ADVERSE EVENTS
ULTIVA produces adverse events that are characteristic of ยต-opioids, such as respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. These adverse events dissipate within minutes of discontinuing or decreasing the infusion rate of ULTIVA. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS on the management of these events.
Adverse event information is derived from controlled clinical trials that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease.
Adults
Approximately 2770 adult patients were exposed to ULTIVA in controlled clinical trials. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 3. Each patient was counted once for each type of adverse event.
Table 3: Adverse Events Reported in ≥1% of Adult Patients in General Anesthesia Studies
at the Recommended Doses
of ULTIVA
| Adverse Event |
Induction/Maintenance |
Postoperative Analgesia |
After Discontinuation |
ULTIVA
(n = 921) |
Alfentanil/Fentanyl
(n = 466) |
ULTIVA
(n = 281) |
Morphine
(n = 98) |
ULTIVA
(n = 929) |
Alfentanil/Fentanyl
(n = 466) |
| Nausea |
8 (<1%) |
0 |
61 (22%) |
15 (15%) |
339 (36%) |
202 (43%) |
| Hypotension |
178 (19%) |
30 (6%) |
0 |
0 |
16 (2%) |
9 (2%) |
| Vomiting |
4 (<1%) |
1 (<1%) |
22 (8%) |
5 (5%) |
150 (16%) |
91 (20%) |
| Muscle rigidity |
98 (11%)
|
37 (8%) |
7 (2%) |
0 |
2 (<1%) |
1 (<1%) |
| Bradycardia |
62 (7%) |
24 (5%) |
3 (1%) |
3 (3%) |
11 (1%) |
6 (1%) |
| Shivering |
3 (<1%) |
0 |
15 (5%) |
9 (9%) |
49 (5%) |
10 (2%) |
| Fever |
1 (<1%) |
0 |
2 (<1%) |
0 |
44 (5%) |
9 (2%) |
| Dizziness |
0 |
0 |
1 (<1%) |
0 |
27 (3%) |
9 (2%) |
| Visual disturbance |
0 |
0 |
0 |
0 |
24 (3%) |
14 (3%) |
| Headache |
0 |
0 |
1 (<1%) |
1 (1%) |
21 (2%) |
8 (2%) |
| Respiratory depression |
1 (<1%) |
0 |
19 (7%) |
4 (4%) |
17 (2%) |
20 (4%) |
| Apnea |
0 |
1 (<1%) |
9 (3%) |
2 (2%) |
2 (<1%) |
1 (<1%) |
| Pruritus |
2 (<1%) |
0 |
7 (2%) |
1 (1%) |
22 (2%) |
7 (2%) |
| Tachycardia |
6 (<1%) |
7 (2%) |
0 |
0 |
10 (1%) |
8 (2%) |
| Postoperative pain |
0 |
0 |
7 (2%) |
0 |
4 (<1%) |
5 (1%) |
| Hypertension |
10 (1%) |
7 (2%) |
5 (2%) |
3 (3%) |
12 (1%) |
8 (2%) |
| Agitation |
2 (<1%) |
0 |
3 (1%) |
1 (1%) |
6 (<1%) |
1 (<1%) |
| Hypoxia |
0 |
0 |
1 (<1%) |
0 |
10 (1%) |
7 (2%) |
In the elderly population (>65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower.
Table 4: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies
at the Recommended Doses
of ULTIVA
Adverse Event
n |
Induction/Maintenance |
Postoperative Analgesia |
After Discontinuation |
| ULTIVA |
Alfentanil/Fentanyl |
ULTIVA |
Morphine |
ULTIVA |
Alfentanil/Fentanyl |
Male
326 |
Female
595 |
Male
183 |
Female
283 |
Male
85 |
Female
196 |
Male
36 |
Female
62 |
Male
332 |
Female
597 |
Male
183 |
Female
283 |
| Nausea |
2% |
<1% |
0 |
0 |
12% |
26% |
8% |
19% |
22% |
45% |
30% |
52% |
| Hypotension |
29% |
14% |
7% |
6% |
0 |
0 |
0 |
0 |
2% |
2% |
2% |
2% |
| Vomiting |
<1% |
<1% |
0 |
<1% |
4% |
10% |
0 |
8% |
5% |
22% |
8% |
27% |
| Muscle rigidity |
17% |
7% |
14% |
4% |
6% |
1% |
0 |
0 |
<1% |
<1% |
0 |
<1% |
The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA in monitored anesthesia care are given in Table 5.
