Ultiva - Remifentanil Hydrochloride injection, Powder, Lyophilized, For Solution

Warnings and Precautions (

ULTIVA is indicated for intravenous (IV) administration:

• •As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.
• •For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting.
• •As an analgesic component of monitored anesthesia care in adult patients.

• •Monitor patients closely for respiratory depression when initiating therapy and following dosage increases and adjust the dosage accordingly. (
  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.
  )
• •
  Initial Dosage in Adults
  : See full prescribing information for recommended doses in adult patients. (
  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.

  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.

  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.

  Maintenance of Anesthesia

  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 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, supplemental 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: Specific Populations: Pediatric Population (12.3)and Dosage and Administration, Table 2 (2.2).]

  Table 1: Dosing Guidelines in Adults – General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care SettingAn initial dose of 1 mcg/kg may be administered over 30 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 1 to 12 years old with An initial dose of 1 mcg/kg may be administered over 30 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. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3)and Clinical Studies (14.4).]	0.4	0.4 – 1.0	1Boluses of 1 mcg/kg were studied in ASA 1 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 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)]

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

  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.

  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.

  Maintenance of Anesthesia

  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 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, supplemental 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: Specific Populations: Pediatric Population (12.3)and Dosage and Administration, Table 2 (2.2).]

  Table 1: Dosing Guidelines in Adults – General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care SettingAn initial dose of 1 mcg/kg may be administered over 30 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 1 to 12 years old with An initial dose of 1 mcg/kg may be administered over 30 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. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3)and Clinical Studies (14.4).]	0.4	0.4 – 1.0	1Boluses of 1 mcg/kg were studied in ASA 1 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.
  )
• •
  Geriatric Patients
  : The starting doses should be decreased by 50% in elderly patients (> 65 years). (
  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)]

  .
  )

For injection: 1 mg, 2 mg, and 5 mg:

• •
  Pregnancy
  : May cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with remifentanil hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, reduced fetal rat body weight and pup weights were reported at 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours. There were no malformations noted when remifentanil was administered via bolus injection to pregnant rats or rabbits during organogenesis at doses approximately 5 times and approximately equal, respectively, to a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours [

  see Data

  ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Clinical Considerations

  Labor or Delivery

  Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. ULTIVA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ULTIVA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

  Data

  Human Data

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

  Animal Data

  Pregnant rats were treated from Gestation Day 6 to 15 with intravenous remifentanil doses of 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced fetal weights were reported in the high dose group; however, no malformations were reported in surviving fetuses despite a non-dose dependent increase in maternal mortality.

  Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day (0.09, 0.4, or 0.7 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). No malformations were reported in surviving fetuses despite clear maternal toxicity (decreased food consumption and body weights and increased mortality in all treatment groups).

  Pregnant rats were treated from Gestation Day 6 to Lactation Day 21 with intravenous boluses of remifentanil 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity (increased mortality in all groups).
  )
• •
  Labor or Delivery
  : Respiratory depression and other opioid effects may occur in newborns whose mothers are given ULTIVA shortly before delivery. (
  8.1 Pregnancy

  Risk Summary

  Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with remifentanil hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, reduced fetal rat body weight and pup weights were reported at 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours. There were no malformations noted when remifentanil was administered via bolus injection to pregnant rats or rabbits during organogenesis at doses approximately 5 times and approximately equal, respectively, to a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours [

  see Data

  ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Clinical Considerations

  Labor or Delivery

  Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. ULTIVA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ULTIVA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

  Data

  Human Data

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

  Animal Data

  Pregnant rats were treated from Gestation Day 6 to 15 with intravenous remifentanil doses of 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced fetal weights were reported in the high dose group; however, no malformations were reported in surviving fetuses despite a non-dose dependent increase in maternal mortality.

  Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day (0.09, 0.4, or 0.7 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). No malformations were reported in surviving fetuses despite clear maternal toxicity (decreased food consumption and body weights and increased mortality in all treatment groups).

  Pregnant rats were treated from Gestation Day 6 to Lactation Day 21 with intravenous boluses of remifentanil 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced birth weights were noted in the high-dose groups in the presence of maternal toxicity (increased mortality in all groups).
  )
• •
  Lactation
  : Infants exposed to ULTIVA through breast milk should be monitored for excess sedation and respiratory depression. (
  8.2 Lactation

  Risk Summary

  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.

  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ULTIVA and any potential adverse effects on the breastfed infant from ULTIVA or from the underlying maternal condition.

  Clinical Considerations

  Infants exposed to ULTIVA through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
  )
• •
  Pediatric Use
  : ULTIVA has not been studied in pediatric patients for use as a postoperative analgesic or as an analgesic component of monitored anesthesia care. (
  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.
  )