SUBSYS- fentanyl spray
Insys Therapeutics, Inc.


Life-Threatening Respiratory Depression
Serious, life-threatening, and/or fatal respiratory depression has occurred in patients treated with SUBSYS, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of SUBSYS or following a dose increase. The substitution of SUBSYS for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.1)]

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. [see Contraindications ( 4)]

Accidental INGESTION
Accidental ingestion of even one dose of SUBSYS especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions ( 5.2 )] .

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 Warnings and Precautions ( 5.2); How Supplied/Storage and Handling ( 16)].

Cytochrome P450 3A4 Interaction
The concomitant use of SUBSYS with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving SUBSYS and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.3), Drug Interactions ( 7), Clinical Pharmacology ( 12.3)] .

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 [see Warnings and Precautions ( 5.4), Drug Interactions ( 7)].

  • Reserve concomitant prescribing of SUBSYS 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.

Risk of 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 [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.5)] .

  • When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to SUBSYS.
  • When dispensing, do not substitute a SUBSYS prescription for other fentanyl products.

Addiction, Abuse, and Misuse
SUBSYS exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing SUBSYS, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.6)] .

Risk Evaluation and Mitigation Strategy (REMS) Access Program
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, pharmacies, outpatients, and healthcare professionals who prescribe to outpatients must enroll in the program. [see Warnings and Precautions ( 5.7)]. Further information is available at or by calling 1-866-822-1483.

Neonatal Opioid Withdrawal Syndrome Prolonged use of SUBSYS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Warnings and Precautions ( 5.8) ].


SUBSYS is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Patients considered opioid tolerant are those who are taking for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking SUBSYS.

Limitations of Use:

  • Not for use in opioid non-tolerant patients.
  • Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency room [see Contraindications ( 4)].
  • As part of the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS Program, SUBSYS may be dispensed only to outpatients enrolled in the program. [see Warnings and Precautions ( 5.7)] . For inpatient administration of SUBSYS, patient enrollment is not required.


2.1 Important Dosage and Administration Instructions

  • Healthcare professionals who prescribe SUBSYS on an outpatient basis must enroll in the TIRF REMS ACCESS program and comply with the requirements of the REMS to ensure safe use of SUBSYS. [see Warnings and Precautions ( 5.7)]
  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5)].
  • It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
  • Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.6)] .
  • Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with SUBSYS and adjust the dosage accordingly [see Warnings and Precautions ( 5.1)].
  • Instruct patients and caregivers to take steps to store SUBSYS securely and to properly dispose of unused SUBSYS as soon as no longer needed [see Warnings and Precautions ( 5.2, 5.6), Patient Counseling Information ( 17)].
  • Other TIRF formulations and SUBSYS are not equivalent. DO NOT substitute a SUBSYS prescription for any other TIRF formulation under any circumstances. Do not convert patients on a mcg per mcg basis from any other fentanyl product to SUBSYS [see Warnings and Precautions ( 5.5)]
  • SUBSYS is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products, other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Warnings and Precautions ( 5.5)].
  • SUBSYS is NOT a generic version of any other oral transmucosal fentanyl product [see Warnings and Precautions ( 5.5)] .

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