SUBSYS

• Healthcare professionals who prescribe SUBSYS for outpatients must enroll in the TIRF REMS 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)] .

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SUBSYS [ see Warnings and Precautions ( 5.1) , Patient Counseling Information ( 17) ].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [ see Warnings and Precautions ( 5.1, 5.4, 5.6) ].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

Initiate treatment with SUBSYS for all patients (including those switching from another fentanyl product) using ONE 100 mcg spray sublingually.

Prescribe an initial titration supply of 100 mcg SUBSYS units, which limits the number of units in the home during titration.

Avoid prescribing a higher dose until patients have used up all units to prevent confusion and possible overdose.

Conversion from Actiq to SUBSYS

The initial dose of SUBSYS is always 100 mcg with the only exception of patients already using Actiq.

1. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq table below ( Table 1). Patients must be instructed to stop the use of Actiq and dispose of any remaining units.

   Table 1. Initial Dosing Recommendations for Patients on ACTIQ

   Current ACTIQ Dose (mcg)	Initial SUBSYS Dose (mcg)
   200	100 mcg spray
   400	100 mcg spray
   600	200 mcg spray
   800	200 mcg spray
   1200	400 mcg spray
   1600	400 mcg spray

2. For patients converting from Actiq doses 400 mcg and below, titration should be initiated with 100 mcg SUBSYS and should proceed using multiples of this strength.
3. For patients converting from Actiq doses of 600 and 800 mcg, titration should be initiated with 200 mcg SUBSYS and should proceed using multiples of this strength.
4. For patients converting from Actiq doses of 1200 and 1600 mcg, titration should be initiated with 400 mcg SUBSYS and should proceed using multiples of this strength.

In cancer patients with mucositis, exposure to SUBSYS was greater than in patients without mucositis. For patients with Grade 1 mucositis, the increased maximum serum concentration and overall exposure requires closer monitoring for respiratory depression and central nervous system depression, particularly during initiation of therapy with SUBSYS. For patients with Grade 2 mucositis or higher, avoid use of SUBSYS unless the benefits outweigh the potential risk of respiratory depression from increased exposure. [see Clinical Pharmacology ( 12.3)]

Individually titrate SUBSYS to a dose that provides adequate analgesia and minimizes adverse reactions.

1. From the 100 mcg initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia using a single SUBSYS dose per breakthrough cancer pain episode with tolerable side effects. Patients should record their use of SUBSYS over several episodes of breakthrough cancer pain and review their experience with their physicians to determine if a dosage adjustment is warranted.
2. For each breakthrough pain episode treated, if pain is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of SUBSYS for any breakthrough pain episode.
3. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with SUBSYS.
4. If there is a need to titrate to a 200 mcg dose, prescribe 200 mcg SUBSYS units.
5. Subsequent titration steps are 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg. See Table 2.
6. To reduce the risk of overdose during titration, patients should have only one strength of SUBSYS available at any time.

SUBSYS Titration Process

Subsys Titration Process

Once titrated to a dose that provides adequate pain relief and tolerable side effects, patients should generally use ONLY ONE SUBSYS dose of the appropriate strength per breakthrough pain episode.

On those occasions when the breakthrough pain episode is not relieved within 30 minutes after administration of the SUBSYS dose, the patient may take ONLY ONE additional dose using the same strength for that episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with SUBSYS. Once a successful dose has been found, patients should limit consumption to four or fewer doses per day.

Dosage adjustment of SUBSYS may be required in some patients in order to continue to provide adequate relief of breakthrough pain.

If signs of excessive opioid effects appear following administration of a single SUBSYS dose, subsequent doses should be decreased.

Generally, only increase the SUBSYS dose when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated. In addition, if pain worsens, re-evaluate the patient for changes in the underlying pain condition.

For patients no longer requiring opioid therapy, consider discontinuing SUBSYS along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, SUBSYS therapy can usually be discontinued immediately. [ see Drug Abuse and Dependence ( 9.3) ].

Patients and caregivers must be advised to dispose of used unit dose systems immediately after use and any unneeded unit dose systems remaining from a prescription as soon as they are no longer needed. Consumed units represent a special risk because they are no longer protected by the child resistant blister package, yet may contain enough medicine to be fatal to a child. [see Patient Counseling Information ( 17)].

Charcoal-lined disposal pouches are provided with every carton dispensed. A charcoal-lined disposal pouch is to be used by patients or their caregivers to dispose of the contents of any unneeded unit dose systems when they are no longer needed. Instructions for usage of the charcoal-lined disposal pouch are included in the Medication Guide and Instructions for Use .

