Data from FDA - Curated by Toby Galbraith - Last updated 21 December 2016

Indication(s)

1 INDICATIONS AND USAGE ABSTRAL (fentanyl) sublingual tablets are 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 opioid therapy for their underlying persistent cancer pain.

Patients considered opioid tolerant are those who are taking around-theclock medicine consisting of at least 60 mg of oral morphine daily, or at least 25 mcg of transdermal fentanyl/hour, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or at least 25 mg oral oxymorphone daily, 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. ABSTRAL is contraindicated for patients who are not already tolerant to opioids because life-threatening respiratory depression and death could result at any dose in patients not on a chronic regimen of opioids.

For this reason, ABSTRAL is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room.

ABSTRAL is intended to be prescribed only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain.

Limitations of Use: As a part of the TIRF REMS Access program, ABSTRAL may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions (5.10)].

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.

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 opioid therapy for their underlying persistent cancer pain.

(1) Limitations of Use: ABSTRAL may be dispensed only to patients enrolled in the TIRF REMS Access program.

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Advisory information

contraindications

4 CONTRAINDICATIONS ABSTRAL is contraindicated in the management of pain in opioid non-tolerant patients, because lifethreatening hypoventilation could occur at any dose in patients not already taking around-the-clock opioid therapy.

Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, or at least 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer.

ABSTRAL is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room.

ABSTRAL is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.

Anaphylaxis and hypersensitivity have been reported in association with the use of other oral transmucosal fentanyl products.

Opioid non-tolerant patients.

(4) Management of acute or postoperative pain including headache/migraines dental pain.

(4) Intolerance or hypersensitivity to fentanyl or components of ABSTRAL. (4)

Adverse reactions

6 ADVERSE REACTIONS Most common (total frequency?

3 %): nausea, somnolence, headache, and constipation.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Galena Biopharma, Inc. at 1-888-227-8725 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug can not 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 most commonly observed adverse reactions with ABSTRAL include typical opioid adverse reactions, such as nausea, constipation, somnolence and headache.

Expect opioid side effects and manage them accordingly.

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.

Table2: 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.

Table3: 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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION 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 (5.10)].

As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

Patients must require and use around-the-clock opioids when taking ABSTRAL (1) Initial dose of ABSTRAL: 100 mcg. (2.1) Individually titrate to a tolerable dose that provides adequate analgesia.

(2.1) No more than two doses can be taken per breakthrough pain episode.

(2.1) Wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL. (2.1) Limit consumption to treat four or fewer breakthrough pain episodes per day once a successful dose is found.

(2.4) Administer on the floor of the mouth directly under the tongue and allow to completely dissolve.

(2.5) 2.1 Dose Titration The objective of dose titration is to identify an effective and tolerable maintenance dose for ongoing management of breakthrough cancer pain episodes.

The effective and tolerable dose of ABSTRAL will be determined by dose titration in individual patients.

Carefully supervise patients until a dose that provides adequate analgesia with tolerable side effects is reached for breakthrough pain control.

Starting Dose: Individually titrate ABSTRAL to a dose that provides adequate analgesia with tolerable side effects.

Begin titration of all patients with an initial dose of ABSTRAL of 100 mcg. Due to differences in the pharmacokinetic properties and individual variability, even patients switching from other fentanyl containing products to ABSTRAL must start with the 100 mcg dose.

However, for patients converting from Actiq, see Table 1: Initial Dosing Recommendations for

Patients on

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 product.

ABSTRAL is NOT a generic version of any other fentanyl product.

Start all patients with a single 100 mcg tablet.

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 ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their health care 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. Titration Steps: 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.

Figure 2.2 Conversion from Actiq The initial dose of Abstral is always 100 mcg with the only exception being patients already using Actiq.

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 mcg 400 200 mcg 600 200 mcg 800 200 mcg 1200 200 mcg 1600 400 mcg 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.

For patients converting from Actiq doses of 600 and 800 mcg, initiate titration with 200 mcg and 200 mcg Abstral, respectively and proceed using multiples of this strength.

For patients converting from Actiq doses of 1200 and 1600 mcg, initiate titration with 200 mcg and 400 mcg Abstral, respectively and proceed using multiples of this strength.

2.3 Maintenance Therapy Once an appropriate dose for pain management has been established, 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 use of ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their health care 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. 2.4 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 more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the longacting 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.

2.5 Administration of ABSTRAL Place ABSTRAL tablets on the floor of the mouth directly under the tongue immediately after removal from the blister unit.

Do not 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. 2.6 Discontinuation of Therapy 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.

Use in special populations

8 USE IN SPECIFIC POPULATIONS Administer ABSTRAL with caution to patients with renal or hepatic dysfunction.

(8.6) 8.1 Pregnancy - Category C There are no adequate and well-controlled studies in pregnant women.