Table 5: Adverse Events Reported in ≥1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses
of ULTIVA
| Adverse Event |
ULTIVA
(n = 159) |
ULTIVA + 2 mg Midazolam
(n = 103) |
Propofol (0.5 mg/kg then 50 mcg/kg/min)
(n = 63) |
| Nausea |
70 (44%) |
19 (18%) |
20 (32%) |
| Vomiting |
35 (22%) |
5 (5%) |
13 (21%) |
| Pruritus |
28 (18%) |
16 (16%) |
0 |
| Headache |
28 (18%) |
12 (12%) |
6 (10%) |
| Sweating |
10 (6%) |
0 |
1 (2%) |
| Shivering |
8 (5%) |
1 (<1%) |
1 (2%) |
| Dizziness |
8 (5%) |
5 (5%) |
1 (2%) |
| Hypotension |
7 (4%) |
0 |
6 (10%) |
| Bradycardia |
6 (4%) |
0 |
7 (11%) |
| Respiratory depression |
4 (3%) |
1 (<1%)
|
0 |
| Muscle rigidity |
4 (3%) |
0 |
1 (2%) |
| Chills |
2 (1%) |
0 |
2 (3%) |
| Flushing |
2 (1%) |
0 |
0 |
| Warm sensation |
2 (1%) |
0 |
0 |
| Pain at study IV site |
2 (1%) |
0 |
11 (17%) |
Other Adverse Events in Adult Patients
The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below.
Event frequencies are calculated as the number of patients who were administered ULTIVA and reported an event divided by the total number of patients exposed to ULTIVA in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1883 general anesthesia, n = 609 monitored anesthesia care).
Incidence Less than 1%
Digestive:
constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, heartburn, ileus.
Cardiovascular:
various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope.
Musculoskeletal:
muscle stiffness, musculoskeletal chest pain.
Respiratory:
cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea.
Nervous:
anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.
Body as a Whole:
decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.
Skin:
rash, urticaria.
Urogenital:
urine retention, oliguria, dysuria, urine incontinence.
Infusion Site Reaction:
erythema, pruritus, rash.
Metabolic and Nutrition:
abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level.
Hematologic and Lymphatic:
anemia, lymphopenia, leukocytosis, thrombocytopenia.
The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA in cardiac surgery are given in Tables 6, 7, and 8. These tables represent adverse events collected during discrete phases of cardiac surgery. Any event should be viewed as temporally associated with drug administration and the phase indicated should not be perceived as the only time the event might occur.
Table 6: Adverse Events Reported in ≥1% of Patients in the Induction/Intubation and Maintenance Phases of Cardiac Surgery Studies at the Recommended Doses
of ULTIVA
|
| Induction/Intubation |
Maintenance |
| Adverse Event |
ULTIVA
(n = 227) |
Fentanyl
(n = 176) |
Sufentanil
(n = 41) |
ULTIVA
(n = 227) |
Fentanyl
(n = 176) |
Sufentanil
(n = 41) |
| Hypotension |
18 (8%) |
6 (3%) |
7 (17%) |
26 (11%) |
6 (3%) |
1 (2%) |
| Bradycardia |
9 (4%) |
5 (3%) |
0 |
3 (1%) |
1 (<1%) |
1 (2%) |
| Hypertension |
3 (1%) |
2 (1%) |
2 (5%) |
8 (4%) |
6 (3%) |
1 (2%) |
| Constipation |
9 (4%) |
1 (<1%) |
3 (7%) |
0 |
0 |
1 (2%) |
| Muscle rigidity |
2 (<1%) |
2 (1%) |
0 |
5 (2%) |
8 (5%) |
0 |
