ABSTRAL FENTANYL- fentanyl citrate tablet, orally disintegrating
For Healthcare Providers >

1. Patient Information
2. Tablets When They Are No Longer Needed?
3. When You Get An Episode Of Breakthrough Pain, Take The Dose Prescribed By Your Healthcare Provider As Follows:
4. Revised: 10/2019document Id:

Patient Information ⮝

Storage and Disposal of Unused and Used ABSTRAL[for proper disposal of ABSTRAL.

DO NOTdrive or operate heavy machinery, until you know how ABSTRAL affects you. ABSTRAL can make you sleepy, dizzy, or lightheaded.

DO NOTdrink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ABSTRALmay cause you to overdose and die.

DO NOT switch from ABSTRALto other medicines that contain fentanyl without talking with your healthcare provider.The amount of fentanyl in a dose of ABSTRALis not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of ABSTRALthat may be different than other medicines containing fentanyl that you may have been taking.

How should I store ABSTRAL?

• Always keep ABSTRALin a safe place away from children and from anyone for whom it has not been prescribed.Protect ABSTRALfrom theft.
• Store ABSTRALat room temperature, 59 F to 86 F (15 C to 30 C) until ready to use.
• Keep ABSTRALin the original blister unit. Do not remove ABSTRALtablets from their blister packaging for storage in a temporary container, such as a pillbox.

How should I dispose of unopened ABSTRAL

Tablets When They Are No Longer Needed? ⮝

• Dispose of expired, unwanted, or unused Abstral by removing the product from the blister cards and promptly flushing down the toilet (if a drug take-back option is not readily available). Visitwww.fda.gov/drugdisposalfor additional information on disposal of unused medicines.
• Do not flush the ABSTRALblister cards, units, or cartons down the toilet.
• If you need help with disposal of ABSTRAL, call 1-888-227-8725 or call your local Drug Enforcement Agency (DEA) office.

General information about ABSTRAL

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.Use ABSTRALonly for the purpose for which it was prescribed. Do not give ABSTRALto other people, even if they have the same symptoms you have.ABSTRALcan harm other people and even cause death. Sharing ABSTRALis against the law.

This Medication Guide summarizes the most important information about ABSTRAL. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about ABSTRALthat is written for healthcare professionals.

For more information about the TIRF REMS Access program, go towww.TIRFREMSAccess.comor call 1- 866-822-1483.

What are the ingredients in ABSTRAL?

Active Ingredient: fentanyl citrate

Inactive Ingredients: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose

Patient Instructions for Use

Before you take ABSTRAL, it is important that you read the Medication Guide and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you take ABSTRALthe right way. Ask your healthcare provider or pharmacist if you have questions about the right way to take ABSTRAL.

When You Get An Episode Of Breakthrough Pain, Take The Dose Prescribed By Your Healthcare Provider As Follows: ⮝

• If your mouth is dry, take a sip of water to moisten it. Spit out or swallow the water. Dry your hands if they are wet before you handle ABSTRALtablets.
• ABSTRALcomes in a blister card with 4 blister units. Each blister unit contains an ABSTRALtablet. It is important that the tablet stays sealed in the blister unit until you are ready to use it.
• When you are ready to take an ABSTRALtablet, pull apart 1 of the blister units from the blister card by tearing along the dotted lines (perforations) until it is fully separated (SeeFigures 1and2).

• When the blister unit is fully separated, peel back the foil starting at the unsealed area where indicated. Gently remove the tablet.Do nottry to push ABSTRALtablets through the foil. This will damage the tablet (SeeFigures 3and4).

• As soon as you remove the ABSTRALtablet from the blister unit:
  • Place it on the floor of your mouth, under your tongue, as far back as you can (SeeFigures 5,6, and7).
  • If more than 1 tablet is required, spread them around the floor of your mouth under your tongue.
  • Let the tablet dissolve completely. ABSTRALdissolves under your tongue and will be absorbed by your body to help provide relief for your breakthrough cancer pain.
  • Do not suck, chew or swallow the tablet.
  • You should not drink or eat anything until the tablet has completely dissolved under your tongue and you can no longer feel it in your mouth.

