2.1 Important Dosage and Administration Information

• Healthcare professionals who prescribe ABSTRAL on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of ABSTRAL [see Warnings and Precautions (5.7)].
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
• It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.6)].
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with ABSTRAL; adjust the dosage accordingly [see Warnings and Precautions (5.1)].
• Instruct patients and caregivers to take steps to store ABSTRAL securely and to properly dispose of unused ABSTRAL as soon as no longer needed [see Warnings and Precautions (5.2, 5.6), Patient Counseling Information (17)].
• ABSTRAL 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)].
• ABSTRAL is NOT a generic version of any other oral transmucosal fentanyl product.

2.2 Initial Dosage

Initiate treatment with ABSTRAL for all patients with a single initial dose of 100 mcg. The initial dose of ABSTRAL is always 100 mcg, with the only exception being patients already using ACTIQ.

• If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg tablet, continue to treat subsequent episodes of breakthrough pain with this dose.
• If adequate analgesia is not obtained after a single dose of ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their healthcare provider. No more than two doses of ABSTRAL may be used to treat an episode of breakthrough pain [see Titration and Maintenances of Therapy(2.3)].
• Patients must wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL.

Due to differences in the pharmacokinetic properties and individual variability, even patients switching from other products containing fentanyl to ABSTRAL must start with the 100 mcg dose (except patients switching from ACTIQ).

ABSTRAL is not equivalent on a mcg per mcg basis with all other fentanyl products. Therefore, do not switch patients on a mcg per mcg basis from any other fentanyl products. ABSTRAL is NOT a generic version of any other fentanyl product.

Converting to ABSTRAL from ACTIQ

1. For patients being converted from ACTIQ, prescribers must use the Initial Dosing Recommendations for Patients on ACTIQ. See Table 1 for initial dosing recommendations. Patients must be instructed to stop the use of ACTIQ and dispose of any remaining units.

   Table 1: Initial Dosing Recommendations for Patients on ACTIQ

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

2. For patients converting from ACTIQ doses of 200 mcg and 400 mcg, initiate titration with 100 mcg and 200 mcg of ABSTRAL, respectively and proceed using multiples of this strength.
3. For patients converting from ACTIQ doses of 600 and 800 mcg, initiate titration with 200 mcg of ABSTRAL and proceed using multiples of this strength.
4. For patients converting from ACTIQ doses of 1200 and 1600 mcg, initiate titration with 200 mcg and 400 mcg of ABSTRAL, respectively and proceed using multiples of this strength.

2.3 Titration and Maintenance of Therapy

Titration

The objective of dose titration is to identify an effective and tolerable maintenance dose. From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia using a single ABSTRAL dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient's mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of ABSTRAL over several episodes of breakthrough cancer pain and review their experience with their healthcare providers to determine if a dosage adjustment is warranted for management of breakthrough cancer pain episodes. The effective and tolerable dose of ABSTRAL will be determined by dose titration in individual patients.

If adequate analgesia was not obtained with the first 100 mcg dose, continue dose escalation in a stepwise manner over consecutive breakthrough episodes until adequate analgesia with tolerable side effects is achieved. Increase the dose by 100 mcg multiples up to 400 mcg as needed. If adequate analgesia is not obtained with a 400 mcg dose, the next titration step is 600 mcg. If adequate analgesia is not obtained with a 600 mcg dose, the next titration step is 800 mcg. During titration, patients can be instructed to use multiples of 100 mcg tablets and/or 200 mcg tablets for any single dose. Instruct patients not to use more than 4 tablets at one time. If adequate analgesia is not obtained 30 minutes after the use of ABSTRAL, the patient may repeat the same dose of ABSTRAL. No more than two doses of ABSTRAL may be used to treat an episode of breakthrough pain. Rescue medication, as directed by the health care provider, can be used if adequate analgesia is not achieved after use of ABSTRAL.

The efficacy and safety of doses higher than 800 mcg have not been evaluated in clinical studies in patients.

In order to minimize the risk of ABSTRAL-related adverse reactions and to identify the appropriate dose, it is imperative that patients be supervised closely by health professionals during the titration process.

