Ultiva Drug Information

Generic name: REMIFENTANIL HYDROCHLORIDE

Save on Ultiva at your pharmacy Compare prices near you and start saving today—no enrollment required.
See Prices

Uses of Ultiva

  • is indicated for intravenous (IV) administration:
  • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.
  • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting.
  • As an analgesic component of monitored anesthesia care in adult patients. ULTIVA is an opioid agonist indicated for intravenous administration:
  • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures. ( 1 )
  • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting. ( 1 )
  • As an analgesic component of monitored anesthesia care in adult patients. ( 1 )

Dosage & Administration of Ultiva

PhaseContinuous IV Infusion ofULTIVA (mcg/kg/min)
Induction of Anesthesia (through intubation) 0.5 – 1
Maintenance of anesthesia with:
Nitrous oxide (66%)0.4
Isoflurane (0.4 to 1.5 MAC)0.25
Propofol (100 to 200 mcg/kg/min)0.25
Continuation as an analgesic into the immediate postoperative period 0.1

Side Effects of Ultiva

  • The following serious adverse reactions are described, or described in greater detail, in other sections:
  • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ]
  • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ]
  • Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions (5.3) ]
  • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.4) ]
  • Serotonin Syndrome [see Warnings and Precautions (5.5) ]
  • Skeletal Muscle Rigidity [see Warnings and Precautions (5.7) ]
  • Bradycardia [see Warnings and Precautions (5.9) ]
  • Hypotension [see Warnings and Precautions (5.10) ]
  • Biliary Tract Disease [see Warnings and Precautions (5.13) ]
  • Seizures [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence ≥ 1%) were respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse event information is derived from controlled clinical studies 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 2,770 adult patients were exposed to ULTIVA in controlled clinical studies. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 11. Each patient was counted once for each type of adverse event. Table 11: Adverse Events Reported in ≥ 1% of Adult Patients in General Anesthesia Studies Does not include adverse events from cardiac studies or the neonatal study. See Tables 14, 15, and 16 for cardiac information. at the Recommended Doses See Table 1 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%). 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%) 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. 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 12: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies Does not include adverse events from cardiac studies or the neonatal study. at the Recommended Doses See Table 1 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. 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 13. Table 13: Adverse Events Reported in ≥ 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses See Table 3 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%). of ULTIVA Adverse Event ULTIVA (n = 159) ULTIVA + 2 mg Midazolam With higher midazolam doses, higher incidences of respiratory depression and apnea were observed. (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 = 1,883 general anesthesia, n = 609 monitored anesthesia care). Incidence Less than 1% Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, 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, 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 14, 15, and 16. 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 14: Adverse Events Reported in ≥ 1% of Patients in the Induction/Intubation and Maintenance Phases of Cardiac Surgery Studies at the Recommended Doses See Table 4 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 15: Adverse Events Reported in ≥ 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses See Table 4 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 16: Adverse Events Reported in ≥ 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses See Table 4 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 studies 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 17. 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 17: Adverse Events Reported in ≥ 1% of Pediatric Patients Receiving ULTIVA in General Anesthesia Studies at the Recommended Doses See Table 2 for recommended doses. of ULTIVA Recovery Follow-up In 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of remifentanil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular : Asystole Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in ULTIVA. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.4) ] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Warnings & Cautions for Ultiva

