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fentanyl (Sublimaze, Subsys, Fentanyl Oralet, Actiq, Fentora, Onsolis, Abstral, Lazanda)

Tradenames: Sublimaze, Duragesic. DEA-controlled substance: class 2. Indications: 1) treatment of moderate to severe acute pain syndromes 2) anesthesia related to pain control 3) do not use patches for unstable or acute pain - for use in opioid tolerant patients Dosage: - Intravenous (IV) - 2-3 ug/kg up to 50 ug, then 25 ug every 1-3 hours (higher doses may be needed in opiate tolerant patients) - infusion: start 20 ug/hr, titrate to effect - conscious sedation/adjunct to surgery: - 25-50 ug every 3-5 minutes, max 500 ug/4 hours [9] higher doses used for major surgery [9] Injection: 0.05 mg/mL (2 mL, 5 mL, 20 mL) Transdermal:* Tradename: Duragesic. (2 generics: Sandoz, Mylan)# - one patch every 3 days. Patches: 25, 50, 75 & 100 ug/hr * reservoir for transdermal fentanyl is the skin removal of patch will NOT remove fentanyl in skin do not cut patches, improper use may cause leakage [11] # Sandoz (same as Duragesic) liquid reservoir [7] Mylan solid reservoir - some say Mylan generic NOT as effective as Duragesic - FDA says both generics equivalent to Duragesic Ionsys Works by iontophoresis Transmucosal lollipops: Tradename: Fentanyl Oralet, Actiq. - 5-15 ug/kg, max 400 ug. Lollipops: 200, 300, 400 ug. Buccal tablet: Tradename: Fentora - Bioavailability about twice that of Actiq Tablets: 100, 200, 400, 600, 800 mg Buccal soluble film formulation for cancer pain: Onsolis Sublingual: Abstral, Sublys* (spray) Nasal spray: Lazanda 100 ug/spray [13] 100 ug IV = 7 mg morphine IV 25 ug patch = 45-134 mg morphine PO daily 50 ug patch = 134-224 mg morphine PO daily 75 ug patch = 225-314 mg morphine PO daily 100 ug patch = 315-404 mg morphine PO daily 125. ug patch >= 405 mg morphine PO daily Patients should be on an equivalent of at least 60 mg of oral morphine daily for at least 1 week prior to using a fentanyl patch [11] Pharmacokinetics: 1) intravenous (IV) - immediate onset of action - duration of action 30-60 minutes - metabolized by liver by cyt P450 3A4 - metabolites eliminated in urine - short 1/2 life, less than morphine or meperidine 2) oral - extensive first-pass metabolism - oral bioavailability of 33% - onset of action is 5-10 minutes 3) transdermal - absorption varies with body temperature & the application of heat to the skin surface - onset of action is 12-24 hours - steady state reached in 72 hours - post-removal, steady state concentrations are seen for 24-48 hours - mean decline of 50% in 17 hours - skin is reservoir for drug delivery [5] - reservoir is skin Adverse effects: 1) common (> 10%) - bradycardia, hypotension, respiratory depression, drowsiness, nausea/vomiting (minimal) 2) less common (1-10%) - arrhythmias, confusion, biliary spasm, blurred vision, CNS depression, orthostatic hypotension 3) uncommon (< 1%) - bronchospasm, circulatory depression, convulsions, pruritus, urticaria, dysesthesia, laryngospasm, depression, delirium, paradoxical CNS excitation, cold & clammy skin, dizziness, biliary spasm, urinary tract spasm 4) other - fentanyl infusions can stimulate chest wall tightness & exacerbate respiratory failure; give prophylactic benzodiazepines - rash, especially with transdermal delivery - respiratory depression (dose & tolerance dependent), greater with IV dosing - dependence (physical &/or psychological) - constipation - overdose & death reported from use of transdermal patch [8] - accidental exposure to fentanyl via transdermal patch, particularly by children [14] - severe necrotic wounds, extending to bone, amputations with illicit fentanyl containing xylazine (veternary sedative) [22,24] Overdose: - fentanyl detected in ~ 2/3 of opioid overdose deaths in southeastern Massachusetts Oct 2014 - March 2015 [20] - 82% involved illicitly manufactured fentanyl. - 90% without pulse when emergency medical services arrived - 36% with evidence overdose within seconds or minutes - 6% with evidence of naloxone administration by bystanders [17] - illicit fentanyl often contains xylazine (veternary sedative) [22,24] - naloxone still works but some patients may respond differently [24] - multiple doses of naloxone may be needed to revive a patient after a fentanyl overdose [19] Drug interactions: 1) any drug that inhibits cyt P450 3A4 may increase levels of fentanyl 2) any drug that induces cyt P450 3A4 may diminish levels of fentanyl 3) benzodiazepines, barbiturates, alcohol in combination increase adverse CNS effects 4) MAO inhibitors within 14 days are CONTRAINDICATED a) severe & unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics b) fatal reactions have occurred 5) naloxone is a direct opiate antagonist 6) scorpion venom in combination increases the toxic effects of the venom Laboratory: - fentanyl in specimen - fentanyl in body fluid - fentanyl in gastric fluid - fentanyl in saliva - fentanyl in serum/plasma/blood - fentanyl in blood - fentanyl in serum/plasma - fentanyl in urine Mechanism of action: 1) opiate agonist 2) phenenylpiperidine derivative 3) alters perception to pain at the level of the spinal cord & higher levels of the CNS 4) alters emotional response to pain 5) causes less of an increase in biliary tract pressure than morphine Comparative biology: - a vaccine has been developed that blocks the euphoric effects of fentanyl in rats [23] Notes: - only 1/2 of Subsys prescriptions (sublingual spray) marketed for treatment of breakthrough cancer pain are written by oncologists - general practice physicians, neurologists & even dentists & podiatrists account for almost 1/2 theprescriptions [18]