2.4 Administration of ABSTRAL

Instruct patients to place ABSTRAL tablets on the floor of the mouth, directly under the tongue, immediately after removal from the blister unit and not to chew, suck, or swallow ABSTRAL tablets. Allow ABSTRAL tablets to completely dissolve in the sublingual cavity. Advise patients not to eat or drink anything until the tablet is completely dissolved.

In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking ABSTRAL.

2.5 Discontinuation of ABSTRAL

For patients no longer requiring opioid therapy, consider discontinuing ABSTRAL, along with a gradual downward titration of other opioids to minimize possible withdrawal effects.

In patients who continue to take their chronic opioid therapy for persistent pain, but no longer require treatment for breakthrough pain, ABSTRAL therapy can usually be discontinued immediately.

2.6 Disposal of ABSTRAL

Patients and their household members must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed. Instructions are included in Patient Counseling Information (17) and in the Medication Guide.

To dispose of any unused ABSTRAL tablets, remove them from the blister cards and flush them down the toilet. Do not dispose of the ABSTRAL blister cards or cartons down the toilet.

If additional assistance is required, call 1-888-227-8725.

5.1 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 ABSTRAL, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with, and following dosage increases of, ABSTRAL.

To reduce the risk of respiratory depression, proper dosing and titration of ABSTRAL are essential [see Dosage and Administration (2.3)]. Overestimating the ABSTRAL dosage can result in a fatal overdose with the first dose. The substitution of ABSTRAL for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].

ABSTRAL 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 ABSTRAL, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.

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, Discontinuation (2.5)].

5.2 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 (TIRF) products.

Patients and their caregivers must be informed that ABSTRAL 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 [see Patient Counseling Information (17)].

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

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

Concomitant use of ABSTRAL 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 (5.1)], particularly when an inhibitor is added after a stable dose of ABSTRAL is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ABSTRAL treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using ABSTRAL with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ABSTRAL-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ABSTRAL until stable drug effects are achieved [see Dosage and Administration (2.3), Drug Interactions (7)].

Concomitant use of ABSTRAL 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 ABSTRAL with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia, or if symptoms of opioid withdrawal occur [see Dosage and Administration (2.3), Drug Interactions (7)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

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

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

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

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

5.5 Risk of Medication Errors

When prescribing, DO NOT convert a patient to ABSTRAL from any other fentanyl products on a mcg per mcg basis as ABSTRAL and other fentanyl products are not equivalent on a microgram per microgram basis.

ABSTRAL is not a generic version of other transmucosal immediate-release fentanyl (TIRF) formulations. When dispensing, do not substitute an ABSTRAL prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and ABSTRAL are not equivalent. Substantial differences exist in the pharmacokinetic profile of ABSTRAL 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 ABSTRAL or 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 [see Dosage and Administration (2.1)]. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of ABSTRAL should always be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects [see Dosage and Administration (2.3)].

5.6 Addiction, Abuse, and Misuse

ABSTRAL contains fentanyl, a Schedule II controlled substance. As an opioid, ABSTRAL 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 ABSTRAL. 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 ABSTRAL, and monitor all patients receiving ABSTRAL 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 ABSTRAL, but use in such patients necessitates intensive counseling about the risks and proper use of ABSTRAL, along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ABSTRAL. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact your local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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

Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence (9)], ABSTRAL is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long- term care facilities that prescribe for inpatient use) of ABSTRAL, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

• Healthcare professionals who prescribe ABSTRAL must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
• To receive ABSTRAL, outpatients must understand the risks and benefits and sign a Patient- Prescriber Agreement.
• Pharmacies that dispense ABSTRAL must enroll in the program and agree to comply with the REMS requirements.
• Wholesalers and distributors that distribute ABSTRAL must enroll in the program and distribute only to authorized pharmacies.

Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

5.8 Neonatal Opioid Withdrawal Syndrome

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

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

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

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

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

5.11 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.

5.12 Severe Hypotension

ABSTRAL may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of ABSTRAL. In patients with circulatory shock, ABSTRAL may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ABSTRAL in patients with circulatory shock.

5.13 Risk 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), ABSTRAL 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 ABSTRAL.