| Premature ventricular beats |
1 (<1%) |
0 |
0 |
3 (1%) |
1 (<1%) |
0 |
| Myocardial ischemia |
0 |
0 |
0 |
7 (3%) |
8 (5%) |
1 (2%) |
| Atrial fibrillation |
0 |
0 |
0 |
7 (3%) |
3 (2%) |
1 (2%) |
| Decreased cardiac output |
0 |
0 |
0 |
5 (2%) |
1 (<1%) |
1 (2%) |
| Tachycardia |
0 |
1 (<1%) |
0 |
4 (2%) |
2 (1%) |
0 |
| Coagulation disorder |
0 |
0 |
0 |
4 (2%) |
0 |
1 (2%) |
| Arrhythmia |
0 |
0 |
0 |
3 (1%) |
0 |
0 |
| Ventricular fibrillation |
0 |
0 |
0 |
3 (1%) |
1 (<1%) |
1 (2%) |
| Postoperative complication |
0 |
0 |
0 |
3 (1%) |
0 |
0 |
| Third degree heart block |
0 |
0 |
0 |
2 (<1%) |
0 |
1 (2%) |
| Hemorrhage |
0 |
0 |
0 |
2 (<1%) |
0 |
1 (2%) |
| Perioperative complication |
0 |
0 |
0 |
2 (<1%) |
1 (<1%) |
1 (2%) |
| Involuntary movement(s) |
0 |
0 |
0 |
2 (<1%) |
3 (2%) |
0 |
| Thrombocytopenia |
0 |
0 |
1 (2%) |
0 |
0 |
0 |
| Oliguria |
0 |
0 |
0 |
0 |
3 (2%) |
0 |
| Anemia |
0 |
0 |
0 |
2 (<1%) |
2 (1%) |
0 |
Table 7: Adverse Events Reported in ≥1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses
of ULTIVA
| Adverse Event |
ULTIVA
n = 227 |
Fentanyl
n = 176 |
Sufentanil
n = 41 |
| Hypertension |
14 (6%) |
8 (5%) |
2 (5%) |
| Hypotension |
12 (5%) |
3 (2%) |
1 (2%) |
| Tachycardia |
9 (4%) |
5 (3%) |
0 |
| Shivering |
8 (4%) |
3 (2%) |
1 (2%) |
| Nausea |
8 (4%) |
3 (2%) |
0 |
| Hemorrhage |
4 (2%) |
1 (<1%) |
1 (2%) |
| Postoperative complication |
4 (2%) |
5 (3%) |
2 (5%) |
| Agitation |
4 (2%) |
1 (<1%) |
1 (2%) |
| Ache |
4 (2%) |
0 |
0 |
| Decreased cardiac output |
3 (1%) |
0 |
0 |
| Arrhythmia |
3 (1%) |
0 |
0 |
| Muscle rigidity |
2 (<1%) |
1 (<1%) |
2 (5%) |
| Bradycardia |
2 (<1%) |
2 (1%) |
0 |
| Vomiting |
1 (<1%) |
2 (1%) |
0 |
| Premature ventricular beats |
1 (<1%) |
2 (1%) |
0 |
| Anemia |
0 |
3 (2%) |
0 |
| Somnolence |
0 |
0 |
1 (2%) |
| Fever |
0 |
2 (1%) |
0 |
Table 8: Adverse Events Reported in ≥1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses
of ULTIVA
| Adverse Event |
ULTIVA
n = 227 |
Fentanyl
n = 176 |
Sufentanil
n = 41 |
| Nausea |
90 (40%) |
63 (36%) |
16 (39%) |
| Vomiting |
33 (15%) |
26 (15%) |
3 (7%) |
| Fever |
30 (13%) |
15 (9%) |
0 |
| Atrial fibrillation |
27 (12%) |
33 (19%) |
4 (10%) |
| Constipation |
20 (9%) |
35 (20%) |
3 (7%) |
| Pleural effusion |
11 (5%) |
2 (1%) |
2 (5%) |
| Hypotension |
8 (4%) |
8 (5%) |
1 (2%) |
| Tachycardia |
9 (4%) |
15 (9%) |
0 |
| Postoperative complication |
10 (4%) |
6 (3%) |
2 (5%) |
| Oliguria |
7 (3%) |
7 (4%) |
1 (2%) |
| Confusion |
7 (3%) |
10 (6%) |
5 (12%) |
| Ache |
6 (3%) |
2 (1%) |
0 |
| Anxiety |
6 (3%) |
6 (3%) |
0 |
| Headache |
6 (3%) |
2 (1%) |
0 |
| Perioperative complication |
5 (2%) |
7 (4%) |
1 (2%) |
| Anemia |
5 (2%) |
5 (3%) |
1 (2%) |
| Agitation |
5 (2%) |
3 (2%) |
1 (2%) |
| Diarrhea |
5 (2%) |
1 (<1%) |
1 (2%) |
| Edema |
4 (2%) |
6 (3%) |
0 |
| Dizziness |
4 (2%) |
3 (2%) |
1 (2%) |
| Postoperative infection |
5 (2%) |
7 (4%) |
0 |
| Hypoxia |
4 (2%) |
5 (3%) |
0 |
| Apnea |
4 (2%) |
1 (<1%) |
1 (2%) |
| Hypertension |
3 (1%) |
3 (2%) |
0 |
| Shivering |
3 (1%) |
1 (<1%) |
