ULTIVA (remifentanil hydrochloride) for Injection is a μ-opioid agonist chemically designated as a 3-[4-methoxycarbonyl-4- [(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester, hydrochloride salt, C₂₀H₂₈N₂O₅•HCl, with a molecular weight of 412.91. It has the following chemical structure:

ULTIVA is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1, 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. When reconstituted as directed, solutions of ULTIVA are clear and colorless and contain remifentanil hydrochloride (HCI) equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions of ULTIVA ranges from 2.5 to 3.5. Remifentanil HCI has a pKa of 7.07. Remifentanil HCI has an n-octanol:water partition coefficient of 17.9 at pH 7.3.

ULTIVA is indicated for IV administration:

1. As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.
2. 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.
3. As an analgesic component of monitored anesthesia care in adult patients.

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.

During 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.

Table 10 summarizes the recommended doses in adult patients, predominately ASA physical status I, II, or III.

Table 10: Dosing Guidelines in Adults - General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care Setting*

Table 11 summarizes the recommended doses in pediatric patients, predominantly ASA physical status I, II, or III. In pediatric patients, remifentanil was administered with nitrous oxide or nitrous oxide in combination with halothane, sevoflurane, or isoflurane.

Table 11: Dosing Guidelines in Pediatric Patients - Maintenance of Anesthesia

During Induction of Anesthesia: ULTIVA should be administered at an infusion rate of 0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the induction of anesthesia. If endotracheal intubation is to occur less than 8 minutes after the start of the infusion of ULTIVA, then an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.

During Maintenance of Anesthesia: After endotracheal intubation, the infusion rate of ULTIVA should be decreased in accordance with the dosing guidelines in Tables 10 (adults) and 11 (pediatric patients). Due to the fast onset and short duration of action of ULTIVA, the rate of administration during anesthesia can be titrated upward in 25% to 100% increments in adult patients or up to 50% increments in pediatric patients, or downward in 25% to 50% decrements every 2 to 5 minutes to attain the desired level of μ-opioid effect. In response to light anesthesia or transient episodes of intense surgical stress, supplem ental bolus doses of 1 mcg/kg may be administered every 2 to 5 minutes. At infusion rates > 1 mcg/kg/min, increases in the concomitant anesthetic agents should be considered to increase the depth of anesthesia. See CLINICAL PHARMACOLOGY: Special Populations: Pediatric Patients, and DOSAGE AND ADMINISTRATION, Table 11 for additional information.

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. The use of bolus injections of ULTIVA to treat pain during the postoperative period is not recommended. 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. The infusion rate may be adjusted every 5 minutes in 0.025-mcg/kg/min increments to balance the patient's Infusion rates greater than 0.2 mcg/kg/min are associated with respiratory depression (respiratory rate less than 8 breaths/min).

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

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)

Analgesic Component of Monitored Anesthesia Care: It is strongly recommended that supplemental oxygen be supplied to the patient whenever ULTIVA is administered.

Table 12 summarizes the recommended doses for monitored anesthesia care in adult patients, predominately ASA physical status I, II, or III. ULTIVA has not been studied for use in children in monitored anesthesia care.

Table 12: Dosing Guidelines in Adults - 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 PRECAUTIONS).

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. 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. 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. Rates greater than 0.2 mcg/kg/min are generally associated with respiratory depression (respiratory rates less than 8 breaths/min). Bolus doses of ULTIVA administered simultaneously with a continuous infusion of ULTIVA to spontaneously breathing patients are not recommended.

Individualization of Dosage

Use 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.

Use in Pediatric Patients: See Table 11 for dosing recommendations for use of ULTIVA in pediatric patients from birth to 12 years of age for maintenance of anesthesia. See CLINICAL PHARMACOLOGY: Special Populations: Pediatric Patients, and DOSAGE AND ADMINISTRATION, Table 11 and During Maintenance of Anesthesia for additional information.

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.

Use in Coronary Artery Bypass Surgery: Table 13 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 described in the Clinical Trials: Coronary Artery Bypass Surgery subsection.

Table 13: Dosing Recommendations* - Coronary Artery Bypass Surgery

Use 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).

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.