  • Life-Threatening Respiratory Depression : Monitor closely, particularly during initiation and titration. ( 5.2 )
  • Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or other CNS Depressants : Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines or other CNS depressants ( 5.3 )
  • Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.4 )
  • Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue ULTIVA if serotonin syndrome is suspected. ( 5.5 )
  • Administration : Continuous infusions of ULTIVA should be administered only by an infusion device. ( 5.6 )
  • Skeletal Muscle Rigidity: is related to the dose and speed of administration. Muscle rigidity induced by ULTIVA should be managed in the context of the patient's clinical condition. ( 5.7 )
  • Potential Inactivation by Nonspecific Esterases in Blood Products : ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. ( 5.8 )
  • Bradycardia : Monitor heart rate during dosage initiation and titration. It is responsive to ephedrine or anticholinergic drugs ( 5.9 )
  • Hypotension : Monitor blood pressure during dosage initiation and titration. It is responsive to decreases in the administration of ULTIVA or to IV fluids or catecholamine administration ( 5.10 )
  • Intraoperative Awareness : Inoperative awareness has been reported in patients under 55 years of age when ULTIVA has been administered with propofol infusion rates of ≤ 75 mcg/kg/min ( 5.11 )
  • Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. ( 5.12 )
  • Risks of Use in Patients with Biliary Tract Disease : Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. ( 5.13 )
  • Increased Risk of Seizures in Patients with Seizure Disorders : Monitor patients with a history of seizure disorders for worsened seizure control during ULTIVA therapy. ( 5.14 )
  • Rapid Offset of Action : Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. ( 5.15 ) 5.1 Addiction, Abuse, and Misuse ULTIVA contains remifentanil, a Schedule II controlled substance. As an opioid, ULTIVA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling ULTIVA. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. ULTIVA should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Resuscitative and intubation equipment, oxygen, and opioid antagonists must be readily available. Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of ULTIVA by 50% or by temporarily discontinuing the infusion [see Overdosage (10) ] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ULTIVA, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially when initiating therapy with and following dosage increases of ULTIVA. ULTIVA should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia care setting. Patients receiving monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure. Oxygen saturation should be monitored on a continuous basis. Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ULTIVA. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression. Monitor such patients closely including vital signs, particularly when initiating and titrating ULTIVA and when ULTIVA is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of ULTIVA are essential [see Dosage and Administration (2.11) ] . 5.3 Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants When benzodiazepines or other CNS depressants are used with ULTIVA, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of ULTIVA are employed, even relatively small dosages of diazepam may cause cardiovascular depression. When ULTIVA is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity. Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7) ] . Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ] . If the decision is made to manage postoperative pain with ULTIVA concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions (7) ] . 5.4 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3) ] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2) , Warnings and Precautions (5.2) ] . 5.5 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ULTIVA with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7) ] . This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTIVA if serotonin syndrome is suspected. 5.6 Administration Continuous infusions of ULTIVA should be administered only by an infusion device. IV bolus administration of ULTIVA should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of ULTIVA should be administered over 30 to 60 seconds. Interruption of an infusion of ULTIVA will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia. Injections of ULTIVA should be made into IV tubing at or close to the venous cannula. Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later point in time. Failure to adequately clear the IV tubing to remove residual ULTIVA has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing. 5.7 Skeletal Muscle Rigidity Skeletal muscle rigidity can be caused by ULTIVA and is related to the dose and speed of administration. ULTIVA may cause chest wall rigidity (inability to ventilate) after single doses of > 1 mcg/kg administered over 30 to 60 seconds, or after infusion rates > 0.1 mcg/kg/min. Single doses < 1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of ULTIVA. Muscle rigidity induced by ULTIVA should be managed in the context of the patient's clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications and can be treated by decreasing the rate or discontinuing the infusion of ULTIVA or by administering a neuromuscular blocking agent. The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. Muscle rigidity seen during the use of ULTIVA in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of ULTIVA. Resolution of muscle rigidity after discontinuing the infusion of ULTIVA occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered. 5.8 Potential Inactivation by Nonspecific Esterases in Blood Products ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. 5.9 Bradycardia Bradycardia has been reported with ULTIVA and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate. 5.10 Hypotension Hypotension has been reported with ULTIVA and is responsive to decreases in the administration of ULTIVA or to IV fluids or catecholamine (ephedrine, epinephrine, norepinephrine, etc.) administration. 5.11 Intraoperative Awareness Intraoperative awareness has been reported in patients under 55 years of age when ULTIVA has been administered with propofol infusion rates of ≤ 75 mcg/kg/min. 5.12 Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTIVA may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure in spontaneously breathing patients. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTIVA. Opioids may also obscure the clinical course in a patient with a head injury. 5.13 Risks of Use in Patients with Biliary Tract Disease The remifentanil in ULTIVA may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.14 Increased Risk of Seizures in Patients with Seizure Disorders The remifentanil in ULTIVA may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ULTIVA therapy. 5.15 Rapid Offset of Action Analgesic activity will subside within 5 to 10 minutes after discontinuation of administration of ULTIVA. However, respiratory depression may continue in some patients for up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to the discontinuation of ULTIVA.

Drug Interactions with Ultiva

  • Table 18 includes clinically significant drug interactions with ULTIVA. Table 18: Clinically Significant Drug Interactions with ULTIVA Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. Patients should be advised to avoid alcohol for 24 hours after surgery [see Warnings and Precautions (5.3) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.5) ] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ULTIVA if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.5) ] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. If urgent use of ULTIVA is necessary, use test doses and frequent titration of small doses while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of ULTIVA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of ULTIVA and/or precipitate withdrawal symptoms. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Consider discontinuing ULTIVA if patient is not responding appropriately to treatment and institute alternative analgesic treatment. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine
  • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : May reduce the analgesic effect of ULTIVA and/or precipitate withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. ( 7 )

Pregnancy Safety for Ultiva

Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with remifentanil hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, reduced fetal rat body weight and pup weights were reported at 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours.

There were no malformations noted when remifentanil was administered via bolus injection to pregnant rats or rabbits during organogenesis at doses approximately 5 times and approximately equal, respectively, to a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. ULTIVA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.

Opioid analgesics, including ULTIVA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data Human Data In a human clinical trial, the average maternal remifentanil concentrations were approximately twice those seen in the fetus. In some cases, however, fetal concentrations were similar to those in the mother. The umbilical arteriovenous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.

