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Fentanyl (Sublingual Spray)


Respiratory Depression

  • Fatal respiratory depression has occurred in patients treated with transmucosal immediate-release fentanyl products such as fentanyl sublingual spray (SUBSYS), including following use in opioid non-tolerant patients and improper dosing. The substitution of SUBSYS for any other fentanyl product may result in fatal overdose.
  • Due to the risk of respiratory depression, SUBSYS is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients.
  • Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. SUBSYS must be kept out of reach of children. [see Patient Counseling Information (17.3) and How Supplied/Storage and Handling (16.1)]
  • The concomitant use of SUBSYS with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions (7)].

Medication Errors

  • Substantial differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.
  • When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to SUBSYS. [see Dosage and Administration (2.1),Warnings and Precautions (5.2,) and Clinical Pharmacolog y(12.3)]
  • When dispensing, do not substitute a SUBSYS prescription for other fentanyl products.

Addition, Abuse, and Misuse

  • SUBSYS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. SUBSYS can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing SUBSYS in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.
  • Because of the risk for misuse, abuse, addiction, and overdose, SUBSYS is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [See Warnings and Precautions (5.11)] Further information is available at or by calling 1-866-822-1483.
  • Patients at increased risk may be prescribed opioids, but use in such patients necessitates intensive counseling about the risks and proper use along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose. 

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants 
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death 

  • Reserve concomitant prescribing of opioids and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.

FDA and Industry Communications

Index to FDA Drug Safety Information 

Approved Risk Evaluation and Mitigation Strategies (REMS)

Transmucosal Immediate-Release Fentanyl (TIRF) Products

Opioid Analgesics

Patient Counseling Information

Medication Guides

Patient Medication Guide - SUBSYS

Package Inserts

Subsys Sublingual Spray

Updated April 2021