 (6.1%)
3 (2.6%)
0
3 (2.6%)
1 (0.9%)
0
2 (1.8%)
1 (0.9%)
4 (3.5%)
During
Surgeryb
After
Surgery
During
Surgeryb
After
Surgery
3 (2.6%)
0
3 (2.6%)
0
Hypotensionc
39 (35.8%)
29 (26.6%)
33 (29.5%)
24 (21.4%)
Arrhythmia
0
1 (0.9%)
1 (0.9%)
0
Tachycardiad
26 (23.9%)
29 (26.6%)
15 (13.4%)
20 (17.9%)
Blindness
0
1 (0.9%)
0
1 (0.9%)
Ataxia
0
1 (0.9%)
0
0
1 (0.9%)
0
0
0
Adverse
Reactiona
Hypothermia
(≤98.0°F)
30 (27.5%)
1 (0.9%)
31 (27.7%)
0
Hyperthermia
(≥103.0°F)
0
40 (36.7%)
0
19 (17.0%)
Hypertension
7 (6.4%)
20 (18.3%)
9 (8.0%)
6 (5.4%)
Anorexia
0
18 (16.5%)
0
15 (13.4%)
Hyperactivity
0
10 (9.2%)
0
4 (3.6%)
5 (4.6%)
1 (0.9%)
8 (7.1%)
0
e
Reduced Oxygen
Saturation of
Hemoglobin (pulse
oximetry ≤90%)
Bradycardia
(≤90 beats/min)
Tachypnea
(≥72 breaths/min)
Arrhythmia
2 (1.8%)
1 (0.9%)
1 (0.9%)
0
0
3 (2.8%)
0
2 (1.8%)
1 (0.9%)
0
1 (0.9%)
0
Hyperesthesia
0
1 (0.9%)
0
0
Blindness
0
1 (0.9%)
0
0
Apnea/Death
0
1 (0.9%)
0
0
Apnea/Death
a. Cats may have experienced more than one type or occurrence of an adverse reaction.
Cats experiencing the same reaction both during and after surgery are presented in both
time periods.
b. During surgery is the time from the administration of the anesthetic induction agent until
discontinuation of the gas anesthetic.
c. Tachycardia is defined as a heart rate ≥180 beats per minute during surgery and
≥200 beats per minute after surgery.
d. Hypotension is defined as a mean blood pressure of ≤60 mmHg during surgery and
90 mmHg after surgery.
e. Hypertension is defined as a mean blood pressure of ≥120 mmHg during surgery and
≥160 mmHg after surgery.
The two cats with apnea in the SIMBADOLTM (buprenorphine injection)
group died from the adverse reaction. The cat in the soft tissue study
underwent a necropsy and a specific cause of death was not found,
although other remarkable findings included metastatic neoplasia affecting
multiple systems. The cat in the orthopedic study experienced apnea during
endotracheal intubation. The cat was healthy and a specific cause of death
was not found.
Two cats in the SIMBADOL group and one cat in the placebo control group
were reported with presumptive post-anesthetic cortical blindness. Both
cats in the SIMBADOL group received blood pressure intervention during
surgery for low blood pressure. All cats regained vision within 7 to 84 days
after surgery; however, one cat in the SIMBADOL group continued to have
some visual and balance deficits.
a. Cats may have experienced more than one type or occurrence of an adverse reaction.
Cats experiencing the same reaction both during and after surgery are presented in both
time periods.
b. During surgery is the time from the administration of the anesthetic induction agent until
discontinuation of the gas anesthetic.
c. Hypotension is defined as a mean blood pressure of ≤60 mmHg during surgery and
≤90 mmHg after surgery.
d. Tachycardia is defined as a heart rate ≥180 beats per minute during surgery and
≥200 beats per minute after surgery.
e. Hypertension is defined as a mean blood pressure of ≥120 mmHg during surgery and
≥160 mmHg after surgery.
One cat in the SIMBADOL group in the soft tissue study was euthanized
after completion of the study due to pulmonary complications. The
complications were considered likely related to the severity of the cat’s
injuries prior to surgery.
To report suspected adverse events, for technical assistance, or to obtain
a copy of the MSDS, contact Abbott Animal Health at (888) 299-7416.
For additional information about adverse drug experience reporting
for animal drugs, contact the FDA at 1-888-FDA-VETS or online at
http://www.fda.gov/AnimalVeterinary/SafetyHealth.
2
CLINICAL PHARMACOLOGY:
ANIMAL SAFETY:
Buprenorphine is a potent, long-acting analgesic acting at opiate receptors
in the central nervous system. Buprenorphine exerts its analgesic effect via
high affinity binding to various subclasses of opiate receptors, particularly μ,
in the central nervous system.1 Buprenorphine binds to opiate receptors with
high affinity and high receptor avidity, such that its disassociation from the
receptor is slow, as demonstrated in in vitro studies. This unique property
of buprenorphine could account for its duration of activity.1
Nine-Day Target Animal Safety Study: In a 9 day safety study, 4 month
old healthy cats (4/sex/group) were administered SIMBADOL subcutaneously
at 0X (saline), 1X (0.24 mg/kg), 3X (0.72 mg/kg), or 5X (1.2 mg/kg) once
daily. All 32 cats survived to study termination.