0 |
| Heartburn |
3 (1%) |
3 (2%) |
0 |
| Atrial flutter |
3 (1%) |
1 (<1%) |
0 |
| Arrhythmia |
3 (1%) |
5 (3%) |
0 |
| Hallucinations |
3 (1%) |
3 (2%) |
0 |
| Pneumonia |
3 (1%) |
3 (2%) |
1 (2%) |
| Pharyngitis |
3 (1%) |
1 (<1%) |
1 (2%) |
| Decreased mental acuity |
3 (1%) |
1 (<1%) |
0 |
| Dyspnea |
3 (1%) |
1 (<1%) |
0 |
| Cough |
3 (1%) |
0 |
0 |
| Decreased cardiac output |
1 (<1%) |
0 |
3 (7%) |
| Renal insufficiency |
1 (<1%) |
5 (3%) |
0 |
| Bradycardia |
1 (<1%) |
1 (<1%) |
1 (2%) |
| Urine retention |
2 (<1%) |
3 (2%) |
0 |
| Cerebral infarction |
2 (<1%) |
2 (1%) |
1 (2%) |
| Premature ventricular beats |
2 (<1%) |
3 (2%) |
0 |
| Cerebral ischemia |
1 (<1%) |
1 (<1%) |
1 (2%) |
| Paresthesia |
2 (<1%) |
2 (1%) |
0 |
| Seizure |
2 (<1%) |
1 (<1%) |
1 (2%) |
| Sleep disorder |
1 (<1%) |
1 (<1%) |
1 (2%) |
| Bronchospasm |
1 (<1%) |
6 (3%) |
0 |
| Atelectasis |
2 (<1%) |
3 (2%) |
0 |
| Respiratory depression |
2 (<1%) |
3 (2%) |
0 |
| Pulmonary edema |
1 (<1%) |
2 (1%) |
0 |
| Respiratory distress |
2 (<1%) |
0 |
1 (2%) |
| Hyperkalemia |
2 (<1%) |
3 (2%) |
0 |
| Electrolyte disorder |
0 |
3 (2%) |
0 |
| Chest congestion |
0 |
3 (2%) |
0 |
| Hemoptysis |
0 |
2 (1%) |
0 |
| Facial ptosis |
0 |
2 (1%) |
0 |
| Hemorrhage |
0 |
2 (1%) |
0 |
| Hematuria |
0 |
1 (<1%) |
1 (2%) |
| Visual disturbance(s) |
0 |
1 (<1%) |
1 (2%) |
| Hypokalemia |
0 |
2 (1%) |
0 |
| Exacerbation of renal failure |
0 |
0 |
1 (2%) |
| Blood in stool |
0 |
0 |
1 (2%) |
| First degree heart block |
0 |
0 |
1 (2%) |
| Pericarditis |
0 |
0 |
1 (2%) |
Pediatrics
ULTIVA has been studied in 342 pediatric patients in controlled clinical trials for maintenance of general anesthesia. In the pediatric population (birth to 12 years), the most commonly reported events were nausea, vomiting, and shivering.
The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 9. Each patient was counted once for each type of adverse event. There were no adverse events ≥1% for any treatment group during the maintenance period in the pediatric patient general anesthesia studies.
Table 9: Adverse Events Reported in ≥1% of Pediatric Patients Receiving ULTIVA in General Anesthesia Studies at the Recommended Doses
of ULTIVA
|
| Recovery |
Follow-up
|
| Adverse Event |
ULTIVA
(n = 342) |
Fentanyl
(n = 103) |
Bupivacaine
(n = 86) |
ULTIVA
(n = 342) |
Fentanyl
(n = 103) |
Bupivacaine
(n = 86) |
| Vomiting |
40 (12%) |
9 (9%) |
10 (12%) |
56 (16%) |
8 (8%) |
12 (14%) |
| Nausea |
23 (8%) |
7 (7%) |
1 (1%) |
17 (6%) |
6 (6%) |
5 (6%) |
| Shivering |
9 (3%) |
0 |
0 |
0 |
0 |
0 |
| Rhonchi |
8 (3%) |
2 (2%) |
0 |
0 |
0 |
0 |
| Postoperative complication |
5 (2%) |
2 (2%) |
0 |
4 (1%) |
0 |
0 |
| Stridor |
4 (1%) |
2 (2%) |
0 |
0 |
0 |
0 |
| Cough |
4 (1%) |
1 (<1%) |
0 |
0 |
0 |
0 |
Observed During Clinical Practice
In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil.
Cardiovascular:
Asystole.
Non-Site Specific:
Anaphylactic/anaphylactoid responses, which in some cases have been severe (e.g., shock).
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