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO ₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of SUBSYS, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of SUBSYS.

To reduce the risk of respiratory depression, proper dosing and titration of SUBSYS are essential [see Dosage and Administration ( 2.5 )] . Overestimating the SUBSYS dosage can result in a fatal overdose with the first dose. The substitution of SUBSYS for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.5 )].

SUBSYS could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

Accidental ingestion or exposure to even one dose of SUBSYS, especially in children, can result in respiratory depression and death due to an overdose of fentanyl.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [ see Patient Counseling Information ( 17 )].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SUBSYS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [ see Patient Counseling Information ( 17 )].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [ see Warnings and Precautions ( 5.4 , 5.6 ), Patient Counseling Information ( 17 )].

Death has been reported in children who have accidentally ingested 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. Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [ see Patient Counseling Information ( 17) ].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of SUBSYS are provided in the SUBSYS Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

Concomitant use of SUBSYS with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [ see Warnings and Precautions ( 5.9) ], particularly when an inhibitor is added after a stable dose of SUBSYS is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in SUBSYS-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using SUBSYS with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in SUBSYS-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of SUBSYS until stable drug effects are achieved [see Drug Interactions ( 7)] .

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 a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using SUBSYS with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [ see Drug Interactions ( 7)] .

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SUBSYS with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7)] .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.1) ].

Advise both patients and caregivers about the risks of respiratory depression and sedation when SUBSYS is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7) and Patient Counseling Information ( 17)].

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. Substantial differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of SUBSYS for any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Dosage and Administration ( 2.1)] . Therefore, for opioid tolerant patients, the initial dose of SUBSYS should always be ONE 100 mcg spray. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects [see Dosage and Administration ( 2.4)] .

SUBSYS contains fentanyl, a Schedule II controlled substance. As an opioid, SUBSYS exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SUBSYS. Addiction can occur at recommended dosages and if the drug is misused or abused.

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. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as SUBSYS, but use in such patients necessitates intensive counseling about the risks and proper use of SUBSYS along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [ see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.1) ].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing SUBSYS. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information ( 17)]. 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.

Because of the risk of accidental exposure, misuse, abuse, addiction, and overdose [ see Warnings and Precautions ( 5.1) ], SUBSYS is available only through a restricted program under a REMS called the TIRF REMS. Under the TIRF REMS, healthcare professionals who prescribe to outpatients, the outpatients themselves, and pharmacies, are required to enroll in the program.

Notable requirements of the TIRF REMS are:

• Prescribers for outpatient use must be certified with the REMS program by enrolling and completing training. Prescribers must document opioid tolerance with every SUBSYS prescription.
• Outpatients must be enrolled in the REMS program and must be opioid tolerant to receive SUBSYS [ see Dosage and Administration ( 2.1) ].
• Outpatient pharmacies must be certified with the REMS program and verify documentation of opioid tolerance with every SUBSYS prescription.
• Inpatient pharmacies must be certified with the REMS program and develop policies and procedures to verify opioid tolerance in inpatients who require SUBSYS while hospitalized.
• Wholesalers and distributers must enroll in the REMS program and distribute only to certified pharmacies.
• Further information, including a list of certified pharmacies and enrolled distributors, is available at www.tirfremsaccess.com or by calling 1-866-822-1483.

Prolonged use of SUBSYS during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1), Patient Counseling Information ( 17)].

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.

Patients with Chronic Pulmonary Disease: SUBSYS treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of SUBSYS [see Warnings and Precautions ( 5.1)] .

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.1)] .

Monitor such patients closely, particularly when initiating and titrating SUBSYS and when SUBSYS is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.9)] . Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of SUBSYS with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7)] . This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue SUBSYS if serotonin syndrome is suspected.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

SUBSYS may cause severe hypotension 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 a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions ( 7)] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of SUBSYS. In patients with circulatory shock, SUBSYS may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of SUBSYS in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO ₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), SUBSYS may reduce respiratory drive, and the resultant CO ₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with SUBSYS.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SUBSYS in patients with impaired consciousness or coma.

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.

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.

SUBSYS may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of SUBSYS and know how they will react to the medication.

Intravenous fentanyl may produce bradycardia. Therefore, use SUBSYS with caution in patients with bradyarrhythmias.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of SUBSYS has been evaluated in a total of 359 opioid-tolerant patients with breakthrough cancer pain. The duration of SUBSYS use varied during the open-label study. Safety data from a long-term extension study showed that the average duration of therapy in the open-label study was 66 days. The maximum duration of therapy was 149 days. The dose range studied in these trials ranged from 100 mcg per dose to 1600 mcg per dose.

