A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Ultiva Pharmacology, Pharmacokinetics, Studies, Metabolism - Remifentanil
Ultiva Pharmacology, Pharmacokinetics, Studies, Metabolism - Remifentanil
CLINICAL PHARMACOLOGY
ULTIVA is a µ-opioid agonist
with rapid onset and peak effect, and short duration
of action. The µ-opioid activity
of ULTIVA is antagonized by opioid
antagonists such as naloxone.
Unlike other opioids, ULTIVA is rapidly metabolized by hydrolysis
of the propanoic acid-methyl ester
linkage by nonspecific
blood and tissue esterases.
ULTIVA is not a substrate
for plasma cholinesterase
(pseudocholinesterase) and, therefore, patients with atypical
cholinesterase
are expected to have a normal
duration of action.
Pharmacodynamics
The analgesic effects
of ULTIVA are rapid in onset and offset. Its effects and side
effects are dose dependent
and similar to other µ-opioids. ULTIVA in humans has a rapid
blood-brain equilibration
half-time of 1±1 minutes (mean ±SD) and a rapid onset
of action. The pharmacodynamic effects of ULTIVA closely follow
the measured blood concentrations,
allowing direct correlation
between dose, blood levels,
and response. Blood concentration decreases 50% in 3 to 6 minutes
after a 1-minute infusion
or after prolonged continuous infusion
due to rapid distribution
and elimination
processes and is independent of duration
of drug administration.
Recovery from the effects of ULTIVA occurs rapidly (within 5 to
10 minutes). New steady-state concentrations occur within 5 to 10
minutes after changes in infusion
rate. When used as a component
of an anesthetic
technique, ULTIVA can be rapidly titrated to the desired depth
of anesthesia/analgesia (e.g., as required by varying levels of
intraoperative
stress) by changing the continuous infusion rate
or by administering an IV
bolus injection.
Hemodynamics
In premedicated patients undergoing anesthesia,
1-minute infusions of <2 mcg/kg of ULTIVA cause
dose-dependent hypotension
and bradycardia. While additional doses >2 mcg/kg (up to 30 mcg/kg)
do not produce any further decreases in heart
rate or blood
pressure, the duration
of the hemodynamic change is increased in proportion to the blood
concentrations achieved. Peak hemodynamic effects occur within 3
to 5 minutes of a single dose of ULTIVA or an infusion
rate increase. Glycopyrrolate,
atropine, and vagolytic
neuromuscular
blocking agents attenuate
the hemodynamic effects associated with ULTIVA. When appropriate,
bradycardia and
hypotension can
be reversed by reduction
of the rate of infusion
of ULTIVA, or the dose of concurrent anesthetics, or by the administration
of fluids or vasopressors.
Respiration
ULTIVA depresses respiration
in a dose-related fashion. Unlike other fentanyl analogs, the duration
of action of ULTIVA at
a given dose does not increase
with increasing duration
of administration, due to lack of drug accumulation. When ULTIVA
and alfentanil were dosed to equal levels of respiratory
depression, recovery
of respiratory drive
after 3-hour infusions was more rapid and less variable
with ULTIVA.
Spontaneous respiration
occurs at blood concentrations
of 4 to 5 ng/mL in the absence
of other anesthetic
agents; for example, after discontinuation of a 0.25-mcg/kg/min
infusion of remifentanil,
these blood concentrations
would be reached in 2 to 4 minutes. In
patients undergoing general anesthesia, the rate
of respiratory recovery
depends upon the concurrent anesthetic; N20 < propofol
< isoflurane.(see CLINICAL TRIALS: Recovery
below)
Muscle Rigidity
Skeletal muscle rigidity
can be caused by ULTIVA and is related to the dose and speed of
administration. ULTIVA may cause
chest wall
rigidity (inability to ventilate) after single doses of >1 mcg/kg
administered over 30 to 60 seconds or infusion
rates >0.1 mcg/kg/min; peripheral muscle rigidity
may occur at lower doses. Administration of doses <1 mcg/kg may
cause chest
wall rigidity
when given concurrently with a continuous infusion of ULTIVA. Prior
or concurrent administration
of a hypnotic (propofol
or thiopental) or a neuromuscular
blocking agent
may attenuate the
development of muscle
rigidity. Excessive muscle
rigidity can be treated
by decreasing the rate
or discontinuing the infusion
of ULTIVA or by administering a neuromuscular blocking
agent.
