ADVERSE EVENTS
ULTIVA produces adverse events that are characteristic of µ-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 | Induction/Maintenance | Postoperative Analgesia | After Discontinuation |
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* Does not include adverse events from cardiac studies or the neonatal study. See Tables 6, 7, and 8 for cardiac information.
† See Table 10 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. Administration of ULTIVA in excess of the recommended dose (i.e., doses > 1 and up to 20 mcg/kg) resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%).
‡ Included in the muscle rigidity incidence is chest wall rigidity (5%). The overall muscle rigidity incidence is < 1% when remifentanil is administered concurrently or after a hypnotic induction agent.
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| ULTIVA | Alfentanil/
Fentanyl | ULTIVA | Morphine | ULTIVA | Alfentanil
/Fentanyl |
| Adverse Event | (n = 921) | (n = 466) | (n = 281) | (n = 98) | (n = 929) | (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 | Induction/Maintenance | Postoperative Analgesia | After Discontinuation |
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* Does not include adverse events from cardiac studies or the neonatal study.
† See Table 10 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid.
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| ULTIVA | Alfentanil/
Fentanyl | ULTIVA | Morphine | ULTIVA | Alfentanil/
Fentanyl |
Adverse
Event
n | 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) |
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* See Table 12 for recommended doses. Administration of ULTIVA in excess of the recommended infusion rate (i.e., starting doses > 0.1 mcg/kg/min) resulted in a higher incidence of some adverse events: nausea (60%), apnea (8%), and muscle rigidity (5%).
† With higher midazolam doses, higher incidences of respiratory depression and apnea were observed.
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| 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 Adults 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 |
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* See Table 13 for recommended doses.
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| 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 |
|
* See Table 13 for recommended doses.
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| 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 |
|
* See Table 13 for recommended doses.
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| 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 ** |
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* See Table 11 for recommended doses.
** In subjects receiving halothane (n=22), 10 (45%) experienced vomiting.
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| 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).
DRUG ABUSE AND DEPENDENCE
ULTIVA is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and has the potential for being abused.
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