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

Manufactured for:
Sentynl Therapeutics, Inc. Solana Beach, CA 92075 Issued: October 2019

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Copyright 2019, Sentynl Therapeutics, Inc. All rights reserved.

ABSTRALand Sentynl Therapeutics, Inc. are trademarks owned by the Sentynl Therapeutics, Inc.

Principal Display Panel - 100 mcg Carton Label

ABSTRAL CII

(fentanyl) sublingual tablets

equivalent to 100 mcg fentanyl base

NDC 42358-100-32 Rx only

32 Sublingual Tablets

(4 Tablets x 8 cards)

Principal Display Panel - 200 mcg Carton Label

ABSTRAL CII

(fentanyl) sublingual tablets

equivalent to 200 mcg fentanyl base

NDC 42358-200-32 Rx only

32 Sublingual Tablets

(4 Tablets x 8 cards)

Principal Display Panel - 300 mcg Carton Label

ABSTRAL CII

(fentanyl) sublingual tablets

equivalent to 300 mcg fentanyl base

NDC 42358-300-32 Rx only

32 Sublingual Tablets

(4 Tablets x 8 cards)

Principal Display Panel - 400 mcg Carton Label

ABSTRAL CII

(fentanyl) sublingual tablets

equivalent to 400 mcg fentanyl base

NDC 42358-400-32 Rx only

32 Sublingual Tablets

(4 Tablets x 8 cards)

Principal Display Panel - 600 mcg Carton Label

ABSTRAL CII

(fentanyl) sublingual tablets

equivalent to 600 mcg fentanyl base

NDC 42358-600-32 Rx only

32 Sublingual Tablets

(4 Tablets x 8 cards)

Principal Display Panel - 800 mcg Carton Label

ABSTRAL CII

(fentanyl) sublingual tablets

equivalent to 800 mcg fentanyl base

NDC 42358-800-32 Rx only

32 Sublingual Tablets

(4 Tablets x 8 cards)

ABSTRAL FENTANYL fentanyl citrate tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42358-100 Route of Administration SUBLINGUAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fentanyl citrate(UNII: MUN5LYG46H) (fentanyl - UNII:UF599785JZ) fentanyl 100 ug

Inactive Ingredients Ingredient Name Strength croscarmellose sodium(UNII: M28OL1HH48) magnesium stearate(UNII: 70097M6I30) mannitol(UNII: 3OWL53L36A) cellulose, microcrystalline(UNII: OP1R32D61U)

Product Characteristics Color white ( WHITE) Score no score Shape ROUND (ROUND) Size 10mm Flavor Imprint Code 1 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42358-100-32 8 in 1 CARTON 10/01/2016 1 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022510 10/01/2016

ABSTRAL FENTANYL fentanyl citrate tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42358-200 Route of Administration SUBLINGUAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fentanyl citrate(UNII: MUN5LYG46H) (fentanyl - UNII:UF599785JZ) fentanyl 200 ug

Inactive Ingredients Ingredient Name Strength croscarmellose sodium(UNII: M28OL1HH48) magnesium stearate(UNII: 70097M6I30) mannitol(UNII: 3OWL53L36A) cellulose, microcrystalline(UNII: OP1R32D61U)

Product Characteristics Color white ( WHITE) Score no score Shape OVAL (OVAL) Size 10mm Flavor Imprint Code 2 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42358-200-32 8 in 1 CARTON 10/01/2016 1 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022510 10/01/2016

ABSTRAL FENTANYL fentanyl citrate tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42358-300 Route of Administration SUBLINGUAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fentanyl citrate(UNII: MUN5LYG46H) (fentanyl - UNII:UF599785JZ) fentanyl 300 ug