Histamine Release: Assays of histamine
in patients and normal volunteers have shown no
elevation in plasma
histamine levels after
administration of ULTIVA in doses up to 30 mcg/kg over 60 seconds.
Analgesia: Infusions of 0.05 to 0.1 mcg/kg/min, producing
blood concentrations of 1 to 3 ng/mL, are typically associated with
analgesia with minimal
decrease in respiratory
rate. Supplemental doses of 0.5 to 1 mcg/kg, incremental increases
in infusion rate
>0.05 mcg/kg/min, and blood concentrations exceeding 5 ng/mL
(typically produced by infusions of 0.2 mcg/kg/min) have been associated
with transient and
reversible respiratory
depression, apnea, and
muscle rigidity.
Anesthesia: ULTIVA is synergistic
with the activity of
hypnotics (propofol and thiopental), inhaled anesthetics, and benzodiazepines
(see CLINICAL TRIALS, PRECAUTIONS,
and DOSAGE AND ADMINISTRATION).
Age: The pharmacodynamic activity
of ULTIVA (as measured by the EC50 for development
of delta waves on the
EEG) increases with increasing age. The EC50 of remifentanil
for this measure was 50% less in patients over 65 years of age
when compared to healthy volunteers (25 years of age) (see DOSAGE
AND ADMINISTRATION).
Gender: No
differences have been shown in the pharmacodynamic activity (as
measured by the EEG) of ULTIVA between men and women.
Intraocular Pressure: There was no
change in intraocular pressure after the administration
of ULTIVA prior to ophthalmic
surgery under monitored anesthesia
care.
Cerebrodynamics: Under isoflurane-nitrous oxide
anesthesia (PaCO2 <30 mmHg), a 1-minute infusion
of ULTIVA (0.5 or 1.0 mcg/kg) produced no
change in intracranial
pressure. Mean arterial
pressure and cerebral perfusion
decreased as expected with opioids. In
patients receiving ULTIVA and nitrous
oxide anesthesia,
cerebrovascular
reactivity to carbon
dioxide remained intact.
In humans, no
epileptiform activity
was seen on the EEG (n =
44) at remifentanil doses up to 8 mcg/kg/min.
Renal Dysfunction: The pharmacodynamics
of ULTIVA (ventilatory response to hypercarbia) are unaltered in
patients with end stage
renal disease (creatinine clearance
<10 mL/min).
Hepatic Dysfunction: The pharmacodynamics
of ULTIVA (ventilatory response to hypercarbia) are unaltered in
patients with severe hepatic dysfunction awaiting liver
transplant.
Pharmacokinetics
After IV doses administered
over 60 seconds, the pharmacokinetics
of remifentanil fit a three-compartment
model with a rapid distribution
half-life of 1 minute, a slower distribution
half-life of 6 minutes,
and a terminal elimination half-life
of 10 to 20 minutes. Since the terminal
elimination component contributes less than 10% of the overall area
under the concentration versus time
curve (AUC), the effective
biological half-life
of ULTIVA is 3 to 10 minutes. This is similar to the 3- to 10-minute
half-life measured
after termination
of prolonged infusions (up to 4 hours) and correlates with recovery
times observed in the clinical
setting after infusions up to 12 hours. Concentrations of remifentanil
are proportional to the dose administered throughout the recommended
dose range. The pharmacokinetics
of remifentanil are unaffected by the presence of renal
or hepatic impairment.
