ABSTRAL (fentanyl) sublingual tablet is a solid formulation of fentanyl citrate, a potent opioid analgesic intended for oral sublingual administration. ABSTRAL is formulated as a white tablet available in six strengths, distinguishable by the shape of the tablet and by de-bossing 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.
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]. 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
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].
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.
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.
ABSTRAL Titration Process
ABSTRAL dosing for a subsequent episode should be separated by at least 2 hours
|200 mcg||2 x 100 mcg tablets, or 1 x 200 mcg tablets|
|300 mcg||3 x 100 mcg tablets, or 1 x 300 mcg tablets|
|400 mcg||4 x 100 mcg tablets, or 2 x 200 mcg tablets, or 1 x 400 mcg tablets|
|600 mcg||3 x 200 mcg tablets, or 1 x 600 mcg tablets|
|800 mcg||4 x 200 mcg tablets, or 1 x 800 mcg tablets|
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.
Conversion From Actiq
The initial dose of Abstral is always 100 mcg with the only exception being patients already using Actiq.
a. 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)|
b. For patients converting from Actiq doses 400 mcg and below, initiate titration with 100 mcg Abstral and proceed using multiples of this strength.
c. 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.
d. 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.
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.
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 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.
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.
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.
Dosage Forms And Strengths
ABSTRAL is formulated as a sublingual tablet and is available in six strengths, distinguishable by the shape of the tablet and by de- bossing on the tablet surface. All tablets are white:
100 microgram tablet is a round tablet marked with the number “1”
200 microgram tablet is an oval-shaped tablet marked with the number “2”
300 microgram tablet is a triangle-shaped tablet marked with the number “3”
400 microgram tablet is a diamond-shaped tablet marked with the number “4”
600 microgram tablet is a “D”-shaped tablet marked with the number “6”
800 microgram tablet is a capsule-shaped tablet marked with the number “8”
[see HOW SUPPLIED/Storage and Handling].
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, and PATIENT INFORMATION].
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.
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 and in the Medication Guide.
To dispose of any unused ABSTRAL tablets, remove them from the blister cards and flush down the toilet. Do Page 18 of 21 not dispose of the ABSTRAL blister cards or cartons down the toilet. If additional assistance is required, call Galena Biopharma, Inc. at 1-888-227-8725.
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 12 (100 mcg, 200 mcg, 300 mcg and 400 mcg strengths) or 32 (all strengths) tablets. Each tablet is white in color, with the strength distinguishable by the shape of the dosage unit and by de-bossing 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||12|
|200 mcg||Oval||“2”||Dark orange||12|
Note: Colors and shapes are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.
Manufactured by: Pharmaceutics International, Inc., Hunt Valley, MD 21031. Manufactured for: Galena Biopharma, Inc. Portland, OR 97239. Issued: July 2014
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse event 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 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 (%)
|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 (%)
|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%)
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.
Immune system disorders: drug hypersensitivity.
Injury, poisoning and procedural complications: accidental overdose.
Metabolism and nutrition disorders: anorexia, decreased appetite.
Reproductive system and breast disorders: erectile dysfunction.
Respiratory, thoracic and mediastinal disorder: dyspnea, oropharyngeal pain, throat tightness.
Vascular disorders: hypotension.
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.
Drug Abuse And Dependence
ABSTRAL contains fentanyl, a Schedule II substance. Schedule II opioid substances such as fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have a high potential for abuse and addiction. ABSTRAL is also subject to misuse and criminal diversion.
Abuse And Addiction
Manage the handling of ABSTRAL to minimize the risk of misuse, including the restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see HOW SUPPLIED/Storage and Handling].
Concerns about abuse, addiction, and diversion must not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers.
Abuse and addiction are separate and distinct from physical dependence and tolerance. 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 addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since ABSTRAL may be diverted for nonmedical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper patient assessment, safe prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Contact your State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Physical dependence is not ordinarily a concern in the treatment of patients with chronic cancer pain, and fear of tolerance and physical dependence must not deter using opiate doses that adequately relieve the pain. Guide the administration of Abstral by the response of the patient.
Opioid analgesics may cause physical dependence that can result in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine).
Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia.