REMIFENTANIL MYLAN

(remifentanil hydrochloride) for injection is an opioid agonist.

The chemical name is 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester, hydrochloride salt.

The molecular weight is 412.91.

Its molecular formula is

C 20 H 28 N 2 O 5 •HCl, and 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 mg, 2 mg, 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 (HCl) equivalent to 1 mg/mL of remifentanil base.

The pH of reconstituted solutions of

ULTIVA ranges from 2.5 to 3.5.

Remifentanil hydrochloride has a pKa of 7.07.

Remifentanil hydrochloride has an n-octanol:water partition coefficient of 17.9 at pH 7.3.

• 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.

Acidosis Lactation History of arrhythmia Atherosclerosis

Glaucoma with narrow angles Pregnancy Hypercapnia Hyperthyroidism Hypovolaemia Hypoxia Hepatic impairment Renal impairment High postload Elderly Peripheral circulatory disorder.

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 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 to 10 minutes).

New steady-state concentrations occur within 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.

Remifentanil produces respiratory depression by direct action on brain stem respiratory centers.

The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Remifentanil causes miosis, even in total darkness.

Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings).

Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Remifentanil causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.

Digestion of food in the small intestine is delayed and propulsive contractions are decreased.

Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Remifentanil produces peripheral vasodilation which may result in orthostatic hypotension or syncope.

Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Caution must be used in hypovolemic patients, such as those suffering acute myocardial infarction, because remifentanil may cause or further aggravate their hypotension.

Caution must also be used in patients with cor pulmonale who have received therapeutic doses of opioids.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models.

The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists.

The minimum effective analgesic concentration of remifentanil for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.

Concentration–Adverse Reaction Relationships There is a relationship between increasing remifentanil plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

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 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.

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.

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.

Figure 1: Recovery of Respiratory Drive After Equipotent * Doses of ULTIVA and Alfentanil Using CO 2 -Stimulated Minute Ventilation in Adult Volunteers (±1.5 SEM) Spontaneous respiration occurs at blood concentrations of 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 to 4 minutes.

In patients undergoing general anesthesia, the rate of respiratory recovery depends upon the concurrent anesthetic; N 2 O < propofol < isoflurane.

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

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.

Infusions of 0.05 to 0.1 mcg/kg/min, producing blood concentrations of 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.

ULTIVA is synergistic with the activity of hypnotics (propofol and thiopental), inhaled anesthetics, and benzodiazepines.

Age The pharmacodynamic activity of

ULTIVA (as measured by the EC for development of delta waves on the EEG) increases with increasing age.

EC of remifentanil for this measure was 50% less in patients over 65 years of age when compared to healthy volunteers (25 years of age) .

No differences have been shown in the pharmacodynamic activity (as measured by the EEG) of ULTIVA between men and women.

In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.

There was no change in intraocular pressure after the administration of ULTIVA prior to ophthalmic surgery under monitored anesthesia care.

Under isoflurane-nitrous oxide anesthesia (PaCO 2 < 30 mmHg), a 1-minute infusion of ULTIVA (0.5 or 1.0 mcg/kg) produced no change in intracranial pressure.

Mean arterial pressure and cerebral perfusion decreased as expected with opioids.

In patients receiving

ULTIVA and nitrous oxide anesthesia, cerebrovascular reactivity to carbon dioxide remained intact.

In humans, no epileptiform activity was seen on the EEG (n = 44) at remifentanil doses up to 8 mcg/kg/min. Renal Dysfunction The pharmacodynamics of ULTIVA (ventilatory response to hypercarbia) are unaltered in patients with end stage renal disease (creatinine clearance < 10 mL/min).

Hepatic Dysfunction The pharmacodynamics of

ULTIVA (ventilatory response to hypercarbia) are unaltered in patients with severe hepatic dysfunction awaiting liver transplant. 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 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 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.

The initial volume of distribution (V d ) of remifentanil is approximately 100 mL/kg and represents distribution throughout the blood and rapidly perfused tissues.

Remifentanil subsequently distributes into peripheral tissues with a steady-state volume of distribution of approximately 350 mL/kg. These two distribution volumes generally correlate with total body weight (except in severely obese patients when they correlate better with ideal body weight [IBW]).

Remifentanil is approximately 70% bound to plasma proteins of which two-thirds is binding to alpha-1-acid-glycoprotein.

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 to 10 minutes.

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 to 6 minutes.

Unlike other fentanyl analogs, the duration of a.

Mechanism of action

Depending on the doses used, three types of dopamine effects can be observed: At low doses ( 20 μg/kg/min) dopamine has an α-stimulating effect: increased peripheral resistance; increased blood pressure (PA), decreased differential and decreased diuresis.

At low or medium doses, dopamine does not increase the rate of the heart rate, increased tayocardi-like effect, increased cardiac rate, increased tayocardi-like effect, increased tayocardi-like effect, increased tayocardi-like effect, increased tayocardi.

Prolactinaemia (decrease) Uremia (increase) Horripilation Functional exploration of abnormal thyroid

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.

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.

• For epidural or intrathecal administration due to the presence of glycine in the formulation.

• In patients with hypersensitivity to remifentanil (e.g., anaphylaxis) .

• In patients with hypersensitivity to remifentanil (e.g., anaphylaxis).

