remifentanil– helping pharmacists surgical …...remi produces adverse events that are...

Remifentanil–Helping pharmacists support the needs of surgical patients

INDICATIONS AND IMPORTANT RISK INFORMATION INDICATIONSULTIVA® (remifentanil HCl) for Injection is indicated for intravenous 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 carein adult patients

IMPORTANT RISK INFORMATION 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.

Please see Important Risk Information continued on page 10, and accompanying full Prescribing Information in pocket for all precautions, warnings, contraindications, and adverse events.

©2015 Mylan Specialty L.P. ULT-2016-0004 February 2016

ULTIVA is a registered trademark of Glaxo Group Limited.The Mylan logo is a registered trademark of Mylan Inc.

Please see Indications and Important Risk Information on the front cover and page 10, and accompanying full Prescribing Information in pocket for all precautions, warnings, contraindications, and adverse events.

The value of Remifentanil

Helping pharmacists support patient care • Rapid response*1

• Rapid recovery†1

• Established hemodynamic profi le1,5

• Early post-op neurological assessment†2,15

• No accumulation1

Remi produces adverse events that are characteristic of μ-opioids, such as respiratory depression, apnea, tachycardia, bradycardia, hypotension, hypertension, and skeletal muscle (including chest wall) rigidity.

* Continuous infusions of Remi should be administered only by an infusion device and continuous monitoring is necessary. Interruption of infusion will result in rapid offset of effect.1

† Within 5 to 10 minutes after discontinuation of Remi, 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. Other analgesics should be administered prior to discontinuation of Remi where postoperative pain is anticipated.1

Please see accompanying full Prescribing Information in pocket for all precautions, warnings, contraindications, and adverse events.