Inactive Ingredients Ingredient Name Strength croscarmellose sodium(UNII: M28OL1HH48) magnesium stearate(UNII: 70097M6I30) mannitol(UNII: 3OWL53L36A) cellulose, microcrystalline(UNII: OP1R32D61U)

Product Characteristics Color white ( WHITE) Score no score Shape TRIANGLE (TRIANGLE) Size 10mm Flavor Imprint Code 3 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42358-300-32 8 in 1 CARTON 10/01/2016 1 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022510 10/01/2016

ABSTRAL FENTANYL fentanyl citrate tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42358-400 Route of Administration SUBLINGUAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fentanyl citrate(UNII: MUN5LYG46H) (fentanyl - UNII:UF599785JZ) fentanyl 400 ug

Inactive Ingredients Ingredient Name Strength croscarmellose sodium(UNII: M28OL1HH48) magnesium stearate(UNII: 70097M6I30) mannitol(UNII: 3OWL53L36A) cellulose, microcrystalline(UNII: OP1R32D61U)

Product Characteristics Color white ( WHITE) Score no score Shape DIAMOND (DIAMOND) Size 10mm Flavor Imprint Code 4 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42358-400-32 8 in 1 CARTON 10/01/2016 1 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022510 10/01/2016

ABSTRAL FENTANYL fentanyl citrate tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42358-600 Route of Administration SUBLINGUAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fentanyl citrate(UNII: MUN5LYG46H) (fentanyl - UNII:UF599785JZ) fentanyl 600 ug

Inactive Ingredients Ingredient Name Strength croscarmellose sodium(UNII: M28OL1HH48) magnesium stearate(UNII: 70097M6I30) mannitol(UNII: 3OWL53L36A) cellulose, microcrystalline(UNII: OP1R32D61U)

Product Characteristics Color white ( WHITE) Score no score Shape SEMI-CIRCLE (SEMI-CIRCLE (D--SHAPE)) Size 10mm Flavor Imprint Code 6 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42358-600-32 8 in 1 CARTON 10/01/2016 1 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022510 10/01/2016

ABSTRAL FENTANYL fentanyl citrate tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42358-800 Route of Administration SUBLINGUAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fentanyl citrate(UNII: MUN5LYG46H) (fentanyl - UNII:UF599785JZ) fentanyl 800 ug

Inactive Ingredients Ingredient Name Strength croscarmellose sodium(UNII: M28OL1HH48) magnesium stearate(UNII: 70097M6I30) mannitol(UNII: 3OWL53L36A) cellulose, microcrystalline(UNII: OP1R32D61U)

Product Characteristics Color white ( WHITE) Score no score Shape CAPSULE (CAPSULE) Size 10mm Flavor Imprint Code 8 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42358-800-32 8 in 1 CARTON 10/01/2016 1 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022510 10/01/2016

Labeler -Sentynl Therapeutics, Inc. (078313706)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmaceutics International, Inc.		878265586	MANUFACTURE(42358-100, 42358-200, 42358-300, 42358-400, 42358-600, 42358-800)

Establishment
Name	Address	ID/FEI	Business Operations
Sharp Packaging Solutions		143696495	PACK(42358-100, 42358-200, 42358-300, 42358-400, 42358-600, 42358-800)

Revised: 10/2019document Id: ⮝

a5edb551-b75b-4930-b557-1a3f1aa5115c34391-3Set id: e60f00e9-2cf4-4c20-b570-1c2ea426c8c7Version: 5Effective Time: 20191008Sentynl Therapeutics, Inc.