• Monitor patients closely for respiratory depression when initiating therapy and following dosage increases and adjust the dosage accordingly.

• Initial Dosage in Adults: See full prescribing information for recommended doses in adult patients.

• Initial Dosage in Pediatric Patients: See full prescribing information for recommended doses in pediatric patients.

• Geriatric Patients: The starting doses should be decreased by 50% in elderly patients (> 65 years). 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.

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.

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.

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 to 60 seconds.

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.

After endotracheal intubation, the infusion rate of ULTIVA should be decreased in accordance with the dosing guidelines in Tables 1 (adults, predominately ASA physical status I, II, or III) and 2 (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 to 5 minutes to attain the desired level of µ-opioid effect.

• In response to light anesthesia or transient episodes of intense surgical stress, supplemental bolus doses of 1 mcg/kg may be administered every 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.

Table 1: Dosing Guidelines in Adults – General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care Setting An initial dose of 1 mcg/kg may be administered over to 60 seconds.

Phase Continuous IV Infusion of

ULTIVA (mcg/kg/min) Range of Infusion Dose ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) Induction of Anesthesia (through intubation) 0.5 – 1 Maintenance of anesthesia with: Nitrous oxide (66%) 0.4 0.1 – 2 1 Isoflurane (0.4 to 1.5 MAC) 0.25 0.05 – 2 1 Propofol (100 to 200 mcg/kg/min) 0.25 0.05 – 2 1 Continuation as an analgesic into the immediate postoperative period 0.1 0.025 – 0.2 not recommended Table 2 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.

The use of atropine may blunt the potential for bradycardia that can occur upon administration of ULTIVA.

Table 2: Dosing Guidelines in Pediatric Patients – Maintenance of Anesthesia Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Range of Infusion Dose ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) Maintenance of anesthesia in patients aged to 12 years old with An initial dose of 1 mcg/kg may be administered over to 60 seconds. : Halothane (0.3 to 1.5 MAC) 0.25 0.05 – 1.3 1 Sevoflurane (0.3 to 1.5 MAC) 0.25 0.05 – 1.3 1 Isoflurane (0.4 to 1.5 MAC) 0.25 0.05 – 1.3 1 Maintenance of anesthesia for patients from birth to 2 months of age with: Nitrous oxide (70%) The clearance rate in neonates is highly variable, on average two times higher than in the young healthy adult population.

Therefore, an increased infusion rate may be necessary to maintain adequate surgical anesthesia, and additional bolus doses may be required.

The use of atropine may blunt the potential for bradycardia that can occur upon administration of ULTIVA. 0.4 0.4 – 1.0 1 Boluses of 1 mcg/kg were studied in ASA and 2, full-term patients weighing at least 2500 gm, undergoing pyloromyotomy who received pretreatment with atropine.

Neonates receiving supplementation with potent inhalation agents or neuraxial anesthesia, those with significant co-morbidities or undergoing significant fluid shifts, or those who have not been pretreated with atropine, may require smaller bolus doses to avoid hypotension and/or bradycardia. 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.

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

• 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 level of analgesia and respiratory rate.

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

• 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 to 60 seconds of ULTIVA may be given 90 seconds before the placement of the local or regional anesthetic block.

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.

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

Table 3: Dosing Guidelines in Adults – Monitored Anesthesia Care Method Timing ULTIVA Alone ULTIVA + 2 mg Midazolam Single IV Dose Given 90 seconds before local anesthetic 1 mcg/kg over to 60 seconds 0.5 mcg/kg over to 60 seconds Continuous IV Infusion Beginning 5 minutes before local anesthetic 0.1 mcg/kg/min 0.05 mcg/kg/min After local anesthetic 0.05 mcg/kg/min (Range: 0.025 to 0.2 mcg/kg/min) 0.025 mcg/kg/min (Range: 0.025 to 0.2 mcg/kg/min) 2.5 Discontinuation Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later time.

The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care. 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. 2.7 Dosage Modifications in Pediatric Patients See Table for dosing recommendations for use of ULTIVA in pediatric patients from birth to 12 years of age for maintenance of anesthesia.

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.

Table 4: Dosing Recommendations See Clinical Studies: Coronary Artery Bypass Surgery subsection for concomitant medication regimens. – Coronary Artery Bypass Surgery Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Range of Infusion Dose ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) Induction of Anesthesia (through intubation) 1 Maintenance of Anesthesia 1 0.125 to 4 0.5 to 1 Continuation as an analgesic into ICU 1 0.05 to 1 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) . 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.

(remifentanil hydrochloride) for Injection, for intravenous use, is supplied as follows: NDC Number Container Concentration Quantity 67457-912-01 3 mL Single-Dose Vial 1 mg lyophilized powder Box of 10 67457-913-02 5 mL Single-Dose Vial 2 mg lyophilized powder Box of 10 67457-914-05 10 mL Single-Dose Vial 5 mg lyophilized powder Box of 10 ULTIVA should be stored at 2° to 25°C (36° to 77°F).

Discard unused portion.

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.

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.

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 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 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 to Lactation Day 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).

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.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Titrate the dosage of

ULTIVA slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression.

Of the total number of subjects in clinical studies of ULTIVA, 486 were and over (age range 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.

ULTIVA slowly in geriatric patients.

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.

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.