2.1 Important Dosage and Administration Instructions

• Healthcare professionals who prescribe FENTORA for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of FENTORA [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 FENTORA 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 FENTORA. 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 FENTORA securely and to properly dispose of unused FENTORA as soon as no longer needed [see Warnings and Precautions (5.1, 5.3)].
• FENTORA 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)].
• FENTORA 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 FENTORA [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 FENTORA is always 100 mcg with the only exception being patients already using ACTIQ.

Patients on ACTIQ

a. For patients being converted from ACTIQ, prescribers must use the Initial Dosing Recommendations for Patients on ACTIQ table below (Table 1). The doses of FENTORA in this table are starting doses and not intended to represent equianalgesic doses to ACTIQ. Patients must be instructed to stop the use of ACTIQ and dispose of any remaining units.

*From this initial dose, titrate patient to effective dose.

b. For patients converting from ACTIQ doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg FENTORA tablet and should proceed using multiples of this tablet strength.

Repeat Dosing

1. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of FENTORA for any episode of breakthrough pain.
2. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA.

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 FENTORA 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 FENTORA 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 FENTORA for any breakthrough pain episode. During titration, one dose of FENTORA 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 FENTORA. To reduce the risk of overdose during titration, patients should have only one strength of FENTORA tablets available at any time.
5. Patients should be strongly encouraged to use all of their FENTORA tablets of one strength prior to being prescribed the next strength. If this is not practical, unused FENTORA should be disposed of safely [see How Supplied/Storage and Handling (16)]. Dispose of any unopened FENTORA 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 FENTORA 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 FENTORA.
4. Dosage adjustment of FENTORA may be required in some patients.
   Generally, the FENTORA 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 FENTORA

Opening the Blister Package:

1. Instruct patients not to open the blister until ready to administer FENTORA.
2. Separate a single blister unit from the blister card by bending and tearing apart at the perforations.
3. Bend the blister unit along the line where indicated.
4. Peel back the blister backing to expose the tablet. Patients should NOT attempt to push the tablet through the blister as this may cause damage to the tablet.
5. Do not store the tablet once it has been removed from the blister package as the tablet integrity may be compromised and, more importantly, because this increases the risk of accidental exposure to the tablet.

Tablet Administration:

Once the tablet is removed from the blister unit, the patient should immediately place the entire FENTORA tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or place the entire FENTORA tablet under the tongue. Patients should not split the tablet.

The FENTORA tablet should not be crushed, sucked, chewed, or swallowed whole, as this will result in lower plasma concentrations than when taken as directed.

The FENTORA tablet should be left between the cheek and gum or under the tongue until it has disintegrated, which usually takes approximately 14-25 minutes.

After 30 minutes, if remnants from the FENTORA tablet remain, they may be swallowed with a glass of water.

It is recommended that patients alternate sides of the mouth when administering subsequent doses of FENTORA in the buccal cavity.

2.7 Discontinuation of FENTORA

For patients no longer requiring opioid therapy, consider discontinuing FENTORA 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, FENTORA therapy can usually be discontinued immediately [see Drug Abuse and Dependence (9.3)].

2.8 Disposal of FENTORA

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

5.1 Addiction, Abuse, and Misuse

FENTORA contains fentanyl, a Schedule II controlled substance. As an opioid, FENTORA 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 FENTORA. 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 FENTORA, and reassess all patients receiving FENTORA 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 FENTORA, but use in such patients necessitates intensive counseling about the risks and proper use of FENTORA 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 FENTORA. 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 FENTORA, 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 FENTORA are essential [see Dosage and Administration (2)]. Overestimating the FENTORA dosage can result in a fatal overdose with the first dose. The substitution of FENTORA for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].

FENTORA 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 FENTORA, 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)].

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 FENTORA. 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.

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 Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.4), Overdosage (10)].

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 FENTORA 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 FENTORA are provided in the FENTORA 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 FENTORA 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 FENTORA 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 FENTORA from any other fentanyl product on a mcg per mcg basis as FENTORA and other fentanyl products are not equivalent on a microgram per microgram basis.

FENTORA is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a FENTORA prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and FENTORA are not equivalent. Substantial differences exist in the pharmacokinetic profile of FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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 FENTORA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in FENTORA-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using FENTORA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in FENTORA-treated patients, evaluate patients at frequent intervals and consider dosage reduction of FENTORA until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of FENTORA 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 FENTORA 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)], FENTORA 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 FENTORA prescription.
• Outpatients must be enrolled in the REMS program and must be opioid-tolerant to receive FENTORA [see Dosage and Administration (2.1)].
• Outpatient pharmacies must be certified with the REMS program and verify documentation of opioid tolerance with every FENTORA prescription.
• Inpatient pharmacies must be certified with the REMS program and develop policies and procedures to verify opioid tolerance in inpatients who require FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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: FENTORA-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 FENTORA [see Warnings and Precautions (5.2)].

