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warnings and cautions
5 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets in patients with impaired consciousness or coma. ( 5.13 ) Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding. ( 5.18 ) 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 (CO 2 ) 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 fentanyl buccal tablets, 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 fentanyl buccal tablets. To reduce the risk of respiratory depression, proper dosing and titration of fentanyl buccal tablets are essential [see Dosage and Administration ( 2.3 )] . Overestimating the fentanyl buccal tablets dosage can result in a fatal overdose with the first dose. The substitution of fentanyl buccal tablets for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.5 )] . Fentanyl buccal tablets 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 fentanyl buccal tablets, especially by children, can result in respiratory depression and death due to an overdose of fentanyl. 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 products. Patients and their caregivers must be informed that fentanyl buccal tablets contain 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 fentanyl buccal tablets are provided in the fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl buccal tablets-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl buccal tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl buccal tablets-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl buccal tablets until stable drug effects are achieved [see Drug Interactions ( 7 )] . Concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets 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 Drug Interactions ( 7 )] . 5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol) Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets are 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 fentanyl buccal tablets from any other fentanyl product on a mcg per mcg basis as fentanyl buccal tablets and other fentanyl products are not equivalent on a microgram per microgram basis. Fentanyl buccal tablets are not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a fentanyl buccal tablets prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and fentanyl buccal tablets are not equivalent. Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablets 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 fentanyl buccal tablets 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 (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Dosage and Administration ( 2.1 )] .Therefore, for opioid tolerant patients, the initial dose of fentanyl buccal tablets should always be 100 mcg. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects [see Dosage and Administration ( 2.3 )] . 5.6 Addiction, Abuse, and Misuse Fentanyl buccal tablets contain fentanyl, a Schedule II controlled substance. As an opioid, fentanyl buccal tablets expose 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 fentanyl buccal tablets. 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 fentanyl buccal tablets, and monitor all patients receiving fentanyl buccal tablets for the development of these behaviors or 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 fentanyl buccal tablets, but use in such patients necessitates intensive counseling about the risks and proper use of fentanyl buccal tablets 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 fentanyl buccal tablets. 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 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 )] , fentanyl buccal tablets are available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, 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 fentanyl buccal tablets, patient and prescriber enrollment is not required. Required components of the TIRF REMS Access program are: Healthcare professionals, who prescribe fentanyl buccal tablets for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements. To receive fentanyl buccal tablets, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement. Pharmacies that dispense fentanyl buccal tablets must enroll in the program and agree to comply with the REMS requirements. Wholesalers and distributors that distribute fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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: fentanyl buccal tablets-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 fentanyl buccal tablets [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 fentanyl buccal tablets and when fentanyl buccal tablets are 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 Fentanyl buccal tablets 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 fentanyl buccal tablets. In patients with circulatory shock, fentanyl buccal tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of fentanyl buccal tablets in patients with circulatory shock. 5.13 Risks 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), fentanyl buccal tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl buccal tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of fentanyl buccal tablets in patients with impaired consciousness or coma. 5.14 Risks of Use in Patients with Gastrointestinal Conditions Fentanyl buccal tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets therapy. 5.16 Risks of Driving and Operating Machinery Fentanyl buccal tablets 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 fentanyl buccal tablets and know how they will react to the medication. 5.17 Cardiac Disease Intravenous fentanyl may produce bradycardia. Therefore, use fentanyl buccal tablets with caution in patients with bradyarrhythmias. 5.18 Application Site Reactions Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding [see Adverse Reactions ( 6 )] . 5.19 MAO Inhibitors Fentanyl buccal tablets are not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics [see Drug Interactions ( 7 )] .