The most serious adverse reactions associated with all opioids including SUBSYS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression.

The most common adverse reaction leading to discontinuation of SUBSYS was nausea. There were also adverse reactions of abdominal distension, anorexia, confusional state, disorientation, somnolence, and constipation.

The clinical trials of SUBSYS were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received SUBSYS for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain.

Table 4 lists adverse reactions with an overall frequency of 5% or greater that occurred during titration in the clinical trials. Adverse reactions are listed in descending order of frequency within each system organ class.

The following adverse reactions occurred during titration in the clinical trials with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class.

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Diarrhea, stomatitis, dry mouth

General Disorders and Administration Site Conditions: Application site irritation, pyrexia, edema peripheral, fatigue, asthenia

Metabolism and Nutrition Disorders: Decreased appetite

Nervous System Disorders: Lethargy, sedation, tremor, headache

Psychiatric Disorders: Depression, confusional state, hallucination, insomnia

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Pruritus

The following reactions occurred during titration in the clinical trials with an overall frequency of less than 1% and are listed in descending order of frequency within each system organ class.

Eye Disorders: Vision blurred, dry eye

Gastrointestinal Disorders: Abdominal pain

Infections and Infestations: Oral candidiasis, cellulitis

Injury, Poisoning and Procedural Complications: Fall

Metabolism and Nutrition Disorders: Dehydration, anorexia

Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, joint swelling

Psychiatric Disorders: Anxiety, agitation

Renal and Urinary Disorders: Urinary retention

Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, dysphonia, pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Vascular Disorders: Hot flush

Table 5 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to titration during the clinical trials.

The following adverse reactions occurred during the dosing period of the clinical trial with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class.

Blood and Lymphatic System Disorders: Anemia, neutropenia, lymphadenopathy, thrombocytopenia, leukopenia

Cardiac Disorders: Tachycardia, sinus tachycardia

Gastrointestinal Disorders: Diarrhea, stomatitis, abdominal pain, abdominal distension, gastritis, dysphagia, dyspepsia, gastroesophageal reflux disease, ascites, hematemesis

General Disorders and Administration Site Conditions: Edema peripheral, fatigue, pyrexia, chest pain, drug withdrawal syndrome, chills, irritability, malaise, application site irritation

Infections and Infestations: Oral candidiasis, pneumonia, urinary tract infection, oral herpes, gastroenteritis, laryngitis

Injury, Poisoning and Procedural Complications: Contusion

Investigations: Weight decreased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood glucose increased, blood lactate increased

Metabolism and Nutrition Disorders: Anorexia, dehydration, hypokalemia, decreased appetite, hyponatremia, hypocalcemia, hypoalbuminemia, cachexia

Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, muscular weakness

Nervous System Disorders: Hypoesthesia, lethargy, sedation, tremor, somnolence, headache, dizziness

Psychiatric Disorders: Depression, restlessness, agitation, confusional state, insomnia, hallucination, disorientation

Renal and Urinary Disorders: hypertension, hypotension

Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, wheezing, pharyngolaryngeal pain, hypoxia, dyspnea exertional

Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus

In a single-dose mucositis study, a group of patients with Grade 1 or 2 oral mucositis (n=9) and without oral mucositis (n=9) were included in a clinical trial designed to support the safety of SUBSYS. Two of the nine subjects with mucositis (one with Grade 1 and one with Grade 2) reported a burning sensation in the oral mucosa after treatment. Both of these events were considered mild and probably related to treatment. There was no change in grade of mucositis after treatment for any subject.

The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SUBSYS.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] .

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.8)] . Available data with SUBSYS in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [ see Data ].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.8)] .

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. SUBSYS is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including SUBSYS, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of SUBSYS on a mg/m ² basis) and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of SUBSYS based on a mg/m ² basis). There was no evidence of teratogenicity was reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg SUBSYS per pain episode on a mg/m ² basis and produced mean steady-state plasma levels that are 5.3 times higher than the mean C _max observed following administration of 800 mcg dose of SUBSYS in humans.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SUBSYS.

Clinical Considerations

Monitor infants exposed to SUBSYS through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6), Clinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)] .

Safety and efficacy in pediatric patients below the age of 18 years have not been established.

Of the 359 patients in clinical studies of SUBSYS in breakthrough cancer pain, 27% were 60 years of age and older, 17% were 65 years of age and older, and 3% were 75 years of age and older. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in SUBSYS clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, monitor patients for respiratory depression and CNS effects when titrating SUBSYS in elderly patients.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of SUBSYS slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [ see Warnings and Precautions ( 5.1)] .

