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 (see Figure 1).
Figure 1: Recovery of Respiratory Drive After Equipotent*
Doses of ULTIVA and Alfentanil Using CO2-Stimulated Minute Ventilation
in Adult Volunteers (±1.5 SEM)
*Equipotent refers to level of respiratory depression.
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; N2O < propofol
< isoflurane (see Clinical Trials: Recovery).
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.
Drug Interactions: In animals the duration of muscle paralysis
from succinylcholine is not prolonged by remifentanil.
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; see Figure 2) 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-[(1oxopropyl)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 (see Figure 2). 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.
Figure 2: Mean Concentration (sd) versus Time
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: Pediatrics: In pediatric patients, 5 days
to 17 years of age (n = 47), the clearance and volume of distribution of remifentanil
were increased in younger children and declined to young healthy adult values
by age 17. The average clearance of remifentanil in neonates (less than 2 months
of age) was approximately 90.5 ±36.8 mL/min/kg (mean ±SD) while in adolescents
(13 to 16 years) this value was 57.2 ±21.1 mL/min/kg. The total (steady-state)
volume of distribution in neonates was 452 ±144 mL/kg versus 223 ±30.6 mL/kg
in adolescents. The half-life of remifentanil was the same in neonates and adolescents.
Clearance of remifentanil was maintained at or above normal adult values in
patients 5 days to 17 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.
Drug Interactions: Remifentanil clearance is not altered by concomitant
administration of thiopental, isoflurane, propofol, or temazepam during anesthesia.
In vitro studies with atracurium, mivacurium, esmolol, echothiophate,
neostigmine, physostigmine, and midazolam revealed no inhibition of remifentanil
hydrolysis in whole human blood by these drugs.
Clinical Trials
ULTIVA was evaluated in 3341 patients undergoing general anesthesia (n = 2706)
and monitored anesthesia care (n = 639). These patients were evaluated in the
following settings: inpatient (n = 2079) which included cardiovascular (n =
426), and neurosurgical (n = 61), and outpatient (n = 1349). Four-hundred and
eighty-six (486) elderly patients (age range 66 to 90 years) and 410 pediatric
patients (age range birth to 12 years) 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.
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) |
1 |
0.1 |
1 (3%) |
0 |
27 (77%) |
| ULTIVA (35) |
1 |
0.4 |
3 (9%) |
0 |
11 (31%) |
| Alfentanil (35) |
20 |
1.0 |
2 (6%) |
0 |
26 (74%) |
| Study 2: |
| ULTIVA (116) |
1 |
0.5 |
9 (8%) |
5 (4%) |
17 (15%) |
| Alfentanil (118) |
25 |
1.0 |
6 (5%) |
5 (4%) |
33 (28%) |
| Study 3: |
| ULTIVA (134) |
1 |
0.5 |
2 (1%) |
4 (3%) |
25 (19%) |
| Alfentanil (66) |
20 |
2.0 |
0 |
0 |
19 (29%) |
| Study 4: |
| ULTIVA (98) |
1 |
0.2 |
11(11%)† |
2 (2%) |
35 (36%) |
| ULTIVA (91) |
2‡ 0.4 |
11 |
(12%)† 2 |
(2%) 12 |
(13%) |
| Fentanyl (97) |
3 |
NA |
1 (1%) |
1 (1%) |
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) |
|
0.1 |
0 |
20 (57%) |
33 (94%) |
6 (17%) |
| ULTIVA (35) |
Nitrous oxide |
0.4 |
0 |
3 (9%)† |
12 (34%) |
2 (6%) |
| Alfentanil (35) |
|
1.0 |
0 |
24 (69%) |
33 (94%) |
12 (34%) |
| Study 2: |
| ULTIVA (116) |
Isoflurane + |
0.25 |
35 (30%)† |
9 (8%)† |
66 (57%) |
19 (16%) |
| Alfentanil (118) |
Nitrous oxide |
0.5 |
12 (10%) |
20 (17%) |
85 (72%) |
25 (21%) |
| Study 3: |
| ULTIVA (134) |
Propofol |
0.5 |
3 (2%) |
14 (11%)† |
70 (52%) |
25 (19%) |
| Alfentanil (66) |
|
2.0 |
2 (3%) |
21 (32%) |
47 (71%) |
13 (20%) |
| Study 4: |
| ULTIVA (98) |
|
0.2 |
13 (13%) |
12 (12%)† |
67 (68%) |
7 (7%) |
| ULTIVA (91) |
Isoflurane |
0.4 |
16 (18%)† |
4 (4%)† |
44 (48%) |
3 (3%) |
| Fentanyl (97) |
|
1.5-3 mcg/kg prn |
7 (7%) |
32 (33%) |
84 (87%) |
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 for maintenance of general
anesthesia in 410 pediatric patients from birth to 12 years undergoing inpatient
and outpatient procedures. Four clinical trials have been performed.