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

5.14 Risk of Use in Patients with Gastrointestinal Conditions

ABSTRAL is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in ABSTRAL may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

The fentanyl in ABSTRAL may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ABSTRAL therapy.

5.16 Risks of Driving and Operating Machinery

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

5.17 Cardiac Disease

Intravenous administration of fentanyl may produce bradycardia. Therefore, use ABSTRAL with caution in patients with bradyarrhythmias.

6.1 Clinical Trials 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 ABSTRAL has been evaluated in 311 opioid-tolerant cancer patients with breakthrough pain. Two hundred and seventy (270) of these patients were treated in multiple-dose studies. The duration of therapy for patients in multiple-dose studies ranged from 1-405 days with an average duration of 131 days and with 44 patients treated for at least 12 months.

The clinical trials of ABSTRAL 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 reaction data presented in Table 2 reflect the actual percentage of patients experiencing reactions among patients who received ABSTRAL for breakthrough pain along with concomitant opioid use for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of ABSTRAL therapy, or cancer-related symptoms.

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

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

The frequencies listed below represent adverse reactions that occurred in ≥1% of patients from two clinical trials who experienced that reaction while receiving ABSTRAL. Reactions are classified by system organ class.

Adverse Reactions (≥ 1%)

Cardiac disorders: bradycardia, tachycardia.

Eye disorders: vision blurred.

Gastrointestinal disorders: abdominal pain, abdominal pain upper, aphthous stomatitis, constipation, dry mouth, dyspepsia, gingival ulceration, impaired gastric emptying, lip ulceration, mouth ulceration, nausea, stomach discomfort, stomatitis, tongue disorder, vomiting.

General disorders and administration site conditions: asthenia, drug withdrawal syndrome, fatigue, malaise.

Immune system disorders: drug hypersensitivity.

Injury, poisoning and procedural complications: accidental overdose.

Metabolism and nutrition disorders: anorexia, decreased appetite.

Nervous system disorders: amnesia, disturbance in attention, dizziness, dysgeusia, headache, hypoesthesia, lethargy, parosmia, somnolence, tremor.

Psychiatric disorders: affect lability, anxiety, confusional state, depression, disorientation, dysphoria, euphoric mood, insomnia, mental status changes, paranoia, sleep disorder.

Reproductive system and breast disorders: erectile dysfunction.

Respiratory, thoracic and mediastinal disorder: dyspnea, oropharyngeal pain, throat tightness.

Skin and subcutaneous disorders: hyperhidrosis, night sweats, pruritus, rash, skin lesion.

Vascular disorders: hypotension.

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.

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

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

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

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

8.1 Pregnancy - Category C

There are no adequate and well-controlled studies in pregnant women.

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of ABSTRAL have not been established in patients below 18 years of age.

8.5 Geriatric Use

Of the 270 opioid tolerant patients with breakthrough cancer pain in the Phase 3 clinical studies of ABSTRAL, 58 (21%) were 65 years of age and older. There was no difference in the median titrated dose in patients aged 65 years and older compared to those <65 years. No clinically meaningful difference was noted in the safety profile of the group 65 years of age and older, as compared to younger patients in ABSTRAL clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when it is administered intravenously, compared with the younger adult population. Therefore, exercise caution when individually titrating ABSTRAL 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 ABSTRAL slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)].

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

8.6 Patients with Renal and Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of ABSTRAL in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system, and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, use the drug with caution because of the reduced hepatic metabolism and renal excretion capacity in such patients.

8.7 Sex

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

9.1 Controlled Substance

ABSTRAL contains fentanyl, a Schedule II substance.

9.2 Abuse and Addiction

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

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

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

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

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

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

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

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

9.3 Dependence

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

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

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

Clinical Presentation

Acute overdose with ABSTRAL 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, 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 Overdosage

In case of overdose, priorities are the reestablishment 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 techniques.

The opioid antagonists, naloxone or nalmefene, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in ABSTRAL, 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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Storage and Disposal of Unused and Used ABSTRAL [see Instructions for Use]

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ABSTRAL securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.2, 5.6), Drug Abuse and Dependence (9.2)]. Inform patients that leaving ABSTRAL unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused ABSTRAL should be disposed of by removing ABSTRAL from the blister cards and flushing the unused medication down the toilet (if a drug take-back option is not readily available). 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.

• Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ABSTRAL are provided in the ABSTRAL Medication Guide. Ensure patients read this information in its entirety and give them an opportunity to have their questions answered.
• In the event that a caregiver requires additional assistance in disposing of excess units that remain in the home after the drug is no longer needed, instruct them to call the toll-free number for Sentynl Therapeutics, Inc. 1-888-227-8725 or seek assistance from their local DEA office.

Advise the patient to read FDA-approved patient labeling (Medication Guide).

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ABSTRAL or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.1)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Increased Risk of Overdose and Death in Children Due to 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 (5.2)].
• Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].
• Instruct patients to take steps to store ABSTRAL securely and to dispose of unused ABSTRAL by removing them from the blister cards and flushing them down the toilet [see Disposal of Unopened ABSTRAL Blister Packages When No Longer Needed].
• Instruct patients and caregivers to keep both used and unused ABSTRAL out of the reach of children [see Warnings and Precautions (5.2)].

Interactions with Benzodiazepines and Other CNS Depressants

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

Addiction, Abuse, and Misuse

Inform patients that the use of ABSTRAL, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.6)]. Instruct patients not to share ABSTRAL with others and to take steps to protect ABSTRAL from theft or misuse.

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

Advise patients of the following information pertaining to the TIRF REMS:

• Inform outpatients that they must be enrolled in the TIRF REMS Access program before they can receive ABSTRAL.
• Allow patients the opportunity to ask questions and discuss any concerns regarding ABSTRAL or the TIRF REMS Access program.
• As required by the TIRF REMS Access program, review the contents of the ABSTRAL Medication Guide with every patient before initiating treatment with ABSTRAL.
• Advise the patient that ABSTRAL is available only from pharmacies that are enrolled in the TIRF REMS Access program, and provide them with the telephone number and website for information on how to obtain the drug.
• Advise the patient that only enrolled healthcare providers may prescribe ABSTRAL.
• Inform the patient that they must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of ABSTRAL.
• Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access program [see Warnings and Precautions (5.7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare and potentially life-threatening condition 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 ABSTRAL while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ABSTRAL [see Warnings and Precautions (5.10), Drug Interactions (7)].

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 (5.11)].

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

• Instruct patients not to take ABSTRAL 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.
• Inform patients on the meaning of opioid tolerance and that ABSTRAL 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.
• Advise patients that, if they are not taking an opioid medication on a regular around-the-clock basis, they must not take ABSTRAL.
• Instruct patients to place ABSTRAL tablets on the floor of the mouth directly under the tongue immediately after removal from the blister unit.
• Instruct patients not to chew, suck, or swallow ABSTRAL tablets.
• Instruct patients to allow ABSTRAL tablets to completely dissolve in the sublingual cavity.
• Advise patients not to eat or drink anything until the tablet is completely dissolved [see Dosage and Administration (2.4), ABSTRAL Medication Guide].
• In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking ABSTRAL. Instruct patients not to take more than 2 doses of ABSTRAL for each episode of breakthrough cancer pain.
• Instruct patients to wait two hours before treating a new episode of breakthrough pain with ABSTRAL.
• Instruct patients NOT to share ABSTRAL and that sharing ABSTRAL with anyone else could result in the other individual's death due to overdose.
• Instruct patients to use ABSTRAL exactly as prescribed by their doctor and not to take ABSTRAL more often than prescribed.

Hypotension

Inform patients that ABSTRAL 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 (5.12)].

Anaphylaxis

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

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform patients that prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that ABSTRAL can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise nursing mothers to monitor 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 chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that ABSTRAL 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 (5.16)].

Constipation

Advise patients of the potential for severe constipation and when to seek medical attention [see Adverse Reactions (6)].

Manufactured by:
Pharmaceutics International, Inc.
Hunt Valley, MD 21031

Manufactured for and Distributed by:
Sentynl Therapeutics, Inc.

Solana Beach, CA 92075