Mechanism Of Action
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
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.
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.
Effects On The Central Nervous
respiratory depression by direct action on brain stem respiratory centers. The
respiratory depression involves both a reduction in the responsiveness of the
brain stem respiratory centers to increases in carbon dioxide tension and to
electrical stimulation. Remifentanil causes miosis, even in total darkness.
Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g.,
pontine lesions of hemorrhagic or ischemic origins may produce similar
findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose
Effects On The Gastrointestinal Tract And Other Smooth
Remifentanil causes a reduction in motility associated
with an increase in smooth muscle tone in the antrum of the stomach and
duodenum. Digestion of food in the small intestine is delayed and propulsive
contractions are decreased. Propulsive peristaltic waves in the colon are
decreased, while tone may be increased to the point of spasm resulting in
constipation. Other opioid-induced effects may include a reduction in biliary
and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations
in serum amylase.
Effects On The Cardiovascular System
Remifentanil produces peripheral vasodilation which may
result in orthostatic hypotension or syncope. Manifestations of histamine
release and/or peripheral vasodilation may include pruritus, flushing, red eyes
and sweating and/or orthostatic hypotension. Caution must be used in
hypovolemic patients, such as those suffering acute myocardial infarction,
because remifentanil may cause or further aggravate their hypotension. Caution
must also be used in patients with cor pulmonale who have received therapeutic
doses of opioids.
Effects On The Endocrine System
Opioids inhibit the secretion of adrenocorticotropic
hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also
stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of
insulin and glucagon.
Effects On The Immune System
Opioids have been shown to have a variety of effects on
components of the immune system in in vitro and animal models. The clinical
significance of these findings is unknown. Overall, the effects of opioids
appear to be modestly immunosuppressive.
The minimum effective analgesic concentration will vary
widely among patients, especially among patients who have been previously
treated with potent agonist opioids [see DOSAGE AND ADMINISTRATION]. The
minimum effective analgesic concentration of remifentanil for any individual
patient may increase over time due to an increase in pain, the development of a
new pain syndrome and/or the development of analgesic tolerance.
ConcentrationÃ¢â¬“Adverse Reaction Relationships
There is a relationship between increasing remifentanil
plasma concentration and increasing frequency of dose-related opioid adverse
reactions such as nausea, vomiting, CNS effects, and respiratory depression. In
opioid-tolerant patients, the situation may be altered by the development of
tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION].
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.
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
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
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.
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.
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.
ULTIVA is synergistic with the
activity of hypnotics (propofol and thiopental), inhaled anesthetics, and
benzodiazepines [see Clinical Studies, WARNINGS AND PRECAUTIONS,
and DOSAGE AND ADMINISTRATION].
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].
No differences have been shown in the pharmacodynamic
activity (as measured by the EEG) of ULTIVA between men and women.
In animals the duration of muscle paralysis from succinylcholine
is not prolonged by remifentanil.
There was no change in intraocular pressure after the
administration of ULTIVA prior to ophthalmic surgery under monitored anesthesia
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
The pharmacodynamics of ULTIVA (ventilatory response to
hypercarbia) are unaltered in patients with end stage renal disease (creatinine
clearance < 10 mL/min).
The pharmacodynamics of ULTIVA (ventilatory response to
hypercarbia) are unaltered in patients with severe hepatic dysfunction awaiting
After IV doses administered over 60 seconds, the
pharmacokinetics of remifentanil fit a three-compartment model with a rapid
distribution half-life of one 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
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.
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.
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
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). Remifentanil is not metabolized by plasma
cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the
liver or lung.
The carboxylic acid metabolite
is excreted by the kidneys with an elimination half-life of approximately 90
Age: Geriatric Population
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.
Age: Pediatric Population
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.
There is no significant difference in the
pharmacokinetics of remifentanil in male and female patients after correcting
for differences in weight.
The pharmacokinetics of remifentanil and its carboxylic
acid metabolite are unchanged in patients with severe hepatic 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%.
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 Interaction Studies
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.
ULTIVA was evaluated in 3,341 patients undergoing general
anesthesia (n = 2,706) and monitored anesthesia care (n = 639). These patients
were evaluated in the following settings: inpatient (n = 2,079) which included
cardiovascular (n = 426), and neurosurgical (n = 61), and outpatient (n =
1,349). 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
The efficacy of ULTIVA was investigated in 1,562 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 = 1,562). 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 19). Overall, hypotension occurred in 5% of
patients receiving ULTIVA compared to 2% of patients receiving the other
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 19: Response to Intubation (Propofol/Opioid
|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
|a Propofol was titrated to loss of
consciousness. Not all doses of ULTIVA were equipotent to the comparator
b Differences were statistically significant (P< 0.02).
c 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 20) 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 20: Intraoperative Responsesa
|Opioid Treatment Group/(No. of Patients)
||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
||1.5-3 mcg/kg prn
|a Not all doses of ULTIVA were equipotent to
the comparator opioid.
b Differences were statistically significant (P < 0.05).
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.
In 2,169 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 WARNINGS AND 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.
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.
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 studies
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
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
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. [See CLINICAL
PHARMACOLOGY: Specific Populations: Pediatric Population and DOSAGE
AND ADMINISTRATION, Table 2]
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
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.
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
Continuation Of Analgesic Use Into The Immediate
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.
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 studies. 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
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