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. ULTIVA should be diluted to a recommended final concentration of 20, 25, 50, or 250 mcg/mL prior to administration (see Table 14). ULTIVA should not be administered without dilution.

Table 14: Reconstitution and Dilution of ULTIVA analgesic into ICU

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 15:

Table 15: IV Infusion Rates of ULTIVA (mL/kg/h)

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 16 is a guideline for milliliter-per-hour delivery for a solution of 20 mcg/mL with an infusion device.

Table 16: IV Infusion Rates of ULTIVA (mL/h) for a 20-mcg/mL Solution

Table 17 is a guideline for milliliter-per-hour delivery for a solution of 25 mcg/mL with an infusion device.

Table 17: IV Infusion Rates of ULTIVA (mL/h) for a 25-mcg/mL Solution

Table 18 is a guideline for milliliter-per-hour delivery for a solution of 50 mcg/mL with an infusion device.

Table 18: IV Infusion Rates of ULTIVA (mL/h) for a 50-mcg/mL Solution

Table 19 is a guideline for milliliter-per-hour delivery for a solution of 250 mcg/mL with an infusion device.

Table 19: IV Infusion Rates of ULTIVA (mL/h) for a 250-mcg/mL Solution

Compatibility And Stability

Reconstitution and Dilution Prior to Administration: ULTIVA is stable for 24 hours at room temperature after reconstitution and further dilution to concentrations of 20 to 250 mcg/mL with the IV fluids listed below.

Sterile Water for Injection, USP

5% Dextrose Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

0.9% Sodium Chloride Injection, USP

0.45% Sodium Chloride Injection, USP

Lactated Ringer's and 5% Dextrose Injection, USP

ULTIVA is stable for 4 hours at room temperature after reconstitution and further dilution to concentrations of 20 to 250 mcg/mL with Lactated Ringer's Injection, USP.

ULTIVA has been shown to be compatible with these IV fluids when coadministered into a running IV administration set.

Compatibility With Other Therapeutic Agents: ULTIVA has been shown to be compatible with DIPRIVAN® (propofol) Injection when coadministered into a running IV administration set. The compatibility of ULTIVA with other therapeutic agents has not been evaluated.

Incompatibilities: Nonspecific esterases in blood products may lead to the hydrolysis of remifentanil to its carboxylic acid metabolite. Therefore, administration of ULTIVA into the same IV tubing with blood is not recommended.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product should be a clear, colorless liquid after reconstitution and free of visible particulate matter.

ULTIVA does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

ULTIVA should be stored at 2° to 25°C (36° to 77°F). ULTIVA for IV use is supplied as follows:

ULTIVA is a registered trademark of Abbott Laboratories., DIPRIVAN® is a registered trademark of Zeneca Pharmaceuticals. Revised: August, 2006, Manufactured by: Hospira, Inc., Lake Forest, IL 60045 USA. For: Abbott Laboratories, North Chicago, IL 60064 USA. FDA revision date: 3/8/2004

Adverse Events

ULTIVA produces adverse events that are characteristic of μ-opioids, such as respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. These adverse events dissipate within minutes of discontinuing or decreasing the infusion rate of ULTIVA. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS on the management of these events.

Adverse event information is derived from controlled clinical trials that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease.

Adults: Approximately 2770 adult patients were exposed to ULTIVA in controlled clinical trials. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 3. Each patient was counted once for each type of adverse event.

Table 3: Adverse Events Reported in 1% of Adult Patients in General Anesthesia Studies* at the Recommended Doses† of ULTIVA

In the elderly population ( > 65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower.

Table 4: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies* at the Recommended Doses† of ULTIVA

The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA in monitored anesthesia care are given in Table 5.

Table 5: Adverse Events Reported in 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses* of ULTIVA

Other Adverse Events in Adult Patients: The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below.

Event frequencies are calculated as the number of patients who were administered ULTIVA and reported an event divided by the total number of patients exposed to ULTIVA in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1883 general anesthesia, n = 609 monitored anesthesia care).

Incidence Less than 1%

Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, heartburn, ileus.

Cardiovascular: various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope.

Musculoskeletal: muscle stiffness, musculoskeletal chest pain.

Respiratory: cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea.

