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 and dental pain [see Contraindications (4)].
• As a part of the TIRF REMS, fentanyl buccal tablet may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions (5.7)]. For inpatient administration of fentanyl buccal tablet, patient and prescriber enrollment are not required.

2.1 Important Dosage and Administration Instructions

• Healthcare professionals who prescribe fentanyl buccal tablet for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of fentanyl buccal tablet [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)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of fentanyl buccal tablet for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 (5.1)].
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with fentanyl buccal tablet. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].
• Instruct patients and caregivers to take steps to store fentanyl buccal tablet securely and to properly dispose of unused fentanyl buccal tablet as soon as no longer needed [see Warnings and Precautions (5.1, 5.3)].
• Fentanyl buccal tablet 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)].
• Fentanyl buccal tablet is NOT a generic version of any other transmucosal fentanyl product [see Warnings and Precautions (5.5)].

2.2 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 fentanyl buccal tablet [see Warnings and Precautions (5.2)].

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, 5.2, 5.4)].

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

2.3 Initial Dosage

The initial dose of fentanyl buccal tablet is always 100 mcg with the only exception being patients already using ACTIQ.

2.4 Dose Titration

1. From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of fentanyl buccal tablet/s over several episodes of breakthrough pain and discuss their experience with their healthcare provider to determine if a dosage adjustment is warranted.
2. Patients whose initial dose is 100 mcg and who need to titrate to a higher dose, can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this dosage is not successful, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the 200 mcg fentanyl buccal tablet for doses above 400 mcg (600 mcg and 800 mcg). Note: Do not use more than 4 tablets simultaneously.
3. In cases where the breakthrough pain episode 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 fentanyl buccal tablet for any breakthrough pain episode. During titration, one dose of fentanyl buccal tablet may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg).
4. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet. To reduce the risk of overdose during titration, patients should have only one strength of fentanyl buccal tablet/s available at any time.
5. Patients should be strongly encouraged to use all of their fentanyl buccal tablets of one strength prior to being prescribed the next strength. If this is not practical, unused fentanyl buccal tablets should be disposed of safely [see How Supplied/Storage and Handling (16)]. Dispose of any unopened fentanyl buccal tablets remaining from a prescription as soon as they are no longer needed.

2.5 Maintenance Dosing

1. Once titrated to an effective dose, patients should generally use only ONE fentanyl buccal tablet of the appropriate strength per breakthrough pain episode.
2. On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode.
3. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet.
4. Dosage adjustment of fentanyl buccal tablet may be required in some patients.
   Generally, the fentanyl buccal tablet dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
5. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the around-the-clock opioid used for persistent pain should be re-evaluated.
6. Once an effective dose is determined using the titration scheme outlined above, an alternate route of administration is sublingual (placing the tablet under the tongue).

2.6 Administration of Fentanyl Buccal Tablet

2.7 Discontinuation of Fentanyl Buccal Tablet

For patients no longer requiring opioid therapy, consider discontinuing fentanyl buccal tablet along with a gradual downward tapering (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, fentanyl buccal tablet therapy can usually be discontinued immediately [see Drug Abuse and Dependence (9.3)].

2.8 Disposal of Fentanyl Buccal Tablets

To dispose of unused fentanyl buccal tablets, remove fentanyl buccal tablets from blister packages and flush down the toilet. Do not flush fentanyl buccal tablets blister packages or cartons down the toilet. If you need additional assistance with disposal of fentanyl buccal tablets, call Teva Pharmaceuticals at 1-888-483-8279.

5.1 Addiction, Abuse, and Misuse

Fentanyl buccal tablet contains fentanyl, a Schedule II controlled substance. As an opioid, fentanyl buccal tablet 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 fentanyl buccal tablet. 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 fentanyl buccal tablet, and reassess all patients receiving fentanyl buccal tablet for the development of these behaviors and 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 fentanyl buccal tablet, but use in such patients necessitates intensive counseling about the risks and proper use of fentanyl buccal tablet along with frequent reevaluation 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 (5.2)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing fentanyl buccal tablet. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. 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.

5.2 Life-Threatening Respiratory Depression

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 (CO2) 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 fentanyl buccal tablet, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of fentanyl buccal tablet is essential [see Dosage and Administration (2)]. Overestimating the fentanyl buccal tablet dosage can result in a fatal overdose with the first dose. The substitution of fentanyl buccal tablet for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].