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Insufficient information exists to make recommendations regarding the use of SUBSYS in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, monitor patients closely for signs of respiratory and central nervous system depression.

Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.

SUBSYS contains fentanyl a Schedule II controlled substance.

SUBSYS contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. SUBSYS can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions ( 5.6)] .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

SUBSYS, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to the Abuse of SUBSYS

SUBSYS is for sublingual transmucosal use only. Abuse of SUBSYS poses a risk of overdose and death. The risk is increased with concurrent abuse of SUBSYS with alcohol and other central nervous system depressants.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [ see Use in Specific Populations ( 8.1)] .

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2)] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2)] .

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.

Concentration–Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1, 2.3, 2.5)] .

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours.

Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration [see Warnings and Precautions ( 5.1)].

Absorption

Following the single dose administration of SUBSYS, 400 mcg, the mean absolute bioavailability of fentanyl is 76% as measured by AUC0-∞. Fentanyl pharmacokinetic profile and bioavailability depend on the fraction of the dose that is absorbed through the sublingual mucosa and the fraction swallowed from the gastrointestinal tract.

In a study that compared the relative bioavailability of SUBSYS and oral transmucosal fentanyl citrate [OTFC]) in 21 healthy adult subjects, the rate and extent of fentanyl absorption were considerably greater with SUBSYS [34% greater maximum plasma concentration (Cmax) and 38% greater systemic exposure (AUCinf)] (Table 7 and Figure 1) [ see Dosage and Administration ( 2.1, 2.3, 2.5) and Warnings and Precautions ( 5.5) ].

Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 4 hours.

Figure 1 Mean Fentanyl Plasma Concentration-Time Profiles Following Single Dose Administration of SUBSYS 400 mcg and OTFC 400 mcg in Healthy Adult Subjects

Figure 1

Neither peak fentanyl concentration nor total exposure was appreciably affected by the pretreatment of oral cavity with hot water or refrigerated iced water, low or high pH beverages when SUBSYS was administered under fasted condition.

Dose proportionality among the five available strengths of SUBSYS (100, 200, 400, 600, and 800 mcg) has been evaluated in a crossover study in healthy subjects. Mean plasma fentanyl levels following these five dose levels of SUBSYS are shown in Figure 2. The curves for each dose level are similar in shape with increasing dose levels producing increasing plasma fentanyl levels. The C _max and AUC _0-∞ values increased in a dose-dependent manner that is approximately proportional to the SUBSYS doses administered.

Figure 2. Mean Fentanyl Plasma Concentration-Time Profiles (36 hours) after Administration of SUBSYS 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg in Healthy Subjects

Figure 2

The pharmacokinetic parameters of the five strengths of SUBSYS tested are shown in Table 8. The mean Cmax ranged from 0.202 – 1.610 ng/mL. The median time of maximum plasma concentration (T _max) across these five doses of SUBSYS varied from 0.67 - 1.25 hours (range of 0.08 – 4.00 hours) as measured after the start of administration.

Distribution

Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.

Elimination

Metabolism

Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see Drug Interactions ( 7 )] .

Excretion

Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important. The total plasma clearance of fentanyl was 0.5 L/hr/kg (range 0.3 - 0.7 L/hr/kg). The terminal half-life after SUBSYS administration is from 5 to 12 hours.

Specific Population

Patients with mucositis:

The effect of mucositis (Grades 1 and 2) on the pharmacokinetics of SUBSYS was studied in a group of cancer patients with mucositis (N = 7 for Grade 1 and N = 2 for Grade 2) and without mucositis (N = 8). A single 100 mcg dose was administered. Mean summary statistics (standard deviation in parentheses) for patients with Grade 1 mucositis and patients without mucositis are presented in Table 9. Cancer patients with Grade 1 mucositis exhibited 73% greater Cmax and 52% greater AUClast values in comparison to patients without mucositis. The two cancer patients with Grade 2 mucositis had 4- and 7-fold higher C _max and ≥3- fold higher AUC _last values compared to patients without mucositis.

Monitor patients with Grade 1 mucositis closely for signs of respiratory and central nervous system depression particularly during initiation of therapy with SUBSYS. As a result of the large and variable increase in exposure of fentanyl, use of SUBSYS should be avoided in patients with Grade 2 and more severe mucositis unless the benefits are expected to outweigh the risk of respiratory depression.

Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of fentanyl have not been conducted

Mutagenesis
Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

Impairment of Fertility
Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg intravenously and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for SUBSYS.