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 (5.2)].

Regularly evaluate patients, particularly when initiating and titrating FENTORA and when FENTORA is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

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

FENTORA 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 FENTORA. In patients with circulatory shock, FENTORA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of FENTORA 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), FENTORA 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 FENTORA.

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

5.15 Risks of Use in Patients with Gastrointestinal Conditions

FENTORA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in FENTORA 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 FENTORA 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 FENTORA therapy.

5.17 Risks of Driving and Operating Machinery

FENTORA 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 FENTORA and know how they will react to the medication.

5.18 Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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.

*Three hundred and two (302) patients were included in the safety analysis.

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 FENTORA. There was no evidence of excess toxicity in this subset of patients.

Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesia to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited, and only resulted in treatment discontinuation for 2% of patients.

The duration of exposure to FENTORA varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving FENTORA. Events are classified by system organ class.

Adverse Events (≥1%)

Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration

General Disorders and Administration Site Conditions: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess

Injury, Poisoning, and Procedural Complications: Fall, Spinal Compression Fracture

Investigations: Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy

Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic, and Mediastinal Disorders: Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat

Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis

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.

Nervous System Disorders:

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

- Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

Endocrine Disorders:

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

- Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Immune System Disorders:

- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in FENTORA.

General Disorders and Administration Site Conditions:

- Drug withdrawal syndrome

Metabolic and Nutritional Disorders:

- Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

8.1 Pregnancy

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.8)]. Available data with FENTORA in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of FENTORA for an extended period of time during pregnancy (see Clinical Considerations).

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 were noted in animal studies completed to date [see Data].

The 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 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time 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 of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. 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. FENTORA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including FENTORA, 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 (25, 50, or 100 mcg/kg) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison).

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of FENTORA on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of FENTORA based on a mg/m2 basis). 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 FENTORA per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean Cmax observed following administration of 800 mcg dose of FENTORA in humans.

In a postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.

8.2 Lactation

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 FENTORA.

Clinical Considerations

Monitor infants exposed to FENTORA 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 breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Use of opioids for an extended period of time 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 (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and efficacy of FENTORA 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 FENTORA, 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 FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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

FENTORA contains fentanyl, a Schedule II controlled substance.

9.2 Abuse

FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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 FENTORA 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.

FENTORA, 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.

Risks Specific to Abuse of FENTORA

Abuse of FENTORA poses a risk of overdose and death. The risk is increased with concurrent use of FENTORA with alcohol and/or other CNS depressants.

FENTORA is approved for oral transmucosal use only.

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)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Effects on the Central Nervous System

The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem to both increases in carbon dioxide 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 origin 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 in the 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 the 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

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)]. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Use of opioids for an extended period of time 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 [see Dosage and Administration (2.1)].

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 [see Dosage and Administration (2.1, 2.5)].

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, 2.4, 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), Overdosage (10)].

12.3 Pharmacokinetics

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

Absorption

Following buccal administration of FENTORA, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of FENTORA 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 FENTORA and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with FENTORA) (Table 5).

* Based on venous blood samples.

** Data for Tmax presented as median (range).

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

Similarly, in another bioavailability study exposure following administration of FENTORA 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 FENTORA 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 FENTORA.

Figure 1. Mean Plasma Concentration Versus Time Profiles Following Single Doses of FENTORA 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.

* Based on venous sampling.

** Data for Tmax presented as median (range).

Figure 2. Mean Plasma Concentration Versus Time Profiles Following Single 100, 200, 400, and 800 mcg Doses of FENTORA 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 FENTORA 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.

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

Distribution

Fentanyl is highly lipophilic. 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 mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.

Elimination

Metabolism

The metabolic pathways following buccal administration of FENTORA have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active [see Drug Interactions (7)].

Excretion

Disposition of fentanyl following buccal administration of FENTORA has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered 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 following intravenous administration is approximately 42 L/h.

Sex

Systemic exposure was higher for women than men (mean Cmax and AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.

Race

In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects (mean Cmax and AUC values were approximately 50% and 20% higher, respectively). The observed differences were largely attributed to the lower mean weight of the Japanese subjects compared to U.S. subjects (57.4 kg versus 73 kg).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 2.3- and 3.4-times the exposure of a single human dose of 800 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.

Mutagenesis

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

Impairment of Fertility

In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 8.6 times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison. Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm. The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 5.7- times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.

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