References: 1. ULTIVA [package insert]. Rockford, IL: Mylan Institutional LLC; 2013. 2. Wilhelm W, Schlaich N, Harrer J, et al. Recovery and neurological examination after remifentanil-desfl urane or fentanyl-desfl urane anaesthesia for carotid artery surgery. Br J Anaesth. 2001;86(1):44-49. 3. Egan TD. Remifentanil pharmacokinetics and pharmacodynamics: a preliminary appraisal. Clin Pharmacokinet. 1995;29(2):80-94. 4. Goldenberg D, Goldstein BJ. Handbook of Otolaryngology: Head and Neck Surgery. New York, NY: Thieme Medical Publishers, Inc; 2011:38. 5. Twersky RS, Jamerson B, Warner DS, Fleisher LA, Hogue S. Hemodynamics and emergence profi le of remifentanil versus fentanyl prospectively compared in a large population of surgical patients. J Clin Anesth. 2001;13(6):407-416. Sponsored by Glaxo Wellcome Inc. 6. Guy J, Hindman BJ, Baker KZ, et al. Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions. Anesthesiology. 1997;86(3):514-524. Supported in part by funding from Glaxo Wellcome Inc. 7. Imani F, Jafarian A, Hassani V, Khan ZH. Propofol-alfentanil vs propofol-remifentanil for posterior spinal fusion including wake-up test. Br J Anaesth. 2006;96(5):583-586. 8. Samra SK, Dy EA, Welch KB, Lovely LK, Graziano GP. Remifentanil- and fentanyl-based anesthesia for intraoperative monitoring of somatosensory evoked potentials. Anesth Analg. 2001;92(6):1510-1515. Supported by a grant (investigator-initiated protocol) from Glaxo Wellcome to Dr. Samra. 9. Lison S, Schill M, Conzen P. Fast-track cardiac anesthesia: effi cacy and safety of remifentanil versus sufentanil. J Cardiothorac Vasc Anesth. 2007;21(1):35-40. Supported by a grant from GlaxoSmithKline. 10. Howie MB, Cheng D, Newman MF, et al. A randomized double-blinded multicenter comparison of remifentanil versus fentanyl when combined with isofl urane/propofol for early extubation in coronary artery bypass graft surgery. Anesth Analg. 2001;92(5):1084-1093. Supported in part by Glaxo Wellcome Inc. 11. Bonfreschi V, Giuliani E, Malagnino FC, et al. Analgesia during abdominal aortic aneurysm endovascular repair: remifentanil vs fentanyl-midazolam—a randomized controlled trial. Eur J Anaesthesiol. 2009;26(9):782-787. 12. Winterhalter M, Brandl K, Rahe-Meyer N, et al. Endocrine stress response and infl ammatory activation during CABG surgery: a randomized trial comparing remifentanil infusion to intermittent fentanyl. Eur J Anaesthesiol. 2008;25(4):326-335. 13. Gerhardt MA, Grichnik KP. Early extubation and neurologic examination following combined carotid endarterectomy and coronary artery bypass grafting using remifentanil. J Clin Anesth. 1998;10(3):249-252. 14. Gesztesi Z, Mootz BL, White PF. The use of a remifentanil infusion for hemodynamic control during intracranial surgery. Anesth Analg. 1999;89(5):1282-1287. 15. Bilotta F, Caramia R, Paoloni FP, et al. Early postoperative cognitive recovery after remifentanil-propofol or sufentanil-propofol anaesthesia for supratentorial craniotomy: a randomized trial. Eur J Anaesthesiol. 2007;24(2):122-127. 16. Scheufl er KM, Zentner J. Total intravenous anesthesia for intraoperative monitoring of the motor pathways: an integral view combining clinical and experimental data. J Neurosurg. 2002;96(3):571-579. 17. Grottke O, Dietrich PJ, Wiegels S, Wappler F. Intraoperative wake-up test and postoperative emergence in patients undergoing spinal surgery: a comparison of intravenous and inhaled anesthetic techniques using short-acting anesthetics. Anesth Analg. 2004;99(5):1521-1527. 18. Eberhart LH, Folz BJ, Wulf H, Geldner G. Intravenous anesthesia provides optimal surgical conditions during microscopic and endoscopic sinus surgery. Laryngoscope. 2003;113(8):1369-1373. 19. Wormald PJ, van Renen G, Perks J, Jones JA, Langton-Hewer CD. The effect of the total intravenous anesthesia compared with inhalational anesthesia on the surgical fi eld during endoscopic sinus surgery. Am J Rhinol. 2005;19(5):514-520. 20. Chen J, Li W, Wang D, Hu X. The effect of remifentanil on cough suppression after endoscopic sinus surgery: a randomized study. Acta Anaesthesiol Scand. 2010;54(10):1197-1203. 21. Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology. 1998;89(3):562-573. 22. Bidgoli J, Delesalle S, De Hert SG, Reiles E, Van der Linden PJ. A randomised trial comparing sufentanil versus remifentanil for laparoscopic gastroplasty in the morbidly obese patient. Eur J Anaesthesiol. 2011;28(2):120-124. 23. Gaszynski TM, Strzelczyk JM, Gaszynski WP. Post-anesthesia recovery after infusion of propofol with remifentanil or alfentanil or fentanyl in morbidly obese patients. Obes Surg. 2004;14(4):498-503; discussion 504. 24. Alvarez AO, Cascardo A, Albarracin Menendez S, Capria JJ, Cordero RA. Total intravenous anesthesia with midazolam, remifentanil, propofol and cisatracurium in morbid obesity. Obes Surg. 2000;10(4):353-360.

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* Remifentanil is commonly referred to as Remi by anesthesia providers.