Distribution: The initial
volume of distribution
(Vd ) of remifentanil is approximately 100 mL/kg and
represents distribution throughout the blood
and rapidly perfused tissues. Remifentanil subsequently distributes
into peripheral tissues
with a steady-state volume
of distribution of approximately 350 mL/kg. These two distribution
volumes generally correlate with total body
weight (except in severely
obese patients when they
correlate better with ideal
body weight
[IBW]). Remifentanil is approximately 70% bound to plasma
proteins of which two-thirds is binding to alpha-1-acid-glycoprotein.
Metabolism: Remifentanil is an esterase-metabolized
opioid. A labile ester
linkage renders this
compound susceptible
to hydrolysis by nonspecific
esterases in blood and
tissues. This hydrolysis
results in the production
of the carboxylic acid
metabolite (3-[4-methoxycarbonyl-4-[(1-oxopropyl)
phenylamino]-1-piperidine]propanoic acid), and represents the principal
metabolic pathway for
remifentanil (> 95%). The carboxylic acid
metabolite is essentially inactive (1/4600 as potent
as remifentanil in dogs) and is excreted by the kidneys with an
elimination half-life
of approximately 90 minutes. Remifentanil is not metabolized by
plasma cholinesterase
(pseudocholinesterase) and is not appreciably metabolized by the
liver or lung.
Elimination: The clearance
of remifentanil in young, healthy adults is approximately 40 mL/min/kg.
Clearance generally correlates with total body
weight (except in severely
obese patients when it
correlates better with IBW). The high clearance
of remifentanil combined with a relatively small volume
of distribution
produces a short elimination
half-life of approximately
3 to 10 minutes. This value
is consistent with the time
taken for blood or effect
site concentrations to
fall by 50% (context-sensitive
half-times) which is approximately 3 to 6 minutes. Unlike other
fentanyl analogs, the duration
of action does not increase
with prolonged administration.
Titration to Effect
The rapid elimination
of remifentanil permits the titration
of infusion rate without concern for prolonged duration. In
general, every 0.1-mcg/kg/min change in the IV
infusion rate
will lead
to a corresponding
2.5-ng/mL change in blood
remifentanil concentration
within 5 to 10 minutes. In
intubated patients only, a more rapid increase (within 3 to 5 minutes)
to a new steady state can be achieved with a 1.0-mcg/ kg
bolus dose
in conjunction with an infusion
rate increase.
Special Populations
Children: In
children 2 to 12 years of age
(n = 13), the blood concentrations of remifentanil after a 1-minute
infusion of 5.0 mcg/kg
were similar to those seen in adults receiving the same dose. The
pharmacokinetic parameters of remifentanil in children (volume of
distribution, clearance, and half-life) were similar to adults after
correcting for differences in weight. The pharmacokinetics
of remifentanil have not been studied in patients under 2 years
of age.
Renal Impairment: The pharmacokinetic profile
of ULTIVA is not changed in patients with end
stage renal
disease (creatinine
clearance <10 mL/min). In
anephric patients,
the half-life of the
carboxylic acid metabolite increases from 90 minutes to 30 hours.
The metabolite is
removed by hemodialysis
with a dialysis extraction
ratio of approximately
30%.
Hepatic Impairment: The pharmacokinetics
of remifentanil and its carboxylic acid
metabolite are unchanged
in patients with severe hepatic impairment.
Elderly: The clearance
of remifentanil is reduced (approximately 25%) in the elderly (>
65 years of age) compared to young adults (average 25 years of age).
However, remifentanil blood
concentrations fall as
rapidly after termination
of administration
in the elderly as in young adults.
Gender: There is no
significant difference
in the pharmacokinetics of remifentanil in male
and female patients after
correcting for differences in weight.
Obesity: There is no
difference in the pharmacokinetics of remifentanil in non-obese
versus obese (greater
than 30% over IBW) patients when normalized to IBW.
Cardiopulmonary Bypass (CPB): Remifentanil clearance
is reduced by approximately 20% during hypothermic CPB.
