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%) |
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%) |
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 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 ≥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.
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