Buprenorphine-related clinical observations included difficulty in handling,
lower incidence of urination, abnormal oral dryness, dilated pupils, and
decreased pupillary light reflex. The incidence of temperatures ≥103°F
was higher in the buprenorphine-treated groups compared to the control
group. The highest temperature observed in the buprenorphine-treated
group was 103.8°F in a 5X cat.
One 1X cat and one 3X cat experienced an episode of hyperactivity,
difficulty in handling, slight disorientation, agitation, dilated pupils (which
were responsive to light), and respiratory sinus arrhythmia. One 1X cat
(one episode) and one 3X cat (three episodes) were reported with nystagmus.
One 1X and one 3X cat were reported with decreased blink response (one
episode). Three cats in the 5X group lost body weight (79 g or less) during
the study which correlated with decreased food consumption. All other
cats gained weight during the study.
The incidence of “moderate responses” (minor vocalization or wincing and
quick resolution) and “severe responses” (tried to bite or scratch or had
marked vocalization or persistent attention to the injection site) to injection
was higher in the buprenorphine-treated groups compared to the control
group.
Respiratory rate, heart rate, and blood pressure were similar between all
groups, including the control group.
Buprenorphine-related clinical pathology findings included an increase
in creatine kinase values in the 3X and 5X groups and correlated with
subcutaneous inflammation at the injection sites.
Histologic lesions included minimal to moderate subacute inflammation at
the injection sites, which correlated with the administration of buprenorphine
compared to the control group. The incidence of inflammation was similar
between buprenorphine-treated groups; however, more sites with mild and
moderate inflammation were observed in the 5X group compared to the 1X
and 3X groups where more sites with minimal inflammation were observed.
Mineralization at an injection site was seen in one 1X and one 3X cat.
Chronic inflammation in the heart (valve or myocardium) was seen in two
5X cats. Subacute liver inflammation was seen in one control cat, two
1X cats, three 3X cats, and three 5X cats. Lymphoid hyperplasia of the
mediastinal lymph node was seen in one 1X cat, and acute inflammation
was seen in the mediastinal lymph node of one 3X cat. Lymphoid hyperplasia
of the Peyer’s Patches was seen in two 1X cats and one 5X cat. Lymphoid
hyperplasia, lymphocytic infiltrate, or subacute inflammation of the stomach
was seen in four 1X cats, four 3X cats, and three 5X cats. Subacute
inflammation or lymphocytic infiltrate of the thyroid glands was seen in
two 1X cats, one 3X cat, and four 5X cats.
Arterial Blood Pressure Study in Cats: Healthy 8.5 to 29.1 month old
cats (4/sex/group) were subcutaneously administered SIMBADOL at
0.24 mg/kg (1X) or meloxicam (control), 1 hour prior to anesthetic induction
for a 1 hour exploratory laparotomy. Arterial blood pressure was monitored
following anesthetic induction and through laparotomy, with indirect blood
pressure monitoring prior to anesthesia and for 8 hours following anesthetic
recovery. All 16 animals were clinically healthy for the duration of the study.
There were no differences between treatment groups in mean blood
pressure during the study.
During surgery and postoperatively, heart rate was higher for the
buprenorphine group. During surgery, the incidence of heart rates
≥180 beats/minute was higher in the buprenorphine-treated group
compared to the control group. Post-operatively, the incidence of
heart rates ≥200 beats/minute was higher in the buprenorphine-treated
group compared to the control group. During surgery, respiration rate
was lower for the buprenorphine group. Post-operatively, body temperature
was higher for the buprenorphine group. Four cats in the buprenorphine
group had temperatures ≥103°F post-operatively compared to none in
the control group. The highest temperature observed in the buprenorphine
group was 104.3°F. Electrocardiograms were qualitatively normal in all
cats. During surgery, one cat in the buprenorphine group had hemoglobin
saturation less than 90% (88% at one time point).
