Abstral Sublingual Tablet

Name: Abstral Sublingual Tablet

Indications and Usage for Abstral Sublingual Tablet

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.

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)].

Warnings and Precautions

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 opioidtolerant.

Accidental ingestion of even one dose of ABSTRAL, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.

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.

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)].

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)].

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)].

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.

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.

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)].

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.

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), 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.

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.

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.

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.

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.

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.

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.

Cardiac Disease

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

Drug Abuse and Dependence

Controlled Substance

ABSTRAL contains fentanyl, a Schedule II substance.

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.

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)].

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.

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.

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