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

Accidental ingestion of even one dose of fentanyl buccal tablet, especially by children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions (5.3)].

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.

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 (2.7)].

5.3 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.

Patients and their caregivers must be informed that fentanyl buccal tablet contains a medicine in an amount which can be fatal to a child. Healthcare providers 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.

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

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol)

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl buccal tablet with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including 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 (5.2)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when fentanyl buccal tablet 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)].

5.5 Risk of Medication Errors

When prescribing, do not convert a patient to fentanyl buccal tablet from any other fentanyl product on a mcg per mcg basis as fentanyl buccal tablet and other fentanyl products are not equivalent on a microgram per microgram basis.

Fentanyl buccal tablet is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a fentanyl buccal tablet prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and fentanyl buccal tablet are not equivalent. Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablet 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 fentanyl buccal tablet 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 except ACTIQ. (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 fentanyl buccal tablet should always be 100 mcg. Individually titrate each patient's dose to provide adequate analgesia while minimizing side effects [see Dosage and Administration (2.4)].

5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of fentanyl buccal tablet 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 (5.2)], particularly when an inhibitor is added after a stable dose of fentanyl buccal tablet is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl buccal tablet-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl buccal tablet with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl buccal tablet-treated patients, evaluate patients at frequent intervals and consider dosage reduction of fentanyl buccal tablet until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of fentanyl buccal tablet with CYP3A4 inducers or discontinuation of a 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 fentanyl buccal tablet with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients 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)].

5.7 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS)

Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)], fentanyl buccal tablet is available only through a restricted program 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 fentanyl buccal tablet prescription.
• Outpatients must be enrolled in the REMS program and must be opioid-tolerant to receive fentanyl buccal tablet [see Dosage and Administration (2.1)].
• Outpatient pharmacies must be certified with the REMS program and verify documentation of opioid tolerance with every fentanyl buccal tablet prescription.
• Inpatient pharmacies must be certified with the REMS program and develop policies and procedures to verify opioid tolerance in inpatients who require fentanyl buccal tablet while hospitalized.
• Wholesalers and distributors 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.

5.8 Neonatal Opioid Withdrawal Syndrome

Use of fentanyl buccal tablet for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

5.9 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.7)].

5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl buccal tablet 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) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue fentanyl buccal tablet if serotonin syndrome is suspected.

5.11 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of fentanyl buccal tablet in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

5.12 Adrenal Insufficiency

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.

5.13 Severe Hypotension

Fentanyl buccal tablet 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)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of fentanyl buccal tablet. In patients with circulatory shock, fentanyl buccal tablet may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of fentanyl buccal tablet in patients with circulatory shock.

5.14 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 (e.g., those with evidence of increased intracranial pressure or brain tumors), fentanyl buccal tablet may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl buccal tablet.

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

5.15 Risks of Use in Patients with Gastrointestinal Conditions

Fentanyl buccal tablet is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in fentanyl buccal tablet may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.16 Increased Risk of Seizures in Patients with Seizure Disorders

The fentanyl in fentanyl buccal tablet 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during fentanyl buccal tablet therapy.

5.17 Risks of Driving and Operating Machinery

Fentanyl buccal tablet 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 fentanyl buccal tablet and know how they will react to the medication.

5.18 Cardiac Disease

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

5.19 Application Site Reactions

Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding [see Adverse Reactions (6)].

6.1 Clinical Studies Experience

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 fentanyl buccal tablets has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months.

The clinical trials of fentanyl buccal tablets were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain.

The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received fentanyl buccal tablets for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of fentanyl buccal tablets therapy or cancer-related symptoms.

Table 2 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.

Table 3 lists, by successful dose, adverse events with an overall frequency of ≥5% within the total population that occurred after a successful dose had been determined.

In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of fentanyl buccal tablets. There was no evidence of excess toxicity in this subset of patients.

6.2 Postmarketing Experience

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of fentanyl buccal tablet have not been established in pediatric patients below the age of 18 years.

8.5 Geriatric Use

Of the 304 patients with cancer in clinical studies of fentanyl buccal tablets, 69 (23%) were 65 years of age and older. Patients over the age of 65 years tended to titrate to slightly lower doses than younger patients. Patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. Therefore, caution should be exercised in individually titrating fentanyl buccal tablet in elderly patients to provide adequate efficacy while minimizing risk.