1. Highlights Of Prescribing Information
2. See Full Prescribing Information For Complete Boxed Warning.
3. Recent Major Changes
4. Indications And Usage
5. Dosage And Administration
6. Dosage Forms And Strengths
7. Contraindications
8. Warnings And Precautions
9. Adverse Reactions
10. Drug Interactions
11. Use In Specific Populations
12. Warning: Life-threatening Respiratory Depression; Accidental Ingestion; Risk From Cytochrome P450 3a4 Interaction; Risks From Concomitant Use With Benzodiazepines Or Other Cns Depressants; Risk Of Medication Errors; Addiction, Abuse, And Misuse; Rems; And Neonatal Opioid Withdrawal Syndrome
13. 1 Indications And Usage
14. 2 Dosage And Administration
15. 3 Dosage Forms And Strengths
16. 4 Contraindications
17. 5 Warnings And Precautions
18. 6 Adverse Reactions
19. 7 Drug Interactions
20. 8 Use In Specific Populations
21. 9 Drug Abuse And Dependence
22. 10 Overdosage
23. 11 Description
24. 12 Clinical Pharmacology
25. 13 Nonclinical Toxicology
26. 14 Clinical Studies
27. 16 How Supplied/storage And Handling

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ABSTRAL safely and effectively. See Full Prescribing Information for ABSTRAL .
ABSTRAL (fentanyl) sublingual tablets CII
Initial U.S. Approval: 1968

See Full Prescribing Information For Complete Boxed Warning. ⮝

• Serious, life-threatening, and/or fatal respiratory depression has occurred. Monitor closely, especially upon initiation or following a dose increase. ABSTRAL is contraindicated in opioid non-tolerant patients (1) and in management of acute or postoperative pain, including headache/migraines (4, 5.1).
• Accidental ingestion of ABSTRAL , especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal (2.6, 5.2).
• Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl (5.3, 7).
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation (5.4).
• When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ABSTRAL (2.2, 5.5).
• When dispensing, do not substitute with any other fentanyl products (5.5).
• ABSTRAL exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor closely for these behaviors and conditions (5.6).
• ABSTRAL is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program (5.7).
• Prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.8).

Recent Major Changes ⮝

Warnings and Precautions (5.1)

10/2019

Indications And Usage ⮝

ABSTRAL is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain (1).

Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg per hour of transdermal fentanyl, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily. Patients must remain on around-the- clock opioids while taking ABSTRAL.

Limitations of Use (1)

• Not for use in opioid non-tolerant patients.
• Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency department (4).
• As a part of the TIRF REMS Access program, ABSTRAL may be dispensed only to outpatients enrolled in the program. For inpatient administration of ABSTRAL (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

Dosage And Administration ⮝

• Patients must require and use around-the-clock opioids when taking ABSTRAL (1).
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse (2.1).
• Administer on the floor of the mouth directly under the tongue and allow to completely dissolve (2.4).
• Initial dose of ABSTRAL: 100 mcg (2.2).
• No more than two doses can be taken per breakthrough pain episode (2.2).
• Individually titrate to a tolerable dose that provides adequate analgesia (2.3).
• Wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL (2.3).
• Limit consumption to treat four or fewer breakthrough pain episodes per day once a successful dose is found (2.3).
• When opioid therapy is no longer required, consider discontinuing ABSTRAL along with a gradual downward titration of other opioids to minimize possible withdrawal effects (2.5).

Dosage Forms And Strengths ⮝

• Sublingual tablets: 100 mcg, 200 mcg, 300 mcg, 400 mcg, 600 mcg and 800 mcg strengths as fentanyl base (3).

Contraindications ⮝

• Opioid non-tolerant patients (4).
• Management of acute or postoperative pain including headache/migraines dental pain, or use in the emergency department (4).
• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4).
• Known or suspected gastrointestinal obstruction, including paralytic ileus (4).
• Known hypersensitivity to fentanyl or components of ABSTRAL (4).

Warnings And Precautions ⮝

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration (5.9).
• Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue ABSTRAL if serotonin syndrome is suspected (5.10).
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid (5.11).
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of ABSTRAL in patients with circulatory shock (5.12).
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of ABSTRAL in patients with impaired consciousness or coma (5.13).

Adverse Reactions ⮝

• Most common (total frequency 3%): nausea, somnolence, headache, and constipation (6).

