ABSTRAL® (fentanyl) sublingual tablets

ABSTRAL® (fentanyl) sublingual tablets

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ABSTRAL® (fentanyl) sublingual tablets

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.

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.

Mechanism of Action

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

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.

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-theclock opioids while 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
  • 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
  • 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
  • Administer on the floor of the mouth directly under the tongue and allow to completely dissolve
  • Initial dose of ABSTRAL: 100 mcg
  • No more than two doses can be taken per breakthrough pain episode
  • Individually titrate to a tolerable dose that provides adequate analgesia
  • Wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL
  • Limit consumption to treat four or fewer breakthrough pain episodes per day once a successful dose is found
  • When opioid therapy is no longer required, consider discontinuing ABSTRAL along with a gradual downward titration of other opioids to minimize possible withdrawal effects

Contraindications

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

Warnings and precautions

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.

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

Accidental Ingestion: Accidental ingestion of even one dose of ABSTRAL®, especially by children, can result in a fatal overdose of fentanyl.

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. ABSTRAL® must be kept out of reach of children.

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.

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.

  • Reserve concomitant prescribing of ABSTRAL® and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression andsedation.

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.

  • When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ABSTRAL®.
  • When dispensing, do not substitute an ABSTRAL® prescription for other fentanylproducts.

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.

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.

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

Adverse reactions

Most common (total frequency ≥3%): nausea, somnolence, headache, and constipation

Drug interactions

Inhibitors of CYP3A4: 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. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice

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CYP3A4 Inducers: The concomitant use of ABSTRAL with CYP3A4 inducers can decrease the plasma concentrations of fentanyl, resulting in decreased efficacy or onset of withdrawal syndrome in patients who have developed physical dependence to fentanyl. Examples: rifampin, carbamazepine, phenytoin.

Benzodiazepines and other Central Nervous System (CNS) Depressants: 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. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. 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): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Examples: phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: May reduce the analgesic effect of ABSTRAL and/or precipitate withdrawal symptoms. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Use in specific populations

Pregnancy – Category C: There are no adequate and well-controlled studies in pregnant women.

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

Lactation: 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.

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

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.

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.

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.

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.

Overdosage

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

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.

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.

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