REMIFENTANIL MYLAN

Remifentanil (marketed by Abbott as Ultiva) is a potent ultra short-acting synthetic opioid given to patients during surgery for pain relief and adjunctive to an anaesthetic.

Remifentanil is a specific mu-type-opioid receptor agonist which means it reduces sympathetic nervous system tone, and causes respiratory depression and analgesia.

For use during the induction and maintenance of general anesthesia.

Remifentanil is an opioid agonist with rapid onset and peak effect and ultra-short duration of action.

The opioid activity of remifentanil is antagonized by opioid antagonists such as naloxone.

The analgesic effects of remifentanil are rapid in onset and offset.

Its effects and side effects are dose dependent and similar to other opioids.

Remifentanil in humans has a rapid blood-brain equilibration half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action.

By hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases.

Remifentanil is an esterase-metabolized opioid.

The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs) and is excreted by the kidneys with an elimination half-life of approximately 90 minutes.

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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.