2.1 Important Dosage and Administration Instructions

Monitor patients closely for respiratory depression when initiating therapy and following dosage increases with ULTIVA and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

ULTIVA is for IV use only. Continuous infusions of ULTIVA should be administered only by an infusion device. The injection site should be close to the venous cannula and all IV tubing should be cleared at the time of discontinuation of infusion.

ULTIVA should not be administered without dilution.

Consider an alternative to ULTIVA for patients taking mixed agonist/antagonist and partial agonist opioid analgesics due to reduced analgesic effect or potential withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ULTIVA if patient is not responding appropriately to treatment.

Discard unused portion.

2.2 General Anesthesia

ULTIVA is not recommended as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. ULTIVA is synergistic with other anesthetics; therefore, clinicians may need to reduce doses of thiopental, propofol, isoflurane, and midazolam by up to 75% with the coadministration of ULTIVA. The administration of ULTIVA must be individualized based on the patient's response.

2.3 Continuation as an Analgesic into the Immediate Postoperative Period Under the Direct Supervision of an Anesthesia Practitioner

Infusions of ULTIVA may be continued into the immediate postoperative period for select patients for whom later transition to longer acting analgesics may be desired.

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ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period.

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The use of bolus injections of ULTIVA to treat pain during the postoperative period is not recommended.

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When used as an IV analgesic in the immediate postoperative period, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min.

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The infusion rate may be adjusted every 5 minutes in 0.025 mcg/kg/min increments to balance the patient's level of analgesia and respiratory rate.

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Infusion rates greater than 0.2 mcg/kg/min are associated with respiratory depression (respiratory rate less than 8 breaths/min).

Due to the rapid offset of action of ULTIVA, no residual analgesic activity will be present within 5 to 10 minutes after discontinuation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care [see Clinical Studies (14)].

2.4 Analgesic Component of Monitored Anesthesia Care

It is strongly recommended that supplemental oxygen be supplied to the patient whenever ULTIVA is administered.

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ULTIVA has not been studied for use in children in monitored anesthesia care.

Single Dose

A single IV dose of 0.5 to 1 mcg/kg over 30 to 60 seconds of ULTIVA may be given 90 seconds before the placement of the local or regional anesthetic block [see Warnings and Precautions (5.6)].

Continuous Infusion

When used alone as an IV analgesic component of monitored anesthesia care, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min beginning 5 minutes before placement of the local or regional anesthetic block.

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Because of the risk for hypoventilation, the infusion rate of ULTIVA should be decreased to 0.05 mcg/kg/min following placement of the block.

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Thereafter, rate adjustments of 0.025 mcg/kg/min at 5 minute intervals may be used to balance the patient's level of analgesia and respiratory rate.

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Rates greater than 0.2 mcg/kg/min are generally associated with respiratory depression (respiratory rates less than 8 breaths/min).

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Bolus doses of ULTIVA administered simultaneously with a continuous infusion of ULTIVA to spontaneously breathing patients are not recommended.

Table 3 summarizes the recommended doses for monitored anesthesia care in adult patients, predominately ASA physical status I, II, or III.

2.5 Discontinuation

Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later time.

For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care [see Clinical Studies (14)].

2.6 Dosage Modifications in Geriatric Patients

The starting doses of ULTIVA should be decreased by 50% in elderly patients (> 65 years). ULTIVA should then be cautiously titrated to effect [see Use in Specific Populations (8.5)].

2.7 Dosage Modifications in Pediatric Patients

See Table 2 for dosing recommendations for use of ULTIVA in pediatric patients from birth to 12 years of age for maintenance of anesthesia. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 and Maintenance of Anesthesia (2.2).]

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

2.8 Dosage Modifications in Coronary Artery Bypass Surgery

Table 4 summarizes the recommended doses for induction, maintenance, and continuation as an analgesic into the ICU in adult patients, predominantly ASA physical status III or IV. To avoid hypotension during the induction phase, it is important to consider the concomitant medication regimens. [See Clinical Studies: Coronary Artery Bypass Surgery (14.5).]