Nervous: anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, sleep disorder, seizure, amnesia.

Body as a Whole: decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.

Skin: rash, urticaria.

Urogenital: urine retention, oliguria, dysuria, urine incontinence.

Infusion Site Reaction: erythema, pruritus, rash.

Metabolic and Nutrition: abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level.

Hematologic and Lymphatic: anemia, lymphopenia, leukocytosis, thrombocytopenia.

The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA in cardiac surgery are given in Tables 6, 7, and 8. These tables represent adverse events collected during discrete phases of cardiac surgery. Any event should be viewed as temporally associated with drug administration and the phase indicated should not be perceived as the only time the event might occur.

Table 6: Adverse Events Reported in 1% of Patients in the Induction/Intubation and Maintenance Phases of Cardiac Surgery Studies at the Recommended Doses* of ULTIVA

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

Table 8: Adverse Events Reported in 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses* of ULTIVA

Pediatrics: ULTIVA has been studied in 342 pediatric patients in controlled clinical trials for maintenance of general anesthesia. In the pediatric population (birth to 12 years), the most commonly reported events were nausea, vomiting, and shivering.

The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 9. Each patient was counted once for each type of adverse event. There were no adverse events 1% for any treatment group during the maintenance period in the pediatric patient general anesthesia studies.

Table 9: Adverse Events Reported in 1% of Pediatric Patients Receiving ULTIVA in General Anesthesia Studies at the Recommended Doses* of ULTIVA

Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil.

Cardiovascular: Asystole.

Non-Site Specific: Anaphylactic/anaphylactoid responses, which in some cases have been severe (e.g., shock).

Drug Abuse And Dependence

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

No information provided. See Drug Interactions under CLINICAL PHARMACOLOGY

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.

USE OF ULTIVA IS ASSOCIATED WITH APNEA AND RESPIRATORY DEPRESSION. 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 RESPIRATORY 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.

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.

RESUSCITATIVE AND INTUBATION EQUIPMENT, OXYGEN, AND AN OPIOID ANTAGONIST 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.

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.

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.

ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.

Vital signs and oxygenation must be continually monitored during the administration of ULTIVA.

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

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.

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.

Rapid Offset of Action: WITHIN 5 TO 10 MINUTES AFTER THE DISCONTINUATION OF ULTIVA, NO RESIDUAL ANALGESIC ACTIVITY WILL BE PRESENT. However, respiratory depression may occur in some patients 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.

ULTIVA should not be used as a sole agent for induction of anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.

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 trials in pediatric patients from birth to 12 years (see Clinical Trials).

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 two 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 : Special Populations: Pediatric Patients, and DOSAGE AND ADMINISTRATION, Table 11 and During Maintenance of Anesthesia).

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

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 and DOSAGE AND ADMINISTRATION).

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).

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been performed with remifentanil.

Remifentanil did not induce gene mutation in prokaryotic cells in vitro and was not genotoxic in the in vivo rat hepatocyte unscheduled DNA synthesis assay. No clastogenic effect was seen in cultured Chinese hamster ovary cells or in the in vivo mouse micronucleus test. In the in vitro mouse lymphoma assay, mutagenicity was seen only with metabolic activation.

Remifentanil has been shown to reduce fertility in male rats when tested after 70+ days of daily IV administration of 0.5 mg/kg, or approximately 40 times the maximum recommended human dose (MRHD) in terms of mg/m² of body surface area. The fertility of female rats was not affected at IV doses as high as 1 mg/kg when administered for at least 15 days before mating.

Pregnancy Category C: Teratogenic effects were not observed following administration of remifentanil at doses up to 5 mg/kg in rats and 0.8 mg/kg in rabbits. These doses are approximately 400 times and 125 times the MRHD, respectively, in terms of mg/m² of body surface area. Administration of radiolabeled remifentanil to pregnant rabbits and rats demonstrated significant placental transfer to fetal tissue. There are no adequate and well-controlled studies in pregnant women. ULTIVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of remifentanil to rats throughout late gestation and lactation at IV doses up to 5 mg/kg, or approximately 400 times the MRHD in terms of mg/m² of body surface area, had no significant effect on the survival, development, or reproductive performance of the F1 generation.