Study 1, an open-label, randomized, controlled clinical trial (n = 129), compared
ULTIVA (n = 68) with alfentanil (n = 19), isoflurane (n = 22), or propofol (n
= 20) 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).
Study 2, a double-blind, randomized, controlled trial (n = 222), compared ULTIVA
(n = 119) to fentanyl (n = 103) in children 2 to 12 years of age undergoing
tonsillectomy with or without adenoidectomy. After induction of anesthesia,
patients received a 0.25 mcg/kg/min infusion of ULTIVA or fentanyl by IV bolus
with nitrous oxide/oxygen (2:1) and either halothane or sevoflurane for maintenance
of anesthesia. The mean infusion rate required during maintenance of anesthesia
was 0.3 mcg/kg/min (range 0.2 to 1.3 mcg/kg/min). The continuous infusion rate
was decreased to 0.05 mcg/kg/min approximately 10 minutes prior to the end of
surgery. Time to spontaneous purposeful movement was a median of 8 minutes (range
1 to 19 minutes). Time to extubation was a median of 9 minutes (range 2 to 19
minutes).
Study 3, an open-label, randomized, controlled trial (n = 271), compared ULTIVA
(n = 185) with a regional anesthetic technique (n = 86) in children 1 to 12
years of age undergoing major abdominal, urological, or orthopedic surgery.
Patients received a 0.25 mcg/kg/min infusion of ULTIVA following a 1.0 mcg/kg
bolus or bupivacaine by epidural infusion, along with isoflurane and nitrous
oxide after the induction of anesthesia. The mean infusion rate required during
maintenance of anesthesia was 0.25 mcg/kg/min (range 0 to 0.75 mcg/kg/min).
Both treatments were effective in attenuating responses to skin incision during
surgery. The hemodynamic profile of the ULTIVA group was consistent with an
opioid-based general anesthetic technique. Time to spontaneous purposeful movement
was a median of 15 minutes (range, 2 to 75 minutes) in the remifentanil group.
Time to extubation was a median of 13 minutes (range, 4 to 31 minutes) in the
remifentanil group.
Study 4, an open-label, randomized, controlled trial (n=60), compared ULTIVA
(n = 38) with halothane (n = 22) in ASA 1 or 2, full term neonates and infants
8 weeks of age weighing at least 2500 grams who were undergoing pyloromyotomy.
After induction of anesthesia, which included the administration of atropine,
patients received 0.4 mcg/kg/min of ULTIVA or 0.4% halothane with 70% nitrous
oxide for initial maintenance of anesthesia and then both agents were adjusted
according to clinical response. Bolus doses of 1 mcg/kg administered over 30
to 60 seconds were used to treat brief episodes of hypertension and tachycardia,
and infusion rates were increased by 50% to treat sustained hypertension and
tachycardia. The range of infusion rates of ULTIVA required during maintenance
of anesthesia was 0.4 to 1 mcg/kg/min. [Seventy-one percent (71%) of Ultiva
patients required supplementary boluses or rate increases from the starting
dose of 0.4 mcg/kg/min to treat hypertension, tachycardia, movement or somatic
signs of light anesthesia. Twenty-four percent of the patients required an increase
from the initial rate of 0.4 mcg/kg/min prior to incision and 26% of patients
required an infusion rate between 0.8 and 1.0 mcg/kg/min, most often during
gastric manipulation. The continuous infusion rate was decreased to 0.05 mcg/kg/min
approximately 10 minutes before the end of surgery. In the ULTIVA group, median
time from discontinuation of anesthesia to spontaneous purposeful movement was
6.5 minutes (range, 1 to 13 minutes) and median time to extubation was 8.5 minutes
(range, 1 to 14 minutes). The initial maintenance infusion regimen of Ultiva
evaluated in pediatric patients from birth to 2 months of age was 0.4 mcg/kg/min,
the approved adult regimen for use with N2O. The clearance rate observed in
the neonatal population was highly variable and on average was two times higher
than in the young healthy adult population. Therefore, while a starting infusion
of 0.4 mcg/kg/min may be appropriate for some neonates, an increased infusion
rate may be necessary to maintain adequate surgical anesthesia, and additional
bolus doses may be required. The individual dose for each patient should be
carefully titrated. (See CLINICAL PHARMACOLOGY: Special Populations:
Pediatric Patients, and DOSAGE AND ADMINISTRATION,
Table 11).