To report SUSPECTED ADVERSE REACTIONS, contact Sentynl at 1-888-227-8725 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with ABSTRAL because they may reduce analgesic effect of ABSTRAL or precipitate withdrawal symptoms (7).

Use In Specific Populations ⮝

• Pregnancy: May cause fetal harm (8.1).
• Lactation: Not Recommended (8.2).
• Renal and Hepatic Impairment: Administer ABSTRAL with caution (8.6).

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 10/2019

Warning: Life-threatening Respiratory Depression; Accidental Ingestion; Risk From Cytochrome P450 3a4 Interaction; Risks From Concomitant Use With Benzodiazepines Or Other Cns Depressants; Risk Of Medication Errors; Addiction, Abuse, And Misuse; Rems; And Neonatal Opioid Withdrawal Syndrome  ⮝

Life-Threatening Respiratory Depression

Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ABSTRAL , including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ABSTRAL or following a dose increase. The substitution of ABSTRAL for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.1)].

Due to the risk of respiratory depression, ABSTRAL is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [see Contraindications (4)].

Accidental Ingestion

Accidental ingestion of even one dose of ABSTRAL , especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions (5.2)].

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. ABSTRAL must be kept out of reach of children [see Warnings and Precautions (5.2), Patient Counseling Information (17), Storage and Handling (16)].

Cytochrome P450 3A4 Interaction

The concomitant use of ABSTRAL with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving ABSTRAL and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.3), Drug Interactions (7), Clinical Pharmacology (12)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)].

a.

Reserve concomitant prescribing of ABSTRAL and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

b.

Limit dosages and durations to the minimum required.

c.

Follow patients for signs and symptoms of respiratory depression and sedation.

Risk of Medication Errors

Substantial differences exist in the pharmacokinetic profile of ABSTRAL compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose [see Dosage and Administration (2.1), Warnings and Precautions (5.5)].

d.

When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ABSTRAL .

e.

When dispensing, do not substitute an ABSTRAL prescription for other fentanyl products.

Addiction, Abuse, and Misuse

ABSTRAL exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing ABSTRAL , and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.6)].

Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose, ABSTRAL is available only through a restricted program required by the Food and Drug Administration called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program [see Warnings and Precautions (5.7)]. Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.8)].

1 Indications And Usage  ⮝

ABSTRAL is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain.

Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine per day, or at least 25 mcg per hour of transdermal fentanyl, or at least 30 mg of oral oxycodone per day, or at least 8 mg of oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60 mg oral hydrocodone per day or an equianalgesic dose of another opioid medication daily for a week or longer. Patients must remain on around-the- clock opioids when taking ABSTRAL .

Limitations of Use:

• Not for use in opioid non-tolerant patients.
• Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency department [see Contraindications (4)].
• As a part of the TIRF REMS Access program, ABSTRAL may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions (5.7)]. For inpatient administration of ABSTRAL (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

2 Dosage And Administration  ⮝

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.

Maintenance Therapy

Once titrated to an effective dose, instruct patients to use only one ABSTRAL tablet of the appropriate strength per dose. Maintain patients on this dose.

If adequate analgesia is not obtained after initial 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.

Patients must wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL.

Dose Re-Adjustment

If the response (analgesia or adverse reactions) to the titrated ABSTRAL dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the ABSTRAL dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of breakthrough pain and opioid-related adverse reactions.

If more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the long- acting opioid used for persistent underlying cancer pain. If the long-acting opioid or dose of long-acting opioid is changed, re-evaluate and re-titrate the ABSTRAL dose, as necessary, to ensure the patient is on an appropriate dose.

Limit the use of ABSTRAL to treat four or fewer episodes of breakthrough pain per day.

It is imperative that any dose re-titration is monitored carefully by a healthcare professional.

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.