CLINICAL TRIALS
ULTIVA was evaluated in 2808 patients undergoing general anesthesia
(n = 2169) and monitored anesthesia
care (n = 639). These patients were evaluated in the following settings:
inpatient (n = 1573)
which included cardiovascular (n = 225), and neurosurgical (n =
61), and outpatient
(n = 1235). Three hundred seventy-seven (377) elderly patients (age
range 66 to 90 years) and 68 pediatric
patients received ULTIVA. Of the general anesthesia patients, 682
also received ULTIVA as an IV
analgesic agent during
the immediate postoperative
period.
Induction and Maintenance of General Anesthesia Inpatient/Outpatient
The efficacy of ULTIVA
was investigated in 1562 patients in 15 randomized, controlled trials
as the analgesic component
for the induction
and maintenance of general anesthesia. Eight of these studies compared
ULTIVA to alfentanil and two studies compared ULTIVA to fentanyl.
In these studies, doses of
ULTIVA up to the ED90 were compared to recommended doses
(approximately ED50) of alfentanil or fentanyl. If alfentanil
or fentanyl were administered in doses equipotent to the ED90
of ULTIVA, an intraoperative profile similar to the results below
for ULTIVA could be expected.
Induction of Anesthesia: ULTIVA was administered
with isoflurane, propofol, or thiopental for the induction
of anesthesia (n
= 1562). The majority of patients (80%) received propofol
as the concurrent agent. ULTIVA reduced the propofol
and thiopental requirements for loss of consciousness. Compared
to alfentanil and fentanyl, a higher relative dose of ULTIVA resulted
in fewer responses to intubation
(see Table 1). Overall, hypotension
occurred in 5% of patients receiving ULTIVA compared to 2% of patients
receiving the other opioids.
ULTIVA has been used as a primary
agent for the induction
of anesthesia; however, it should not be used as a sole
agent because loss
of consciousness cannot be assured and because of a high incidence
of apnea, muscle
rigidity, and tachycardia. The administration
of an induction dose
of propofol or thiopental
or a paralyzing dose of
a muscle relaxant
prior to or concurrently with ULTIVA during the induction
of anesthesia markedly
decreased the incidence of muscle
rigidity from 20% to
<1%.
Table 1: Response to Intubation (Propofol/Opioid
Induction*)
|
Opioid Treatment
Group/( No. of
Patients)
|
Initial
Dose
(mcg/kg)
|
Pre-Intubation
Infusion Rate
(mcg/kg/min)
|
No. (%)
Muscle
Rigidity
|
No. (%)
Hypotension
During Induction
|
No. (%)
Response
to Intubation
|
| Study 1:
ULTIVA (35)
ULTIVA (35)
Alfentanil (35)
|
1
1
20
|
0.1
0.4
1.0
|
1 (3%)
3 (9%)
2 (6%)
|
0
0
0
|
27 (77%)
11 (31%)
26 (74%)
|
| Study 2:
ULTIVA (116)
Alfentanil (118)
|
1
25
|
0.5
1.0
|
9 (8%)
6 (5%)
|
5 (4%)
5 (4%)
|
17 (15%)
33 (28%)
|
| Study 3:
ULTIVA (134)
Alfentanil (66)
|
1
20
|
0.5
2.0
|
2 (1%)
0
|
4 (3%)
0
|
25 (19%)
19 (29%)
|
| Study 4:
ULTIVA (98)
ULTIVA (91)
Fentanyl (97)
|
1
2
3
|
0.2
0.4
NA
|
11 (11%)
11 (12%)
1 (1%)
|
2 (2%)
2 (2%)
1 (1%)
|
35 (36%)
12 (13%)
29 (30%)
|
| *Propofol
was titrated to loss
of consciousness. Not all doses of ULTIVA were equipotent
to the comparator opioid. |
| Differences
were statistically significant (P <0.02). |
| Initial
doses greater than 1 mcg/kg are not recommended |
Use During Maintenance of Anesthesia: ULTIVA was investigated
in 929 patients in seven well-controlled general surgery
studies in conjunction with nitrous
oxide, isoflurane, or propofol
in both inpatient
and outpatient settings. These studies demonstrated that ULTIVA
could be dosed to high levels of opioid
effect and rapidly titrated
to optimize analgesia
intraoperatively without delaying or prolonging recovery.