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 fentanyl buccal tablet slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.11)].

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 regularly evaluate renal function.

8.6 Patients with Renal or Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of fentanyl buccal tablet in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

8.7 Sex

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.

8.8 Race

The pharmacokinetic effects of race with the use of fentanyl buccal tablet have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects.

9.1 Controlled Substance

Fentanyl buccal tablet contains fentanyl, a Schedule II controlled substance.

9.2 Abuse

Fentanyl buccal tablet contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of fentanyl buccal tablet increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of fentanyl buccal tablet with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl buccal tablet abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl buccal tablet in combination with other abused drugs.

"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 healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Fentanyl buccal tablet, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

9.3 Dependence

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), 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 use.

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)].

Clinical Presentation

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl buccal tablet, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of fentanyl buccal tablet increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.

Absorption

Following buccal administration of fentanyl buccal tablet, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of fentanyl buccal tablet is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after buccal administration. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract.

In a study that compared the absolute and relative bioavailability of fentanyl buccal tablet and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with fentanyl buccal tablet) (Table 5).

Table 5. Pharmacokinetic Parameters* in Adult Subjects Receiving Fentanyl Buccal Tablet or ACTIQ

Pharmacokinetic Parameter (mean)	Fentanyl Buccal Tablet 400 mcg	ACTIQ 400 mcg (adjusted dose)†
* Based on venous blood samples. † ACTIQ data was dose adjusted (800 mcg to 400 mcg). ‡ Data for Tmax presented as median (range).
Absolute Bioavailability	65% ± 20%	47% ± 10.5%
Fraction Absorbed Transmucosally	48% ± 31.8%	22% ± 17.3%
Tmax (minute)‡	46.8 (20-240)	90.8 (35-240)
Cmax (ng/mL)	1.02 ± 0.42	0.63 ± 0.21
AUC0-tmax (ng∙hr/mL)	0.40 ± 0.18	0.14 ± 0.05
AUC0-inf (ng∙hr/mL)	6.48 ± 2.98	4.79 ± 1.96

Similarly, in another bioavailability study exposure following administration of fentanyl buccal tablet was also greater (approximately 50%) compared to ACTIQ.

Due to differences in drug delivery, measures of exposure (Cmax, AUC0-tmax, AUC0-inf) associated with a given dose of fentanyl were substantially greater with fentanyl buccal tablet compared to ACTIQ (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another [see Dosage and Administration (2.3), Warnings and Precautions (5.5)]. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tmax for fentanyl buccal tablet.

Figure 1. Mean Plasma Concentration Versus Time Profiles Following Single Doses of Fentanyl Buccal Tablet and ACTIQ in Healthy Subjects

ACTIQ data was dose adjusted (800 mcg to 400 mcg).

Mean pharmacokinetic parameters are presented in Table 6. Mean plasma concentration versus time profiles are presented in Figure 2.

Table 6. Pharmacokinetic Parameters* Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets in Healthy Subjects

Pharmacokinetic Parameter (mean±SD)	100 mcg	200 mcg	400 mcg	800 mcg
* Based on venous sampling. † Data for Tmax presented as median (range).
Cmax (ng/mL)	0.25 ± 0.14	0.40 ± 0.18	0.97 ± 0.53	1.59 ± 0.90
Tmax, minute† (range)	45.0 (25.0 - 181.0)	40.0 (20.0 - 180.0)	35.0 (20.0 - 180.0)	40.0 (25.0 - 180.0)
AUC0-inf (ng∙hr/mL)	0.98 ± 0.37	2.11 ± 1.13	4.72 ± 1.95	9.05 ± 3.72
AUC0-tmax (ng∙hr/mL)	0.09 ± 0.06	0.13 ± 0.09	0.34 ± 0.23	0.52 ± 0.38
T1/2, hr†	2.63 (1.47 - 13.57)	4.43 (1.85 - 20.76)	11.09 (4.63 - 20.59)	11.70 (4.63 - 28.63)

Figure 2. Mean Plasma Concentration Versus Time Profiles Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets in Healthy Subjects

Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.

The effect of mucositis (Grade 1) on the pharmacokinetic profile of fentanyl buccal tablet was studied in a group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean summary statistics (standard deviation in parentheses, expected tmax where range was used) are presented in Table 7.