3 Dosage Forms And Strengths  ⮝

Sublingual tablets: All tablets are white and available in six strengths, distinguishable by the shape of the tablet and by debossing on the tablet surface:

100 microgram tablet: round tablet marked with the number "1"

200 microgram tablet: oval-shaped tablet marked with the number "2" 300 microgram tablet: triangle-shaped tablet marked with the number "3"

400 microgram tablet: diamond-shaped tablet marked with the number "4" 600 microgram tablet: "D"-shaped tablet marked with the number "6"

800 microgram tablet: capsule-shaped tablet marked with the number "8" [see How Supplied/Storage and Handling (16)].

4 Contraindications  ⮝

ABSTRAL is contraindicated in:

• Opioid non-tolerant patients. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage (1), Warnings and Precautions (5.1)].
• Acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency department.
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)].
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)].
• Known hypersensitivity to fentanyl (e.g., anaphylaxis) [see Adverse Reactions (6.2)].

5 Warnings And Precautions  ⮝

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.

Patients with Chronic Pulmonary Disease: ABSTRAL-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 ABSTRAL [see Warnings and Precautions (5.1)].

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

Monitor such patients closely, particularly when initiating and titrating ABSTRAL and when ABSTRAL is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.1)].

Alternatively, consider the use of non-opioid analgesics in these patients.

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 Adverse Reactions  ⮝

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.1)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)]
• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.6)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.8)]
• Serotonin Syndrome [see Warnings and Precautions (5.10)]
• Adrenal Insufficiency [see Warnings and Precautions(5.11)]
• Severe Hypotension [see Warnings and Precautions(5.12)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)]
• Seizures [see Warnings and Precautions (5.15)]

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 2: Adverse Reactions Which Occurred During Titration at a Frequency of 5%

System Organ Class Preferred term N (%)	100 mcg (n=22)	200 mcg (n=23)	300 mcg (n=55)	400 mcg (n=38)	600 mcg (n=52)	800 mcg (n=80)	Total (n=270)
Gastrointestinal disorders
Nausea	1 (4.5)	4 (17.4)	5 (9.1)	1 (2.6)	2 (3.8)	2 (2.5)	15 (5.6)
Nervous system disorders
Somnolence	0	2 (8.7)	4 (7.3)	2 (5.3)	2 (3.8)	2 (2.5)	12 (4.4)
Dizziness	0	0	3 (5.5)	2 (5.3)	0	1 (1.3)	6 (2.2)
Headache	0	0	0	1 (2.6)	3 (5.8)	1 (1.3)	5 (1.9)

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.

Table 3: Adverse Reactions Which Occurred During Maintenance Therapy at a Frequency of 5%

System Organ Class Preferred term, N (%)	100 mcg (n=7)	200 mcg (n=12)	300 mcg (n=22)	400 mcg (n=20)	600 mcg (n=35)	800 mcg (n=72)	Total (n=168)
Gastrointestinal disorders
Nausea	1 (14.3)	0	2 (9.1)	0	1 (2.9)	6 (8.3)	10 (6.0)
Stomatitis	0	1 (8.3)	1 (4.5)	0	0	1 (1.4)	3 (1.8)
Constipation	0	0	1 (4.5)	2 (10.0)	1 (2.9)	4 (5.6)	8 (4.8)
Dry mouth	0	0	0	1 (5.0)	2 (5.7)	0	3 (1.8)
Nervous system disorders
Headache	0	0	0	2 (10.0)	1 (2.9)	2 (2.8)	5 (3.0)
Dysgeusia	1 (14.3)	0	0	0	0	1 (1.4)	2 (1.2)
General disorders and administration site conditions
Fatigue	0	0	0	1 (5.0)	2 (5.7)	0	3 (1.8)
Injury, poisoning and procedural complications
Accidental overdose	1 (14.3)	0	0	0	0	0	1 (0.6)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0	1 (8.3)	0	0	0	0	1 (0.6)
Skin and subcutaneous disorders
Hyperhidrosis	1 (14.3)	0	0	0	0	1 (1.4)	2 (1.2)

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.