Following subcutaneous injection in cats, there is considerable inter-cat
variability in plasma concentration and pharmacokinetic parameters.2
Formulated as an immediate release product, buprenorphine is quickly
absorbed after subcutaneous injection. Pharmacological effects (e.g.,
mydriasis) may occur within minutes after injection. Buprenorphine plasma
concentrations following subcutaneous injection did not appear to correlate
to pharmacodynamics measurements (change in the thermal threshold
data). In studies with SIMBADOL analgesic effects of buprenorphine
appeared about one hour after injection with a 24 to 28 hour duration of
action. Combined pharmacokinetic and pharmacodynamic studies have
demonstrated a marked time delay between plasma concentrations and the
onset and offset of the analgesic effect which is due to the slow equilibration
between drug concentrations in the biophase and the slow association and
dissociation of drug binding to the receptor. 2,3
Buprenorphine is metabolized in the liver. The major route of excretion of
buprenorphine is in the feces. Buprenorphine undergoes oxidative metabolism
by N-dealkylation to form norbuprenorphine (an active metabolite) via
CYP3A4. Buprenorphine and norbuprenorphine subsequently form inactive
glucuronide conjugates in the intestinal wall and the liver and its metabolites
are excreted via the bile into the gastro-intestinal tract.4 The elimination
half-life in cats is reported to be similar to that associated with humans and
slower than that observed in dogs.5 It is also noted that because the cat is
devoid of uridine diphosphate glucuronosyltransferase enzymes, conjugated
metabolites may be absent.5
EFFECTIVENESS:
The effectiveness of SIMBADOL was demonstrated in two randomized,
masked, placebo-controlled, multi-site field studies involving client-owned
cats of various breeds. In one study (soft tissue), 221 cats underwent a
soft tissue surgical procedure. In the other study (orthopedic), 229 cats
underwent an onychectomy alone or in combination with castration or
ovariohysterectomy. Cats received either a subcutaneous injection of
0.24 mg/kg of SIMBADOL or physiologic saline approximately 60 minutes
prior to surgery at the same time as pre-anesthetic medication. SIMBADOL
or physiologic saline was given once daily for two additional treatments
24 and 48 hours after the initial treatment. A descriptive, interactive pain
assessment system was used by the trained assessor over the 72 hour
post-operative period to determine pain control. Treatment success was
defined as a cat that made it through the entire 72 hour period without
rescue analgesia. In the soft tissue field study, a statistically significant
difference in the proportion of treatment successes in the SIMBADOL
treatment group (66/93 or 71.0%) compared to the placebo control
group (45/102 or 44.1%) was observed. Twenty-seven out of 93 (29.0%)
SIMBADOL cases and 57 out of 102 (55.9%) placebo cases were treatment
failures. In the orthopedic field study, a statistically significant difference in
the proportion of treatment successes in the SIMBADOL treatment group
(64/105 or 61.0%) compared to the placebo control group (33/102 or
32.4%) was observed. Forty-one out of 105 (39.0%) SIMBADOL cases
and 69 out of 102 (67.6%) placebo cases were treatment failures. For both
studies, the majority of the treatment failures required rescue within 4 hours
after anesthetic recovery.
Combining both studies (450 cats), sedation was observed in 68 cats in
the buprenorphine group and 62 cats in the placebo control group for up
to 4 hours after anesthetic recovery. In both studies, during surgery, mean
respiratory rates and mean blood pressures were lower in the buprenorphine
group compared to the placebo control group. There were a higher number
of cats and a higher number of incidences of pain on injection in the
buprenorphine group (20 cats, 28 incidences) compared to the placebo
control group (8 cats, 10 incidences).
The results of two field studies demonstrate that SIMBADOL is effective and
has an acceptable safety margin for the control of postoperative pain in cats.
3
STORAGE INFORMATION:
Store at temperatures up to 25°C (77°F). Protect from light and excessive
heat (above 40°C or 104°F). Use within 28 days of first puncture.
HOW SUPPLIED:
SIMBADOL (buprenorphine injection) is supplied in a carton containing one
10 mL amber glass vial. Each multidose vial contains 1.8 mg/mL of
buprenorphine.
NADA 141-434, Approved by FDA
REFERENCES:
1. Heel RC, Brogden RN, Speight TM, et al. Buprenorphine: a review of its
pharmacological properties and therapeutic efficacy. Drugs 1979;
17:81-110.
2. Steagall PV, Pelligand L, Giordano T, et al. Pharmacokinetic and
pharmacodynamic modelling of intravenous, intramuscular and
subcutaneous buprenorphine in conscious cats. Vet Anaesth Analg
2013;40:83-95.
3. Robertson SA, Lascelles BD, Taylor PM, et al. PK-PD modeling of
buprenorphine in cats: intravenous and oral transmucosal administration.
J Vet Pharmacol Ther 2005;28:453-460.
4. Brewster D, Humphrey MJ, McLeavy MA. Biliary excretion, metabolism
and enterohepatic circulation of buprenorphine. Xenobiotica
1981;11:189-196.
5. Court MH. Feline drug metabolism and disposition: pharmacokinetic
evidence for species differences and molecular mechanisms. Vet Clin
Small Anim 2013;43:1039-1054.
SIMBADOL is a trademark of Abbott Laboratories.
Manufactured for:
Abbott Laboratories
North Chicago, IL 60064 USA
Product of United Kingdom
Text taken from SIMBADOL (buprenorphine injection) package insert,
commodity number A1-0074/R1, revised 07/2014.
4
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All trademarks are the property of Zoetis Inc., its affiliates and/or its licensors.
©2015 Zoetis Inc. All rights reserved. March 2015. SIM-00007