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Specific

acetylfentanyl fentanyl topical; fentanyl transdermal (Duragesic, Ionsys) para-fluorofentanyl

General

opiate opioid receptor agonist (narcotic)

Properties

MISC-INFO: elimination route LIVER pregnancy-category B C D safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  5. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
  6. Ferrell B, In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  7. Prescriber's Letter 12(5): 2005 Generic Duragesic (Fentanyl) Patches Detail-Document#: 210504 (subscription needed) http://www.prescribersletter.com
  8. http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Fentanyl http://www.fda.gov/medwatch/safety/2007/safety07.htm#Fentanyl
  9. Lexicomp, select drug information, 2005
  10. Prescriber's Letter 13(11): 2006 Fentora: Buccal Fentanyl Tablets Detail-Document#: 221105 (subscription needed) http://www.prescribersletter.com
  11. Prescriber's Letter 14(10): 2007 Safe Use of Fentanyl (Duragesic) Patches Detail-Document#: 231010 (subscription needed) http://www.prescribersletter.com
  12. Prescriber's Letter 18(5): 2011 New Formulation: Abstral (Fentanyl) Sublingual Tablets Detail-Document#: 270520 (subscription needed) http://www.prescribersletter.com
  13. Prescriber's Letter 18(10): 2011 COMMENTARY: New Formulation: Oxecta (Oxycodone) CHART: Fentanyl Products for Breakthrough Pain CHART: Drugs with REMS and Other Special Prescribing/ Dispensing Requirements Detail-Document#: 271021 (subscription needed) http://www.prescribersletter.com
  14. FDA Issues Warning on Fentanyl Patches 04/19/2012 http://www.medscape.com/viewarticle/762326?sssdmh=dm1.777166&src=nl_newsalert
  15. Elia J Marketing Pushes Powerful Painkiller Far Off-Label. Physician's First Watch, May 15, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org
  16. DEA Issues Nationwide Alert on Fentanyl as Threat to Health and Public Safety. March 18, 2015 http://www.dea.gov/divisions/hq/2015/hq031815.shtml
  17. SUBSYS (fentanyl sublingual spray) Prescribing Information http://subsysspray.com/assets/subsys/client_files/files/PrescribingInfo.pdf
  18. SUBSYS (fentanyl sublingual spray) The First and Only Sublingual Spray for Breakthrough Cancer Pain http://subsysspray.com/?gclid=CPGcrefoq74CFaYF7AodKlYACg
  19. Centers for Disease Control & Prevention (CDC) CDC Health Advisory. Oct 26, 2015 Increases in Fentanyl Drug Confiscations and Fentanyl-related Overdose Fatalities. http://emergency.cdc.gov/han/han00384.asp
  20. Somerville NJ, O'Donnell J, Gladden RM, et al. Characteristics of Fentanyl Overdose - Massachusetts, 2014-2016. MMWR Morb Mortal Wkly Rep 2017;66:382-386 https://www.cdc.gov/mmwr/volumes/66/wr/mm6614a2.htm
  21. NEJM Knowledge+ Internal Medicine Board Review. https://myknowledgeplus.nejm.org/flow/flowjs.html
  22. NEJM Journal Watch. Feb 2, 2021 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Johnson J, Pizzicato L, Johnson C, Viner K. Increasing presence of xylazine in heroin and/or fentanyl deaths, Philadelphia, Pennsylvania, 2010-2019. Inj Prev. 2021 Feb 3:injuryprev-2020-043968 PMID: 33536231
  23. Brooks M Fentanyl Vaccine a Potential 'Game Changer' for Opioid Crisis. Medscape. Nov 18, 2022 https://www.medscape.com/viewarticle/984327 - Haile CN, Baker MD, Sanchez SA et al An Immunconjugate Vaccine Alters Distribution and Reduces the Antinociceptive, Behavioral and Physiological Effects of Fentanyl in Male and Female Rats. Pharmaceutics 2022, 14(11), 2290 PMID: 36365109 Free article https://www.mdpi.com/1999-4923/14/11/2290
  24. Fiore K What Doctors Should Know About Xylazine in Fentanyl. Naloxone still works but additional support may be needed; wound care a challenge. MedPage Today February 1, 2023 https://www.medpagetoday.com/special-reports/features/102915

Component-of

bupivacaine/epinephrine/fentanyl bupivacaine/fentanyl droperidol/fentanyl fentanyl/ropivacaine