7 Drug Interactions  ⮝

Table 4 includes clinically significant drug interactions with ABSTRAL.

Table 4: Clinically Significant Drug Interactions with ABSTRAL

Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of ABSTRAL and CYP3A4 inhibitors can increase the plasma concentration of fentanyl resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of ABSTRAL is achieved [see Warnings and Precautions (5.3)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of ABSTRAL until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the ABSTRAL dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice
CYP3A4 Inducers
Clinical Impact:	The concomitant use of ABSTRAL with CYP3A4 inducers can decrease the plasma concentrations of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.6)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the ABSTRAL dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ABSTRAL dosage reduction and monitor for signs of respiratory depression.
Examples:	rifampin, carbamazepine, phenytoin
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ABSTRAL if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., clyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)].
Intervention:	The use of ABSTRAL is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of ABSTRAL and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected, and decrease the dosage of ABSTRAL and/or the muscle relaxant, as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure, and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when ABSTRAL is used concomitantly with anticholinergic drugs.

8 Use In Specific Populations  ⮝

8.1 Pregnancy - Category C

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

Risk Summary:

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.

Available data with ABSTRAL in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation, fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the heath of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset 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. ABSTRAL is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ABSTRAL, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

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

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

Animal Data

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of ABSTRAL on a mg/m2 basis) and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of ABSTRAL based on a mg/m2 basis). There was no evidence of teratogenicity 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 ABSTRAL per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 6 times higher than the mean Cmax observed following administration of 800 mcg dose of ABSTRAL in humans.

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 ABSTRAL.

Clinical Considerations

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

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.1), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

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 Drug Abuse And Dependence  ⮝

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.

Risks Specific to Abuse of ABSTRAL

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

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)].

10 Overdosage  ⮝

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.

11 Description  ⮝

ABSTRAL (fentanyl) sublingual tablet is a solid formulation of fentanyl citrate, an opioid agonist, intended for oral sublingual administration. ABSTRAL is formulated as a white tablet available in six strengths (100 mcg, 200 mcg, 300 mcg, 400 mcg, 600 mcg, 800 mcg), distinguishable by the shape of the tablet and by debossing on the tablet surface.

Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:

All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 mcg strength tablet contains 100 mcg of fentanyl free base.

Inactive Ingredients: Croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose.

12 Clinical Pharmacology  ⮝

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

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

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

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine 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 gastric, 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

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

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

Effects on the Immune System

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

Concentration Efficacy Relationships

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

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals [see Dosage and Administration (2.3)].

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 (2.2, 2.3)].

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 (2.2, 2.3)].

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 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 cause rigidity in the muscles of respiration resulting in respiratory difficulties [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics

Absorption

Fentanyl is a highly lipophilic drug. Orally administered fentanyl undergoes pronounced hepatic and intestinal first pass effects. Absorption of fentanyl from ABSTRAL sublingual tablets is mainly through the oral mucosa.

The bioavailability of ABSTRAL sublingual tablets has been calculated to be 54%.

Dose proportionality across the 100 mcg to 800 mcg ABSTRAL dose range has been demonstrated (Table 4). Mean plasma fentanyl levels following single doses of ABSTRAL are shown in Figure 1. The median time to maximum plasma concentration (Tmax) across these four doses of ABSTRAL varied from 30 to 60 minutes (range of 15 - 240 minutes).

Figure 1: Mean (+/- SD) Plasma Fentanyl Concentration versus Time after Administration of Single Doses of 100 mcg, 200 mcg, 400 mcg and 800 mcg ABSTRAL to Healthy Subjects

Pharmacokinetic parameters are presented in Table 5.