Compared to alfentanil and fentanyl, these higher relative doses
(ED90) of ULTIVA resulted in fewer responses to intraoperative
stimuli (see Table 2) and a higher frequency
of hypotension (16%
compared to 5% for the other opioids). ULTIVA was infused to the
end of surgery,
while alfentanil was discontinued 5 to 30 minutes before the end
of surgery as recommended.
The mean final infusion
rates of ULTIVA were between 0.25 and 0.48 mcg/kg/min.
Table 2: Intraoperative Responses*
|
Opioid Treatment
Group/(No. of
Patients)
|
Concurrent
Anesthetic
|
Post-Intubation
Infusion Rate
(mcg/kg/min)
|
No. (%) With
Intraoperative
Hypotension
|
No. (%) With
Response to
Skin Incision
|
No. (%) With
Signs of Light
Anesthesia
|
No. (%) With
Response to
Skin Closure
|
| Study 1:
ULTIVA (35)
ULTIVA (35)
Alfentanil (35)
|
Nitrous oxide
|
0.1
0.4
1.0
|
0
0
0
|
20 (57%)
3 (9%)
24 (69%)
|
33 (94%)
12 (34%)
33 (94%)
|
6 (17%)
2 (6%)
12 (34%)
|
| Study 2:
ULTIVA (116)
Alfentanil (118)
|
Isoflurane +
Nitrous oxide
|
0.25
0.5
|
35 (30%)
12 (10%)
|
9 (8%)
20 (17%)
|
66 (57%)
85 (72%)
|
19 (16%)
25 (21%)
|
| Study 3:
ULTIVA (134)
Alfentanil (66)
|
Propofol
|
0.5
2.0
|
3 (2%)
2 (3%)
|
14 (11%)
21 (32%)
|
70 (52%)
47 (71%)
|
25 (19%)
13 (20%)
|
| Study 4:
ULTIVA (98)
ULTIVA (91)
Fentanyl (97)
|
Isoflurane
|
0.2
0.4
1.5-3 mcg/kg
prn
|
13 (13%)
16 (18%)
7 (7%)
|
12 (12%)
4 (4%)
32 (33%)
|
67 (68%)
44 (48%)
84 (87%)
|
7 (7%)
3 (3%)
11 (11%)
|
| *Not all doses of ULTIVA
were equipotent to the comparator opioid. |
| Differences were statistically
significant (P < 0.05). |
In three randomized, controlled studies (n = 407) during general
anesthesia, ULTIVA attenuated the signs of light
anesthesia within
a median time
of 3 to 6 minutes after bolus
doses of 1 mcg/kg with or without infusion
rate increases of 50% to 100% (up to a maximum
rate of 2 mcg/kg/min).
In an additional double-blind, randomized study (n = 103), a constant
rate (0.25 mcg/kg/min) of ULTIVA was compared to doubling the rate
to 0.5 mcg/kg/min approximately 5 minutes before the start of the
major surgical stress event. Doubling the rate
decreased the incidence
of signs of light anesthesia from 67% to 8% in patients undergoing
abdominal hysterectomy,
and from 19% to 10% in patients undergoing radical
prostatectomy. In patients
undergoing laminectomy
the lower dose was adequate.
Recovery
In 2169 patients receiving ULTIVA for periods up to 16 hours, recovery
from anesthesia was
rapid, predictable, and independent of the duration of the infusion
of ULTIVA. In the seven controlled,
general surgery studies,
extubation occurred in a median
of 5 minutes (range: -3 to 17 minutes in 95% of patients) in outpatient
anesthesia and 10
minutes (range: 0 to 32 minutes in 95% of patients) in inpatient
anesthesia. Recovery in studies using nitrous
oxide or propofol
was faster than in those using isoflurane as the concurrent anesthetic.