Table 7. Pharmacokinetic Parameters in Patients with Mucositis

Patient status	Cmax (ng/mL)	tmax (min)	AUC0-tmax (ng∙hr/mL)	AUC0-8 (ng∙hr/mL)
Mucositis	1.25 ± 0.78	25.0 (15 - 45)	0.21 ± 0.16	2.33 ± 0.93
No mucositis	1.24 ± 0.77	22.5 (10 - 121)	0.25 ± 0.24	1.86 ± 0.86

Following sublingual tablet placement, systemic exposure (as measured by AUC and Cmax) of fentanyl is equivalent to systemic exposure following buccal tablet placement.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.)

Protect fentanyl buccal tablet from freezing and moisture. Do not use if the blister package has been tampered with.

Store fentanyl buccal tablet securely and dispose of properly.

Storage and Disposal of Unused and Used Fentanyl Buccal Tablets [see Medication Guide / Instructions for Use].

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl buccal tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving fentanyl buccal tablets unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)].

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl buccal tablets should be disposed of by removing fentanyl buccal tablets from the blister cards and flushing the unused medication down the toilet (if a drug take-back option is not readily available). Do not flush the fentanyl buccal tablet blister packages or cartons down the toilet. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Addiction, Abuse, and Misuse

Inform patients that the use of fentanyl buccal tablet, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share fentanyl buccal tablet with others and to take steps to protect fentanyl buccal tablet from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl buccal tablet or when the dosage is increased, and that it can occur even at recommended dosages.

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 Warnings and Precautions (5.2)].

Accidental Ingestion

• Healthcare providers 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 [see Warnings and Precautions (5.3)].
• Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].
• Instruct patients to take steps to store fentanyl buccal tablet securely and to dispose of unused fentanyl buccal tablet [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.7)].
• Instruct patients and caregivers to keep both used and unused fentanyl buccal tablet out of the reach of children [see Warnings and Precautions (5.3)].

Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)

Inform patients that potentially fatal additive effects may occur if fentanyl buccal tablet is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl buccal tablet. 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) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

Fentanyl buccal tablet is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:

• Outpatients must be enrolled in the REMS program
• Patients must be opioid-tolerant to receive fentanyl buccal tablet.

Fentanyl buccal tablet is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require fentanyl buccal tablet while hospitalized [see Warnings and Precautions (5.7)].

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10), Drug Interactions (7)].

MAOI Interaction

Inform patients to avoid taking fentanyl buccal tablet while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl buccal tablet [see Warnings and Precautions (5.10), Drug Interactions (7)].

Important Administration Instructions [see Dosage and Administration (2)]

• Instruct patients not to take fentanyl buccal tablet for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions.
• Instruct patients on the meaning of opioid tolerance and that fentanyl buccal tablet is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes.
• Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take fentanyl buccal tablet.
• Instruct patients that the titration phase is the only period in which they may take more than ONE tablet to achieve a desired dose (e.g., two 100 mcg tablets for a 200 mcg dose).
• Instruct patients that, if the breakthrough pain episode is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF FENTANYL BUCCAL TABLET USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of fentanyl buccal tablet for any breakthrough pain episode.
• Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet.
• Instruct patients NOT to share fentanyl buccal tablet and that sharing fentanyl buccal tablet with anyone else could result in the other individual's death due to overdose.
• Make patients aware that fentanyl buccal tablet contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
• Instruct patients not to open the blister until ready to use fentanyl buccal tablet and not to store the tablet in a temporary container such as a pill box, once it has been removed from the blister package.
• Instruct patients that fentanyl buccal tablet is not to be swallowed whole; this will reduce the effectiveness of the medication. The tablet is to be placed between the cheek and gum above a molar tooth or under the tongue and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water.
• Caution patients to talk to their healthcare provider if breakthrough pain is not alleviated or worsens after taking fentanyl buccal tablet.
• Instruct patients to use fentanyl buccal tablet exactly as prescribed by their healthcare provider and not to take fentanyl buccal tablet more often than prescribed.
• Provide patients and their caregivers with a Medication Guide each time fentanyl buccal tablet is dispensed because new information may be available.

Driving or Operating Heavy Machinery

Inform patients that fentanyl buccal tablet may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)].

Hypotension

Inform patients that fentanyl buccal tablet may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.13)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in fentanyl buccal tablet. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Lactation

Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].