Table 5. Mean (CV%) Fentanyl Pharmacokinetic Parameters after Single-Dose Administration of 100 mcg, 200 mcg, 400 mcg and 800 mcg Doses of ABSTRAL to Healthy Subjects (n=12 per Dose Level)

a: median (range)
Parameter	Unit	Abstral dose
		100 mcg	200 mcg	400 mcg	800 mcg
Cmax	(ng/mL)	0.187 (33)	0.302 (31)	0.765 (38)	1.42 (33)
Tmaxa	(min)	30 [19-120]	52 [16-240]	60 [30-120]	30 [15-60]
AUC0-inf	(ng.h/mL)	0.974 (34)	1.92 (27)	5.49 (35)	8.95 (33)
T1/2	(h)	5.02 (51)	6.67 (30)	13.5 (37)	10.1 (34)

In another study, dose proportionality between 800 mcg and 1600 mcg in Cmax and AUC has also been demonstrated.

Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets of the equivalent dose.

Distribution

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

Elimination

Metabolism

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

Excretion

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

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

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

Impairment of Fertility

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

14 Clinical Studies  ⮝

The efficacy of ABSTRAL was investigated in a clinical trial in opioid tolerant adult patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in patients with cancer experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications, including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for 1 week or longer. All patients were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain.

A double-blind, placebo-controlled, crossover study was performed in patients with cancer to evaluate the effectiveness of ABSTRAL for the treatment of breakthrough cancer pain. Open-label titration identified a dose of ABSTRAL in which a patient obtained adequate analgesia with tolerable side effects, within the range of 100 mcg to 800 mcg. In the double-blind efficacy study, patients who identified a successful dose were randomized to a sequence of 10 treatments; seven with ABSTRAL and three with placebo.

Of the 131 patients who entered the titration phase of the study, 78 (60%) achieved a successful dose during the titration phase. Sixty-six patients entered the double-blind phase and 60 completed the study. The dose of ABSTRAL was determined by titration starting at 100 mcg. The final titrated dose of ABSTRAL for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain. In a second open-label safety study using an identical titration regimen, 96 of 139 patients (69%) who entered the study titrated to a dose in which the patient obtained adequate analgesia with tolerable side effects during the titration phase. Table 6 presents the final titrated dose for both the double-blind efficacy and open-label safety studies.

Table 6: Final dose of ABSTRAL following initial titration in all clinical efficacy and safety studies

ABSTRAL Dose	N=174 n (%)
100 mcg	11 (6)
200 mcg	15 (9)
300 mcg	35 (20)
400 mcg	25 (14)
600 mcg	40 (23)
800 mcg	48 (28)

The primary outcome measure, the mean sum of pain intensity difference at 30 minutes (SPID30) for ABSTRAL-treated episodes, was statistically significantly higher than for placebo-treated episodes.

Figure 2: Mean Pain Intensity Difference ( SE) for ABSTRAL Compared to Placebo

16 How Supplied/storage And Handling  ⮝

ABSTRAL is supplied in six dosage strengths. Tablets are supplied in child-resistant, protective blister cards with peelable foil. Each blister card contains 4 tablets, in pack sizes of 32 (all strengths) tablets. Each tablet is white in color, with the strength distinguishable by the shape of the dosage unit and by debossing on the tablet surface:

Dosage Strength (fentanyl base)	Tablet Shape	Tablet Markings	Carton/Blister Package Color	Pack size	NDC Number
100 mcg	Round	"1"	Light blue	32	42358-100-32
200 mcg	Oval	"2"	Dark orange	32	42358-200-32
300 mcg	Triangle	"3"	Brown	32	42358-300-32
400 mcg	Diamond	"4"	Violet	32	42358-400-32
600 mcg	"D"	"6"	Turquoise	32	42358-600-32
800 mcg	Capsule	"8"	Indigo	32	42358-800-32

Note: Colors and shapes are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

Store at 20-25 C (68-77 F); excursions permitted between 15-30 C (59-86 F) [see USP Controlled Room Temperature]. Protect from moisture.

Store ABSTRAL securely and dispose of properly [see Patient Counseling Information (17)].