There was no case
of remifentanil-induced delayed respiratory
depression occurring
more than 30 minutes after discontinuation of remifentanil (see
PRECAUTIONS).
In a double-blind, randomized study, administration
of morphine sulfate
(0.15 mg/kg) intravenously 20 minutes before the anticipated end
of surgery to 98 patients did not delay recovery
of respiratory drive
in patients undergoing major surgery
with remifentanil-propofol total IV
anesthesia.
Spontaneous Ventilation Anesthesia
Two randomized, dose-ranging studies (n = 127) examined the administration
of ULTIVA to outpatients undergoing general anesthesia
with a laryngeal mask. Starting infusion
rates of ULTIVA of £0.05 mcg/kg/min
provided supplemental
analgesia while allowing
spontaneous ventilation
with propofol or isoflurane.
Bolus doses of ULTIVA during spontaneous ventilation lead
to transient periods
of apnea, respiratory
depression, and muscle
rigidity.
Pediatric Anesthesia
ULTIVA has been evaluated in one clinical
trial (n = 68) in children 2 to 12 years of age
undergoing strabismus
surgery. After induction
of anesthesia which included the administration
of atropine, ULTIVA was administered as an initial
infusion of 1 mcg/kg/min
with 70% nitrous oxide.
The infusion rate required during maintenance of anesthesia
was 0.73 to 1.95 mcg/kg/min. Time to extubation
and to purposeful movement
was a median of 10 minutes
(range 1 to 24 minutes).
Coronary Artery Bypass Surgery
In preliminary investigations of cardiac
anesthesia, ULTIVA
was administered to 217 patients undergoing elective coronary
artery bypass
graft (CABG) surgery in
two dosefinding studies without active comparators. In
both studies, patients were preloaded with fluid
to PAOP 10 to 15 mmHg and all had preoperative stroke
volume >50 mL.
In the total IV anesthesia
study (n = 132), patients received diazepam or midazolam preoperatively
and randomly received ULTIVA (1, 1.5, or 2 mcg/kg/min) plus propofol
(0.5 mg/kg followed by 50 mcg/kg/min) and muscle relaxant for the
induction and maintenance
of anesthesia. Overall response to sternotomy/maximal sternal
spread was 12% with no relationship
to dose of ULTIVA. Thirty-nine percent
(39%) of patients had treated hypotension reported as an adverse
event.
In the other study, ULTIVA (administered at initial
doses of 1, 2, 3 mcg/kg/min and then titrated to effect) was administered
to 76 patients as a sole
agent following a large
preoperative dose of lorazepam
(40 to 80 mcg/kg). Muscle rigidity
at induction occurred
in 49% of the patients. Responses at sternotomy
occurred in 22% of patients with no
relationship to dose of
ULTIVA. Most patients (75%) required intermittent
isoflurane supplementation for signs of light
anesthesia; significantly more patients in the 1-mcg/kg/min group
required isoflurane.
In both of these CABG
studies, ULTIVA was continued at a rate
of 1 mcg/kg/min in the intensive
care unit (ICU) for up
to 6 hours after surgery. The transition from ULTIVA to other analgesics
(IV morphine sulfate;
0.1 to 0.15 mg/kg) was initiated prior to extubation. This transition
usually occurred over 30 to 90 minutes with additional morphine,
midazolam, and/or propofol
administered as needed. Seventy-one percent
(71%) of patients were eligible for early (< 6 hours after entry
into the I.U. extubation.
Sixty-two percent (62%)
of eligible patients were actually extubated early (range of times
to extubation: 1.4 to 5.9 hours). The rate
of major adverse cardiac
events was 5.1% (myocardial infarction, 3.7%; ventricular
failure, 0.5%; and death
due to cardiac causes,
0.9%).