2.9 Dosage Modifications in Obese Patients

The starting doses of ULTIVA should be based on ideal body weight (IBW) in obese patients (greater than 30% over their IBW) [see Use in Specific Populations (8.6)].

2.10 Dosage Modifications in Preanesthetic Medication

The need for premedication and the choice of anesthetic agents must be individualized. In clinical studies, patients who received ULTIVA frequently received a benzodiazepine premedication.

2.11 Preparation for Administration

To reconstitute solution, add 1 mL of diluent per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL.

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ULTIVA should be diluted to a recommended final concentration of 20, 25, 50, or 250 mcg/mL prior to administration (see Table 5). ULTIVA should not be administered without dilution.

Continuous IV infusions of ULTIVA should be administered only by an infusion device. Infusion rates of ULTIVA can be individualized for each patient using Table 6:

When ULTIVA is used as an analgesic component of monitored analgesia care, a final concentration of 25 mcg/mL is recommended. When ULTIVA is used for pediatric patients 1 year of age and older, a final concentration of 20 or 25 mcg/mL is recommended. Table 7 is a guideline for milliliter-per-hour delivery for a solution of 20 mcg/mL with an infusion device.

Table 8 is a guideline for milliliter-per-hour delivery for a solution of 25 mcg/mL with an infusion device.

Table 9 is a guideline for milliliter-per-hour delivery for a solution of 50 mcg/mL with an infusion device.

Table 10 is a guideline for milliliter-per-hour delivery for a solution of 250 mcg/mL with an infusion device.

2.12 Compatibility and Stability

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 by drug abusers and people with addiction disorders and are subject to criminal diversion. 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 Respiratory Depression in Spontaneously Breathing Patients

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 (CO2) 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

Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,antipsychotics, other opioids, or alcohol). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7)].

5.4 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). 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.

5.5 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.

5.6 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.

5.7 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

Bradycardia has been reported with ULTIVA and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.

5.9 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.

5.10 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.

5.11 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 CO2retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTIVA may reduce respiratory drive, and the resultant CO2 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.

5.12 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.

5.13 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.

5.14 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.

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.

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.

8.1 Pregnancy

8.2 Lactation

8.4 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 [see Clinical Studies (14.4)].

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 N2O. 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. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 and Maintenance of Anesthesia (2.2).]

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

8.5 Geriatric Use

Of the total number of subjects in clinical studies of ULTIVA, 486 were 65 and over (age range 66 to 90 years). While the effective biological half-life of remifentanil is unchanged, elderly patients have been shown to be twice as sensitive as the younger population to the pharmacodynamic effects of remifentanil. The recommended starting dose of ULTIVA should be decreased by 50% in patients over 65 years of age [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2)]. Titrate the dosage of ULTIVA slowly in geriatric patients. [See Warnings and Precautions (5.4).]

The clearance of remifentanil is reduced (approximately 25%) in the elderly (> 65 years of age) compared to young adults (average 25 years of age). However, remifentanil blood concentrations fall as rapidly after termination of administration in the elderly as in young adults.

8.6 Use in Morbidly Obese Patients

As for all potent opioids, caution is required with use in morbidly obese patients because of alterations in cardiovascular and respiratory physiology [see Dosage and Administration (2.2)].

8.7 Long-Term Use in the ICU

No data are available on the long-term (longer than 16 hours) use of ULTIVA as an analgesic in ICU patients.

9.1 Controlled Substance

ULTIVA contains remifentanil, a Schedule II controlled substance.

9.2 Abuse

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

ULTIVA contains remifentanil, a substance with a high potential for abuse similar to other opioids including fentanyl, alfentanil, sufentanil, and meperidine. ULTIVA can be abused and is subject to misuse, addiction, and criminal diversion.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

ULTIVA, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

12.1 Mechanism of Action

ULTIVA is a µ-opioid agonist with rapid onset and peak effect, and short duration of action. The µ-opioid activity of ULTIVA is antagonized by opioid antagonists such as naloxone.