Animal Toxicology: Intrathecal administration of the glycine formulation without remifentanil to dogs caused agitation, pain, hind limb dysfunction, and incoordination. These effects are believed to be caused by the glycine. Glycine is a commonly used excipient in IV products and this finding has no relevance for IV administration of ULTIVA.

Labor and Delivery: Respiratory depression and other opioid effects may occur in newborns whose mothers are given ULTIVA shortly before delivery. The safety of ULTIVA during labor or delivery has not been demonstrated. Placental transfer studies in rats and rabbits showed that pups are exposed to remifentanil and its metabolites. 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.

Nursing Mothers: It is not known whether remifentanil is excreted in human milk. After receiving radioactive-labeled remifentanil, the radioactivity was present in the milk of lactating rats. Because fentanyl analogs are excreted in human milk, caution should be exercised when ULTIVA is administered to a nursing woman.

As with all potent opioid analgesics, overdosage would be manifested by an extension of the pharmacological actions of ULTIVA. Expected signs and symptoms of overdosage include: apnea, chest-wall rigidity, seizures, hypoxemia, hypotension, and bradycardia.

In case of overdosage or suspected overdosage, discontinue administration of ULTIVA, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent or a μ-opioid antagonist may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. Glycopyrrolate or atropine may be useful for the treatment of bradycardia and/or hypotension.

Intravenous administration of an opioid antagonist such as naloxone may be employed as a specific antidote to manage severe respiratory depression or muscle rigidity. Respiratory depression from overdosage with ULTIVA is not expected to last longer than the opioid antagonist, naloxone. Reversal of the opioid effects may lead to acute pain and sympathetic hyperactivity.

Due to the presence of glycine in the formulation, ULTIVA is contraindicated for epidural or intrathecal administration. ULTIVA is also contraindicated in patients with known hypersensitivity to fentanyl analogs.

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.

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.

Hemodynamics: In premedicated patients undergoing anesthesia, 1-minute infusions of < 2 mcg/kg of ULTIVA cause dose-dependent hypotension and bradycardia. While additional doses > 2 mcg/kg (up to 30 mcg/kg) do not produce any further decreases in heart rate or blood pressure, the duration of the hemodynamic change is increased in proportion to the blood concentrations achieved. Peak hemodynamic effects occur within 3 to 5 minutes of a single dose of ULTIVA or an infusion rate increase. Glycopyrrolate, atropine, and vagolytic neuromuscular blocking agents attenuate the hemodynamic effects associated with ULTIVA. When appropriate, bradycardia and hypotension can be reversed by reduction of the rate of infusion of ULTIVA, or the dose of concurrent anesthetics, or by the administration of fluids or vasopressors.

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)

*Equipotent refers to level of respiratory depression.

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 Trials: Recovery).

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 infusion rates > 0.1 mcg/kg/min; peripheral muscle rigidity may occur at lower doses. Administration of doses < 1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of ULTIVA. Prior or concurrent administration of a hypnotic (propofol or thiopental) or a neuromuscular blocking agent may attenuate the development of muscle rigidity. Excessive muscle rigidity can be treated by decreasing the rate or discontinuing the infusion of ULTIVA or by administering a neuromuscular blocking agent.

Histamine Release: Assays of histamine in patients and normal volunteers have shown no elevation in plasma histamine levels after administration of ULTIVA in doses up to 30 mcg/kg over 60 seconds.

Analgesia: Infusions of 0.05 to 0.1 mcg/kg/min, producing blood concentrations of 1 to 3 ng/mL, are typically associated with analgesia with minimal decrease in respiratory rate. Supplemental doses of 0.5 to 1 mcg/kg, incremental increases in infusion rate > 0.05 mcg/kg/min, and blood concentrations exceeding 5 ng/mL (typically produced by infusions of 0.2 mcg/kg/min) have been associated with transient and reversible respiratory depression, apnea, and muscle rigidity.

Anesthesia: ULTIVA is synergistic with the activity of hypnotics (propofol and thiopental), inhaled anesthetics, and benzodiazepines (see Clinical Trials, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Age: The pharmacodynamic activity of ULTIVA (as measured by the EC50 for development of delta wa