‡ Continuous infusions of Remi should be administered only by an infusion device and continuous monitoring is necessary. Interruption of infusion will result in rapid offset of effect.1

¶ Normal recovery score at 30 minutes was achieved by 81% of Remi patients versus 61% of fentanyl patients. Recovery rates were similar at 45 minutes.6

§ Remi should be used with caution in pediatric, geriatric, and morbidly obese patients due to high variability in pharmacodynamics and dose/response.1

Chemical structure allows for rapid metabolism• Unlike other opioids, which are metabolized

through the liver, Remi* is rapidly metabolized by hydrolysis via nonspecific blood and tissue esterases1

• Remi is rapidly broken down to an essentially inactive metabolite, so offset of analgesic effect and recovery from intraoperative opioid analgesia can be rapid†1,2


Different than other IV opioid analgesics

The key to Remi

metabolism is this ester

Allows for metabolism by nonspecific blood and tissue esterases

rather than the liver or lung1

2

# After Remi-desfl urane, the digital symbol substitution test (DSST)and Trieger dot test were impaired signifi cantly less at 30 minutes(and also at 60 minutes for the DSST).2

** There was no signifi cant difference in length of stay between the treatment groups. Median time between end of surgery and eligibility for extubation: 295 minutes (Remi) vs 375 minutes (sufentanil) (P<0.05).9

†† The study recognized that both Remi and fentanyl allowed for early extubation.10

Helping pharmacists support patient care

Intraoperative

RecoveryRecoveryRecovery

No accumulation No accumulation No accumulation in adipose tissuein adipose tissuein adipose tissue1,4

Synergistic effectSynergistic effectSynergistic effectSynergistic effectmay require reduction may require reduction may require reduction may require reduction in dosage of other in dosage of other in dosage of other in dosage of other anesthesia drugsanesthesia drugsanesthesia drugsanesthesia drugs1

Well-established Well-established Well-established Well-established hemodynamic profi lehemodynamic profi lehemodynamic profi lehemodynamic profi lehemodynamic profi lehemodynamic profi le§1,5

Rapid responseto dose adjustment with to dose adjustment with peak effect reached in peak effect reached in peak effect reached in 1 to 2 minutes1 to 2 minutes1 to 2 minutes‡1,3 ‡1,3 ‡1,3

No increaseNo increaseNo increase in duration in duration in duration of action with prolonged of action with prolonged of action with prolonged of action with prolonged administrationadministrationadministrationadministration1

Pharmacokinetics and Pharmacokinetics and Pharmacokinetics and Pharmacokinetics and pharmacodynamics pharmacodynamics pharmacodynamics pharmacodynamics are not altered in are not altered in are not altered in patients with hepatic patients with hepatic patients with hepatic and renal impairmentand renal impairment§1§1§1§1§1

Rapid recoveryto have patientsto have patientsalert sooner than with alert sooner than with alert sooner than with alert sooner than with fentanyl, even afterfentanyl, even afterlong procedureslong procedureslong procedures†1,2,5,6†1,2,5,6¶

Rapid returnRapid return of of cognitive functioncognitive functioncognitive function1,21,2#,6¶

Rapid awakeningRapid awakeningRapid awakeningRapid awakeningfor postoperative for postoperative neurological examneurological examneurological exam†1,6¶,7,8

Helps maintain Helps maintain Helps maintain intraoperative pain intraoperative pain intraoperative pain control and facilitate and facilitate and facilitate early extubationearly extubation†1,9**,101,9**,10††,11

Rapid recoveryRapid recoveryRapid recoveryof respiratory driveof respiratory driveof respiratory drive to have patients breathing have patients breathing independently sooner independently sooner than with alfentanilthan with alfentanil1

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• Helps maintain intraoperative pain control and facilitate early extubation1,9*,10†,11

• Helps manage the intraoperative stress response‡9,12§

• Better protects against intraoperative stimuli at skin incision and maximal sternal spread than sufentanil9¶#

• Maintains hemodynamic stability in cardiac procedures‡1,9,11

“ …in patients undergoing CPB [cardiopulmonary bypass] for coronary revascularization and/or cardiac valve repair, patients anesthetized with remifentanil were eligible for postoperative extubation earlier than patients who had undergone these procedures under sufentanil anesthesia.”9

–– Lison S, et al. J Cardiothorac Vasc Anesth. 2007;21(1):35-40

Within 5 to 10 minutes after discontinuation of Remi, 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. Other analgesics should be administered prior to discontinuation of Remi where postoperative pain is anticipated.