Neurosurgery
ULTIVA was administered to 61 patients undergoing craniotomy
for removal of a supratentorial
mass lesion. In
these studies, ventilation
was controlled to maintain a predicted PaCO2 of approximately
28 mmHg. In one study (n
= 30) with ULTIVA and 66% nitrous
oxide, the median time
to extubation and to patient
response to verbal
commands was 5 minutes (range -1 to 19 minutes). Intracranial pressure
and cerebrovascular
responsiveness to carbon dioxide were normal
(see CLINICAL PHARMACOLOGY
).
A randomized, controlled study compared ULTIVA (n = 31) to fentanyl
(n = 32). ULTIVA (1 mcg/kg/min) and fentanyl (2 mcg/kg/min) were
administered after induction
with thiopental and pancuronium. A similar number
of patients (6%) receiving ULTIVA and fentanyl had hypotension
during induction. Anesthesia was maintained with nitrous
oxide and ULTIVA at a
mean infusion
rate of 0.23 mcg/kg/min
(range 0.1 to 0.4) compared with a fentanyl mean
infusion rate of 0.04 mcg/kg/min (range 0.02 to 0.07). Supplemental
isoflurane was administered as needed. The patients receiving ULTIVA
required a lower mean isoflurane dose
(0.07 MAC-hours) compared with 0.64 MAC-hours for the fentanyl patients
(P = 0.04). ULTIVA was discontinued at the end
of anesthesia, whereas fentanyl was discontinued at the time
of bone flap replacement
(a median time
of 44 minutes before the end
of surgery). Median time to extubation
was similar (5 and 3.5 minutes, respectively, with ULTIVA and fentanyl).
None of the patients receiving ULTIVA required naloxone compared
to seven of the fentanyl patients (P = 0.01). Eighty-one percent
(81%) of patients receiving ULTIVA recovered (awake, alert, and
oriented) within 30 minutes after surgery
compared with 59% of fentanyl patients (P = 0.06). At
45 minutes, recovery
rates were similar (81% and 69% respectively for ULTIVA and fentanyl,
P = 0.27). Patients receiving ULTIVA required an analgesic
for headache sooner
than fentanyl patients (median of 35 minutes compared with 136 minutes,
respectively [P = 0.04] ). No
adverse cerebrovascular effects were seen in this study (see CLINICAL
PHARMACOLOGY).
Continuation of Analgesic Use into the Immediate Postoperative
Period
Analgesia with ULTIVA in the immediate
postoperative period
(until approximately 30 minutes after extubation) was studied in
401 patients in four dose-finding studies and in 281 patients in
two efficacy studies.
In the dose-finding studies,
the use of bolus doses
of ULTIVA and incremental infusion
rate increases ³0.05 mcg/kg/min
led to respiratory depression and muscle
rigidity. Bolus doses of ULTIVA to treat postoperative pain are
not recommended and incremental infusion
rate increases should not
exceed 0.025 mcg/kg/min at 5-minute intervals.
In two efficacy studies,
ULTIVA 0.1 mcg/kg/min was started immediately after discontinuing
anesthesia. Incremental infusion
rate increases of 0.025
mcg/kg/min every 5 minutes were given to treat moderate to severe
postoperative pain. In Study
1, 50% decreases in infusion
rate were made if respiratory
rate decreased below 12
breaths/min and in Study 2, the same decreases were made if respiratory
rate was below 8 breaths/min.
With this difference in criteria for infusion
rate decrease, the incidence
of respiratory depression
was lower in Study 1 (4%) than in Study 2 (12%). In both studies,
ULTIVA provided effective analgesia
(no or mild pain with respiratory
rate ³8
breaths/min) in approximately 60% of patients at mean
final infusion rates
of 0.1 to 0.125 mcg/kg/min.
Study 2 was a double-blind, randomized, controlled study in which
patients received either morphine
sulfate (0.15 mg/kg
administered 20 minutes before the anticipated end
of surgery plus 2-mg
bolus doses for supplemental
analgesia) or ULTIVA (as described above). Emergence from anesthesia
was similar between groups; median
time to extubation
was 5 to 6 minutes for both. ULTIVA provided effective analgesia
in 58% of patients compared to 33% of patients who received morphine.
