WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL INGESTION; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME

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• Serious, life-threatening, and/or fatal respiratory depression has occurred. Monitor closely, especially upon initiation or following a dose increase. Due to the risk of fatal respiratory depression, SUBSYS is contraindicated in opioid non-tolerant patients and in management of acute or postoperative pain, including headache/migraines.
• Accidental ingestion of SUBSYS, especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal.
• Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl.
• 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.
• When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to SUBSYS.
• When dispensing, do not substitute with any other fentanyl products.
• SUBSYS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions.
• SUBSYS is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program.
• Prolonged use of SUBSYS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Contraindications

SUBSYS is contraindicated in:

• Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients
• Acute or postoperative pain including headache/migraine and dental pain, or in the emergency department
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Known hypersensitivity (e.g., anaphylaxis) to fentanyl or components of SUBSYS

Warnings and Precautions

• Life-threatening respiratory distress: has been reported with the use of opioids. If not immediately recognized and treated, respiratory arrest and death may occur. The risk is greatest during initiation and titration of SUBSYS. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases. Opioid use can increase risk of sleep- related breathing disorders including central sleep apnea (CSA) in a dose-dependent fashion.
• Increased Risk of Overdose in Children Due to Accidental Ingestion: death has been reported in children accidentally ingesting transmucosal immediate-release fentanyl products. Patients and their caregivers must be informed that SUBSYS contains a medicine in an amount which can be fatal to a child.
• Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers: Concomitant use of SUBSYS with a CYP3A4 inhibitor or discontinuation of a CYP3A4 inducer may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals. Concomitant use of SUBSYS with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to withdrawal in patients. Monitor patients closely at frequent intervals for signs of withdrawal.
• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants: Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SUBSYS with benzodiazepines or other CNS depressants, such as non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
• Risk of Medication Errors: When prescribing, DO NOT convert a patient to SUBSYS from any other fentanyl product on a mcg per mcg basis as SUBSYS and other fentanyl products are not equivalent on a microgram per microgram basis. SUBSYS is NOT a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, DO NOT substitute a SUBSYS prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and SUBSYS are not equivalent.
• Addiction, Abuse, and Misuse: SUBSYS contains fentanyl, a Schedule II controlled substance. As an opioid, SUBSYS exposes users to the risks of addiction, abuse, and misuse. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing SUBSYS, and monitor all patients receiving SUBSYS for the development of these behaviors or conditions. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
• Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program: SUBSYS is available only through a restricted program under a REMS called the TIRF REMS Access program due to risk of misuse, abuse, addiction, and overdose.
• Neonatal Opioid Withdrawal Syndrome: prolonged use of SUBSYS during pregnancy can result in neonatal withdrawal. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: the use of SUBSYS in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Monitor such patients closely, particularly when initiating and titrating SUBSYS and when SUBSYS is given concomitantly with other drugs that depress respiration.
• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of SUBSYS with serotonergic drugs. Symptoms may include mental status changes, such as agitation, hallucinations, coma, autonomic instability, such as tachycardia, labile blood pressure, hyperthermia, neuromuscular aberrations, such as hyperreflexia, incoordination, rigidity, and/or gastrointestinal symptoms, such as nausea, vomiting, diarrhea.
• Adrenal Insufficiency: has been reported with opioid use, often following more than one month of use. Manifestations may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
• Severe hypotension: may occur including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by reduced blood volume or concurrent administration of certain CNS depressant drugs. Monitor patients for signs of hypotension after initiation or titration of SUBSYS.
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: In patients who may be susceptible to the intracranial effects of CO2 retention, SUBSYS may reduce respiratory drive, resulting in CO2 retention that can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating SUBSYS therapy.
• Risks of use in patients with gastrointestinal conditions: SUBSYS is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in SUBSYS may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
• Increased risk of seizures in patients with seizure disorders: the fentanyl in SUBSYS may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during SUBSYS therapy.
• Risk of driving and operating machinery: SUBSYS may impair mental or physical abilities to perform hazardous activities such as driving a car or operating machinery. Until patients are tolerant to the effects of SUBSYS and know how they will react, warn to not drive or operate machinery.
• Cardiac disease: intravenous fentanyl may produce bradycardia, so SUBSYS should be used with caution in patients with bradyarrhythmia’s.

Adverse Reactions

The most common adverse reactions (≥5%) include: nausea (13.1%), vomiting (10.3%), somnolence (9.5%), dizziness (7.2%), and constipation (5.0%).