* There was no significant difference in length of stay between treatment groups. Median time between end of surgery and eligibility for extubation: 295 minutes (Remi) vs 375 minutes (sufentanil) (P<0.05).9

† The study recognized both Remi and fentanyl allowed for early extubation.10

‡ Tachycardia, bradycardia, hypotension, and hypertension have been reported with Remi.1

§ The authors noted the results must be interpreted cautiously since cardiopulmonary bypass and aortic cross-clamp times were significantly shorter in the Remi group.12


Cardiovascular surgery

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• Rapid response allows for rapid adjustment of depth of analgesia**1

• Maintains hemodynamic stability in carotid artery surgery‡2

• Allows early neurological evaluation with rapid return of psychomotor and cognitive function2,13

• Rapid postoperative awakening and recovery following carotid artery surgery2

“ …rapid postoperative awakening, quicker recovery and earlier neurological examination suggest that remifentanil-desflurane is a suitable alternative to fentanyl-desflurane as a general anaesthetic for patients undergoing carotid artery surgery.”2

— Wilhelm W, et al. Br J Anaesth. 2001;86(1):44-49

¶ Significantly (P<0.05) more patients in the sufentanil group experienced a hemodynamic, somatic, or autonomic response at skin incision and maximal sternal spread vs patients in the Remi group. No differences between groups were found at intubation, sternotomy, or sternal wire placement.9

# The Remi group exhibited significantly higher maximum and average pain scores during the first hour of weaning and extubation, and the Remi group had more patients complain of nausea, wound pain, and suboptimum pain therapy.9

** Continuous infusions of Remi should be administered only by an infusion device and continuous monitoring is necessary. Interruption of infusion will result in rapid offset of effect.1

Carotid artery surgery

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“ Remifentanil may be useful in neuroanesthesia because of its ultra-short duration of action allowing a more predictable emergence and recovery.”6

–– Guy J, et al. Anesthesiology. 1997;86(3):514-524



† Tachycardia, bradycardia, hypotension, and hypertension have been reported with Remi.1

‡In patients receiving Remi and nitrous oxide anesthesia.§ Under isoflurane-nitrous oxide anesthesia (PaCO2<30 mm Hg) and a 1-minute infusion of Remi (0.5 or 1.0 mcg/kg).1


Craniotomy• Rapid response to dose

adjustment (5 to 10 minutes) for predictable control of analgesic coverage*1

• Maintains hemodynamic stability in intracranial surgery†6,14

• No effect on cerebrovascular reactivity to CO2

‡ or intracranial pressure§1

• Rapid offset and recovery with no accumulation regardless of infusion duration1

• Rapid awakening and emergence for neurological assessment6¶,15#

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• Rapid response to dose titration for rapid transition to a wake-up test*,**1,7

††

• Provides confidence in accurate neuromonitoring8‡‡,16

• Maintains hemodynamic stability in spinal surgery†1,17

• Rapid offset and recovery with no accumulation regardless of infusion duration1

• Rapid awakening and emergence for neurological assessment1,8‡‡,17

“ …both remifentanil and fentanyl infusion during balanced anesthesia allow satisfactory monitoring of SSEPs. Remifentanil infusion offers the advantage of quicker recovery from anesthesia and less variability in SSEPs morphology.” 8

–– Samra SK, et al. Anesth Analg. 2001;92(6):1510-1515

¶Normal recovery score at 30 minutes was achieved by 81% of Remi patients versus 61% of fentanyl patients. Recovery rates were similar at 45 minutes.6

# Despite the need for close titration and higher risk of treatable postoperative hypertension, propofol-Remi allowed for earlier cognitive recovery.15

