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Ultiva

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Ultiva

SIDE EFFECTS

Adverse Events

ULTIVA (remifentanil) 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 (remifentanil) in controlled clinical trials. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA (remifentanil) 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 (remifentanil)

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%)
*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 (remifentanil) were equipotent to the comparator opioid. Administration of ULTIVA (remifentanil) 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.

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 (remifentanil)

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%
*Does not include adverse events from cardiac studies or the neonatal study.
† See Table 10 for recommended doses. Not all doses of ULTIVA (remifentanil) were equipotent to the comparator opioid.

The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA (remifentanil) 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 (remifentanil)

Adverse Event ULTIVA
(n = 159)
ULTIVA + 2 mg Midazolam† Propofol
(n = 103)
(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%)
* See Table 12 for recommended doses. Administration of ULTIVA (remifentanil) 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.

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 (remifentanil) and reported an event divided by the total number of patients exposed to ULTIVA (remifentanil) 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 (remifentanil) 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 (remifentanil)

Adverse Event Induction/Intubation Maintenance
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
*See Table 13 for recommended doses.

Table 7: Adverse Events Reported in 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses* of ULTIVA (remifentanil)

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
*See Table 13 for recommended doses.

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 (remifentanil)

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%)
*See Table 13 for recommended doses.

Pediatrics: ULTIVA (remifentanil) 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 (remifentanil) 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 (remifentanil) in General Anesthesia Studies at the Recommended Doses* of ULTIVA (remifentanil)

Adverse Event ULTIVA
(n = 342)
Recovery
Fentanyl
(n = 103)
Bupivacaine
(n = 86)
ULTIVA
(n = 342)
Follow-up**
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
*See Table 11 for recommended doses.
**In subjects receiving halothane (n=22), 10 (45%) experienced vomiting.

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 (remifentanil) is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and has the potential for being abused.

Read the Ultiva (remifentanil) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No information provided. See Drug Interactions under CLINICAL PHARMACOLOGY

Last reviewed on RxList: 5/23/2008
This monograph has been modified to include the generic and brand name in many instances.

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