Animal Data Pregnant rats were treated from Gestation Day 6 to 15 with intravenous remifentanil doses of 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced fetal weights were reported in the high dose group; however, no malformations were reported in surviving fetuses despite a non-dose dependent increase in maternal mortality. Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day (0.09, 0.4, or 0.7 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). No malformations were reported in surviving fetuses despite clear maternal toxicity (decreased food consumption and body weights and increased mortality in all treatment groups). Pregnant rats were treated from Gestation Day 6 to Lactation Day 21 with intravenous boluses of remifentanil 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity (increased mortality in all groups).

Pediatric Use of Ultiva

Pediatric Use The efficacy and safety of ULTIVA as an analgesic agent for use in the maintenance of general anesthesia in outpatient and inpatient pediatric surgery have been established in controlled clinical studies in pediatric patients from birth to 12 years . 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 N 2 O. The clearance rate observed in neonates was highly variable and on average was 2 times higher than in the young healthy adult population. Therefore, while a starting infusion rate 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.

ULTIVA has not been studied in pediatric patients for use as a postoperative analgesic or as an analgesic component of monitored anesthesia care.

Contraindications for Ultiva

  • is contraindicated:
  • For epidural or intrathecal administration due to the presence of glycine in the formulation [see Nonclinical Toxicology (13) ] .
  • In patients with hypersensitivity to remifentanil (e.g., anaphylaxis) [see Adverse Reactions (6.2) ] . ULTIVA is contraindicated:
  • For epidural or intrathecal administration due to the presence of glycine in the formulation. ( 4 )
  • In patients with hypersensitivity to remifentanil (e.g., anaphylaxis). ( 4 )

Overdosage Information for Ultiva

Clinical Presentation Acute overdose with remifentanil can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated.

Cardiac arrest or arrhythmias will require advanced life-support measures. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to remifentanil overdose, stop the infusion or administer an opioid antagonist.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to remifentanil overdose. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered.

If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Clinical Studies of Ultiva

Induction and Maintenance of General Anesthesia - Inpatient/Outpatient

The efficacy of ULTIVA was investigated in 1,562 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 ED 90 were compared to recommended doses (approximately ED 50 ) of alfentanil or fentanyl.

Induction of Anesthesia ULTIVA was administered with isoflurane, propofol, or thiopental for the induction of anesthesia (n = 1,562). 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 19). 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 19: Response to Intubation (Propofol/Opioid Induction Propofol was titrated to loss of consciousness. Not all doses of ULTIVA were equipotent to the comparator opioid. ) 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 1 0.1 1 (3%) 0 27 (77%) ULTIVA 1 0.4 3 (9%) 0 11 (31%) Differences were statistically significant ( P < 0.02). Alfentanil 20 1.0 2 (6%) 0 26 (74%) Study 2: ULTIVA 1 0.5 9 (8%) 5 (4%) 17 (15%) Alfentanil 25 1.0 6 (5%) 5 (4%) 33 (28%) Study 3: ULTIVA 1 0.5 2 (1%) 4 (3%) 25 (19%) Alfentanil 20 2.0 0 0 19 (29%) Study 4: ULTIVA 1 0.2 11 (11%) 2 (2%) 35 (36%) ULTIVA 2 Initial doses greater than 1 mcg/kg are not recommended. 0.4 11 (12%) 2 (2%) 12 (13%) Fentanyl 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 (ED 90 ) of ULTIVA resulted in fewer responses to intraoperative stimuli (see Table 20) 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 20: Intraoperative Responses Not all doses of ULTIVA were equipotent to the comparator opioid. 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 0.1 0 20 (57%) 33 (94%) 6 (17%) ULTIVA Nitrous oxide 0.4 0 3 (9%) Differences were statistically significant ( P < 0.05). 12 (34%) 2 (6%) Alfentanil 1.0 0 24 (69%) 33 (94%) 12 (34%) Study 2: ULTIVA Isoflurane + 0.25 35 (30%) 9 (8%) 66 (57%) 19 (16%) Alfentanil Nitrous oxide 0.5 12 (10%) 20 (17%) 85 (72%) 25 (21%) Study 3: ULTIVA Propofol 0.5 3 (2%) 14 (11%) 70 (52%) 25 (19%) Alfentanil 2.0 2 (3%) 21 (32%) 47 (71%) 13 (20%) Study 4: ULTIVA 0.2 13 (13%) 12 (12%) 67 (68%) 7 (7%) ULTIVA Isoflurane 0.4 16 (18%) 4 (4%) 44 (48%) 3 (3%) Fentanyl 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 2,169 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 . 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 studies 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 N 2 O. 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. 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 PaCO 2 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 . 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 ). No adverse cerebrovascular effects were seen in this study .

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. 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 studies. 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 (SPO 2 < 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.

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

Ready to save on Ultiva?

Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.

Compare Ultiva Prices