** Remi is contraindicated for epidural or intrathecal administration.1

†† The quality of the wake-up test was not significantly better in Remi-treated patients.7

‡‡ Authors note that the advantages of using Remi must be balanced against increased costs and the need for vigilant control of postoperative pain.8

Spinal fusion

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• Helps improve surgical conditions and reduces bleeding to improve surgical visibility when included as part of TIVA18*,19

• Can help achieve deliberate hypotension†18*

• Rapid response allows for rapid adjustment of depth of analgesia‡1

• Helps suppress coughing without prolonging recovery20§

• Rapid recovery after discontinuation with no accumulation regardless of infusion duration1

“ Intravenous anesthesia using propofol-remifentanil provides better surgical conditions compared with a traditional balanced anesthesia technique using isoflurane-alfentanil.”18

— Eberhart LH, et al. Laryngoscope. 2003;113(8):1369-1373


* Compared with balanced anesthesia, Remi may result in hypotension.18

† Respiratory depression, apnea, tachycardia, bradycardia, hypotension, and hypertension have been reported with Remi as adverse events.1

‡ Continuous infusions of Remi should be administered only by an infusion device and continuous monitoring is necessary. Interruption of infusion will result in rapid offset of effect.1


Functional endoscopic sinus surgery (FESS)

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• No accumulation in adipose tissue1,4

• No difference in pharmacokinetics in nonobese vs obese¶ patients when normalized to ideal body weight (IBW)#1,21

• Pharmacokinetics and pharmacodynamics are not altered in hepatic and renal impairment1

• Rapid response allows for rapid adjustment of depth of analgesia‡1

• Rapid recovery to help facilitate early extubation in gastric bypass surgery22**,23††

• Remi should be used with caution in obese patients

“ TIVA with midazolam, remifentanil, propofol and cisatracurium was found to be effective, secure, predictable and economic for the anesthetic management of morbidly obese patients.”24

— Alvarez AO, et al. Obes Surg. 2000;10(4):353-360

§ Study design used Remi in conjunction with propofol. Remi infusions were discontinued after extubation. Authors noted a dose-dependent cough suppression during emergence without impact on recovery.20

# Clearance of Remi generally correlates with total body weight and may vary in morbidly obese patients due to variation in physiology and pharmacodynamics.1

¶ In obese patients (greater than 30% over their IBW), dosing should be based on IBW.

** During the first 4 hours of recovery, pain was reported higher in the Remi group. Duration of stay in the postanesthesia care unit was comparable between sufentanil and Remi.22

†† Postoperative pain and PONV were higher in the Remi group.23

Bariatric surgery

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IMPORTANT RISK INFORMATION (continued from front)

Vital signs and oxygenation must be continuously monitored during ULTIVA® (remifentanil HCl) for Injection administration. ULTIVA produces adverse events that are characteristic of μ-opioids, such as respiratory depression, apnea, tachycardia, bradycardia, hypotension, hypertension, and skeletal muscle (including chest wall) rigidity. Because these effects are dose-dependent and can occur rapidly, continuous monitoring is necessary. ULTIVA should not be used as a sole agent because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.

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.

ULTIVA should be used with caution in pediatric, geriatric, and morbidly obese patients due to high variability in pharmacodynamics and dose/response. Intraoperative awareness has been reported with concomitant administration with propofol infusion ≤75 mcg/kg/min.

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.

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 (within 5 to 10 min) upon discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia particularly where postoperative pain is anticipated.

ULTIVA SHOULD BE USED IN CAREFULLY MONITORED SETTINGS BY SPECIFICALLY TRAINED PERSONS NOT INVOLVED IN THE SURGICAL OR DIAGNOSTIC PROCEDURE. OXYGEN SATURATION IS TO BE CONTINUOUSLY MONITORED. RESUSCITATIVE AND INTUBATION EQUIPMENT, OXYGEN, AND AN OPIOID ANTAGONIST MUST BE READILY AVAILABLE.

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