Ultiva (Remifentanil Hydrochloride) - Side Effects and Adverse Reactions

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 DosesSee Table 13 for 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 DosesSee Table 13 for 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 See Table 13 for 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 See Table 11 for recommended doses. of ULTIVA

	Recovery			Follow-upIn subjects receiving halothane (n=22), 10 (45%) experienced vomiting.
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).