No pediatric patients receiving ULTIVA required naloxone during the immediate
postoperative recovery period.
Coronary Artery Bypass Surgery: ULTIVA was originally administered to
225 subjects undergoing elective CABG surgery in two dose-ranging studies without
active comparators. Subsequently, two double-blind, double-dummy clinical studies
(N = 426) evaluated ULTIVA (n = 236) at recommended doses versus active comparators
(n = 190).
The first comparator study, a multi-center, randomized, double-blind, double-dummy,
parallel-group study (N = 369), compared ULTIVA (n = 201) with fentanyl (n =
168) in adult patients undergoing elective CABG surgery. Subjects received 1
to 3-mg midazolam and 0.05-mg/kg morphine IV as premedication. Anesthesia was
induced with propofol 0.5 mg/kg (higher doses administered with ULTIVA were
associated with excessive hypotension) over one minute plus 10-mg boluses every
10 seconds until loss of consciousness followed by either cisatracurium 0.2
mg/kg or vecuronium 0.15 mg/kg. Patients randomized to ULTIVA received a 1 mcg/kg/min
infusion of ULTIVA followed by a placebo bolus administered over 3 minutes.
In the active control group, a placebo IV infusion was started and a fentanyl
bolus 10 mcg/kg was administered over 3 minutes. All subjects received isoflurane
titrated initially to end tidal concentration of 0.5%. During maintenance, the
group randomized to ULTIVA received as needed 0.5-1 mcg/kg/min IV rate increases
(to a maximum of 4 mcg/kg/min) of ULTIVA and 1 mcg/kg IV boluses of ULTIVA.
The active control group received 2 mcg/kg IV boluses of fentanyl and increases
in placebo IV infusion rate.
The second comparator study, a multi-center, double-blind, randomized, parallel
group study (N = 57), compared ULTIVA (n = 35) to fentanyl (n = 22) in adult
patients undergoing elective CABG surgery with poor left ventricular function
(ejection fraction < 0.35). Subjects received oral lorazepam 40 mcg/kg as
premedication. Anesthesia was induced using etomidate until loss of consciousness,
followed by a low-dose propofol infusion (3 mg/kg/hr) and pancuronium 0.15 mg/kg.
Subjects in the group administered ULTIVA received a placebo bolus dose and
a continuous infusion of ULTIVA 1 mcg/kg/min and subjects in the fentanyl group
received a bolus loading dose of 15 mcg/kg and placebo continuous infusion.
During maintenance, supplemental bolus doses of ULTIVA (0.5 mcg/kg) and infusion
rate increases of 0.5 to 1 mcg/kg/min (maximum rate allowed was 4 mcg/kg/min)
of ULTIVA were administered to one group; while the fentanyl group was given
intermittent maintenance bolus doses of 2 mcg/kg and increases in the placebo
infusion rate.
In these two studies, using a high dose opioid technique with ULTIVA as a component
of a balanced or total intravenous anesthetic regimen, the remifentanil regimen
effectively attenuated response to maximal sternal spread generally better than
the dose and regimen studied for the active control (fentanyl). While this provides
evidence for the efficacy of remifentanil as an analgesic in this setting, caution
must be exercised in interpreting these results as evidence of superiority of
remifentanil over the active control, since these studies did not make any attempt
to evaluate and compare the optimal analgesic doses of either drug in this setting.
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 and3.5 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 0.05 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 8 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 (SPO2 < 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.
Last updated on RxList: 5/23/2008