Use ABSTRAL during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.

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.

Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/ kg intravenously or 160 mcg/ kg subcutaneously.

Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for ABSTRAL. Fentanyl citrate was not teratogenic when administered to pregnant animals.

Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/ kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps, was not teratogenic (the high dose was approximately 6 times the human dose of 800 mcg per pain episode on a mcg/ m2 basis).

Intravenous administration of fentanyl (10 mcg/ kg or 30 mcg/ kg) to pregnant female rats from gestation day 6 to 18, was embryo - or feto-toxic, and caused a slightly increased mean delivery time in the 30 mcg/ kg/day group, but was not teratogenic.

8.2 Labor and Delivery Fentanyl readily crosses the placenta. Therefore do not use ABSTRAL during labor and delivery (including caesarean section) since it may cause respiratory depression in the fetus or in the newborn infant.

8.3 Nursing Mothers Fentanyl is excreted in human milk; therefore, do not use ABSTRAL in women who are nursing because of the possibility of sedation and/or respiratory depression in their infants.

Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using ABSTRAL. 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 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.

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 Gender Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain.

No clinically relevant gender differences were noted either in efficacy or in observed adverse reactions.

Pregnancy and lactation
8.3 Nursing Mothers Fentanyl is excreted in human milk; therefore, do not use ABSTRAL in women who are nursing because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using ABSTRAL.

Interactions

7 DRUG INTERACTIONS Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when ABSTRAL is given concurrently with agents that affect CYP3A4 activity.

The concomitant use of ABSTRAL with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

Patients receiving ABSTRAL who begin therapy with, or increase the dose of, CYP3A4 inhibitors need to be carefully monitored for signs of opioid toxicity over an extended period of time.

Increase dosage conservatively.

The concomitant use of ABSTRAL with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John 's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of ABSTRAL. Patients receiving ABSTRAL who stop therapy with, or decrease the dose of, CYP3A4 inducers need to be monitored for signs of increased ABSTRAL activity and the dose of ABSTRAL must be adjusted accordingly.

See Boxed Warning and Warnings and Precautions (5)

More information

Category Value
Authorisation number NDA022510
Orphan designation No
Product NDC 57881-338,57881-331,57881-333,57881-332,57881-334,57881-336
Date Last Revised 30-11-2014
Type HUMAN PRESCRIPTION DRUG
RXCUI 1053652
Storage and handling

16.1 Storage and Handling ABSTRAL is supplied in individually sealed child-resistant blister packages contained in a cardboard outer carton, in pack sizes of 12 (100 mcg, 200 mcg, 300 mcg and 400 mcg strengths) or 32 (all strengths) tablets.

The packaging is color-coded for each ABSTRAL tablet strength.

The amount of fentanyl contained in ABSTRAL can be fatal to a child, individual for whom it is not prescribed or non-opioid tolerant adult.

Patients and their caregivers must be instructed to keep ABSTRAL out of the reach of children [see Boxed Warning - Warnings: Potential For Abuse and Importance Of Proper Patient Selection and Warnings And Precautions (5), and Patient Counseling Information (17.1)].

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.

Marketing authorisation holder Galena Biopharma, Inc.
Warnings

WARNING:

RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL WARNING:

RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL See full prescribing information for complete boxed warning.

Due to the risk of fatal respiratory depression, ABSTRAL is contraindicated in opioid non-tolerant patients (1) and in management of acute or postoperative pain, including headache/migraines.

(4) Keep out of reach of children.

(5.3) Use with CYP3A4 inhibitors may cause fatal respiratory depression.

(7) When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ABSTRAL. (2.1, 5.2) When dispensing, do not substitute with any other fentanyl products.

(5.2) Contains fentanyl, a Schedule II controlled substance with abuse liability similar to other opioid analgesics.

(9.1) 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.

(5.10) RESPIRATORY DEPRESSION Fatal respiratory depression has occurred in patients treated with immediate-release transmucosal fentanyl, including following use in opioid non-tolerant patients and improper dosing.

The substitution of ABSTRAL for any other fentanyl product may result in fatal overdose.

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)] ABSTRAL must be kept out of reach of children.

[see Patient Counseling Information (17.1) and How Supplied/Storage and Handling (16.1)] The concomitant use of ABSTRAL with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression.

[see Drug Interactions (7)] 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 that could result in fatal overdose.

- When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ABSTRAL. (2.1) - When dispensing, do not substitute an ABSTRAL prescription for other fentanyl products.

ABUSE POTENTIAL ABSTRAL contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics.

ABSTRAL can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing ABSTRAL in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

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 TIRF (Transmucosal Immediate Release Fentanyl) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program [see Warnings and Precautions (5.10)].

Further information is available at www.

TIRFREMSAccess.com or by calling1-866-822-1483.

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