Respiratory depression
occurred in 12% of patients receiving ULTIVA compared to 4% of morphine
patients. For patients who received ULTIVA, morphine sulfate
(0.15 mg/kg) was administered in divided doses 5 and 10 minutes
before discontinuing ULTIVA. Within 30 minutes after discontinuation
of ULTIVA, the percentage of patients with effective analgesia
decreased to 34%.
Monitored Anesthesia Care
ULTIVA has been studied in the monitored anesthesia
care setting in 609 patients in eight clinical
trials. Nearly all patients received supplemental oxygen in these
studies. Two early dose-finding studies demonstrated that use of
sedation as an endpoint
for titration of ULTIVA
led to a high incidence of muscle
rigidity (69%) and
respiratory depression.
Subsequent trials titrated ULTIVA to specific
clinical endpoints
of patient comfort,
analgesia, and adequate respiration
(respiratory rate >8
breaths/min) with a corresponding lower incidence
of muscle rigidity
(3%) and respiratory
depression. With doses of midazolam >2 mg
(4 to 8 mg), the dose of
ULTIVA could be decreased by 50%, but the incidence
of respiratory depression
rose to 32%.
The efficacy of a
single dose of ULTIVA (1.0
mcg/kg over 30 seconds) was compared to alfentanil (7 mcg/kg over
30 seconds) in patients undergoing ophthalmic surgery. More patients
receiving ULTIVA were pain
free at the time of the nerve
block (77% versus 44%,
P = 0.02) and more experienced nausea (12% versus 4%) than those
receiving alfentanil.
In a randomized, controlled study (n = 118), ULTIVA 0.5 mcg/kg
over 30 to 60 seconds followed by a continuous infusion
of 0.1 mcg/kg/min, was compared to a propofol
bolus (500 mcg/kg) followed
by a continuous infusion (50 mcg/kg/min) in patients who received
a local or regional anesthetic
nerve block 5 minutes
later. The incidence
of moderate or severe pain
during placement of the block
was similar between groups (2% with ULTIVA and 8% with propofol,
P = 0.2) and more patients receiving ULTIVA experienced nausea (26%
versus 2%, P < 0.001). The final mean
infusion rate
of ULTIVA was 0.08 mcg/kg/min.
In a randomized, double-blind study, ULTIVA with or without midazolam
was evaluated in 159 patients undergoing superficial
surgical procedures
under local anesthesia.
ULTIVA was administered without midazolam as a 1-mcg/kg dose
over 30 seconds followed by a continuous infusion
of 0.1 mcg/kg/min. In the
group of patients that
received midazolam, ULTIVA was administered as a 0.5-mcg/kg dose
over 30 seconds followed by a continuous infusion of 0.05 mcg/kg/min
and midazolam 2 mg was administered
5 minutes later. The occurrence of moderate or severe pain
during the local anesthetic
injection was similar between groups (16% and 20%). Other effects
for ULTIVA alone and ULTIVA/midazolam were: respiratory
depression with oxygen
desaturation (SPO 2 <90%), 5% and 2%; nausea,
8% and 2%; and pruritus,
23% and 12%. Titration of ULTIVA resulted in prompt
resolution of respiratory
depression (median 3 minutes, range
0 to 6 minutes). The final mean
infusion rate of ULTIVA
was 0.12 mcg/kg/min (range 0.03 to 0.3) for the group
receiving ULTIVA alone and 0.07 mcg/kg/min (range 0.02 to 0.2) for
the group receiving ULTIVA/midazolam.
Because of the risk
for hypoventilation, the infusion
rate of ULTIVA should be
decreased to 0.05 mcg/kg/min following placement of the local or
regional block and titrated
thereafter in increments of 0.025 mcg/kg/min at 5-minute intervals.
Bolus doses of ULTIVA administered simultaneously with a continuous
infusion of ULTIVA
to spontaneously breathing
patients are not recommended.
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