Unlike other opioids, ULTIVA is rapidly metabolized by hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases. ULTIVA is not a substrate for plasma cholinesterase (pseudocholinesterase) and, therefore, patients with atypical cholinesterase are expected to have a normal duration of action.

12.2 Pharmacodynamics

The analgesic effects of ULTIVA are rapid in onset and offset. Its effects and side effects are dose dependent and similar to other µ-opioids. ULTIVA in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action. The pharmacodynamic effects of ULTIVA closely follow the measured blood concentrations, allowing direct correlation between dose, blood levels, and response. Blood concentration decreases 50% in 3 to 6 minutes after a 1-minute infusion or after prolonged continuous infusion due to rapid distribution and elimination processes and is independent of duration of drug administration. Recovery from the effects of ULTIVA occurs rapidly (within 5 to 10 minutes). New steady-state concentrations occur within 5 to 10 minutes after changes in infusion rate. When used as a component of an anesthetic technique, ULTIVA can be rapidly titrated to the desired depth of anesthesia/analgesia (e.g., as required by varying levels of intraoperative stress) by changing the continuous infusion rate or by administering an IV bolus injection.

Respiration

ULTIVA depresses respiration in a dose-related fashion. Unlike other fentanyl analogs, the duration of action of ULTIVA at a given dose does not increase with increasing duration of administration, due to lack of drug accumulation. When ULTIVA and alfentanil were dosed to equal levels of respiratory depression, recovery of respiratory drive after 3-hour infusions was more rapid and less variable with ULTIVA (see Figure 1).

Figure 1: Recovery of Respiratory Drive After Equipotent* Doses of ULTIVA and Alfentanil Using CO2-Stimulated Minute Ventilation in Adult Volunteers (±1.5 SEM)

Spontaneous respiration occurs at blood concentrations of 4 to 5 ng/mL in the absence of other anesthetic agents; for example, after discontinuation of a 0.25 mcg/kg/min infusion of remifentanil, these blood concentrations would be reached in 2 to 4 minutes. In patients undergoing general anesthesia, the rate of respiratory recovery depends upon the concurrent anesthetic; N2O < propofol < isoflurane [see Clinical Studies: Recovery (14.2)].

12.3 Pharmacokinetics

After IV doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a three-compartment model with a rapid distribution half-life of one minute, a slower distribution half-life of 6 minutes, and a terminal elimination half-life of 10 to 20 minutes. Since the terminal elimination component contributes less than 10% of the overall area under the concentration versus time curve (AUC), the effective biological half-life of ULTIVA is 3 to 10 minutes. This is similar to the 3- to 10-minute half-life measured after termination of prolonged infusions (up to 4 hours; see Figure 2) and correlates with recovery times observed in the clinical setting after infusions up to 12 hours. Concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. The pharmacokinetics of remifentanil are unaffected by the presence of renal or hepatic impairment.

Elimination

The clearance of remifentanil in young, healthy adults is approximately 40 mL/min/kg. Clearance generally correlates with total body weight (except in severely obese patients when it correlates better with IBW). The high clearance of remifentanil combined with a relatively small volume of distribution produces a short elimination half-life of approximately 3 to 10 minutes (see Figure 2). This value is consistent with the time taken for blood or effect site concentrations to fall by 50% (context-sensitive half-times) which is approximately 3 to 6 minutes. Unlike other fentanyl analogs, the duration of action does not increase with prolonged administration.

Figure 2: Mean Concentration (sd) versus Time

 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 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 ED90 were compared to recommended doses (approximately ED50) of alfentanil or fentanyl.

14.2 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 [see Warnings and Precautions (5.14)].

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.

14.3 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.

14.4 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 N2O. 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. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 (2.2).]

No pediatric patients receiving ULTIVA required naloxone during the immediate postoperative recovery period.

14.5 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.

14.6 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 PaCO2 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 [see Clinical Pharmacology (12.2)].

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 [P = 0.04]). No adverse cerebrovascular effects were seen in this study [see Clinical Pharmacology (12.2)].

14.7 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%.

14.8 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 (SPO2 < 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.