fentanyl 0.6 MG Sublingual Tablet

INDICATIONS AND USAGE Oral Transmucosal Fentanyl Citrate (OTFC) is indicated for the management of breakthrough pain in cancer patients 16 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 of transdermal fentanyl per hour, 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 of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids when taking OTFC. 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 and dental pain [see Contraindications ( 4 )] . As a part of the TIRF REMS, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions ( 5.7 )] . For inpatient administration of OTFC, patient and prescriber enrollment are not required. OTFC is an opioid agonist indicated for the management of breakthrough pain in cancer patients 16 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. ( 1 ) 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 of transdermal fentanyl per hour, 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 of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking OTFC. 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 or dental pain. ( 4 ) As a part of the TIRF REMS, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program. ( 5.7 ) For inpatient administration of OTFC, patient and prescriber enrollment are not required.

DOSAGE AND ADMINISTRATION Patients must require and use around-the-clock opioids when taking OTFC. ( 1 ) OTFC should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of OTFC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OTFC. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver both when initiating and renewing treatment with OTFC, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.4 ) Initial dose of OTFC: 200 mcg. Prescribe an initial supply of six 200 mcg OTFC units. ( 2.3 ) Individually titrate to a tolerable dose that provides adequate analgesia using single OTFC dosage unit per breakthrough cancer pain episode. ( 2.4 ) No more than two doses can be taken per breakthrough pain episode. ( 2.4 , 2.5 ) Wait at least 4 hours before treating another episode of breakthrough pain with OTFC. ( 2.4 , 2.5 ) Limit consumption to four or fewer units per day once successful dose is found. ( 2.5 ) Periodically reassess patients receiving OTFC to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.5 ) When opioid therapy is no longer required, consider discontinuing OTFC along with a gradual downward of other opioids to minimize possible withdrawal effects. ( 2.7 ) 2.1 Important Dosage and Administration Instructions Healthcare professionals who prescribe Oral Transmucosal Fentanyl Citrate (OTFC) for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of OTFC [see Warnings and Precautions ( 5.7 )] . Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OTFC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OTFC. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. Instruct patients and caregivers to take steps to store OTFC securely and to properly dispose of unused OTFC as soon as no longer needed [see Warnings and Precautions ( 5.1 , 5.3 )]. Other TIRF formulations and OTFC are not equivalent. DO NOT substitute an OTFC prescription for any other TIRF formulation under any circumstances. Do not convert patients on a mcg per mcg basis from any other fentanyl product to OTFC [see Warnings and Precautions ( 5.5 )] . 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose . The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 )]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Individually titrate OTFC to a dose that provides adequate analgesia and minimizes side effects. The initial dose of OTFC to treat episodes of breakthrough cancer pain is always 200 mcg . The OTFC unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg OTFC units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose. Repeat Dosing In cases where the breakthrough pain episode is not relieved after 15 minutes after completion of the OTFC unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of OTFC for any episode of breakthrough pain. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with OTFC. 2.4 Dose Titration From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia using a single OTFC dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of OTFC over several episodes of breakthrough cancer pain and review their experience with their healthcare providers to determine if a dosage adjustment is warranted. In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode. Thus, patients should take a maximum of two doses of OTFC for any breakthrough pain episode. Patients must wait at least 4 hours before treating another episode of breakthrough pain with OTFC. To reduce the risk of overdosing during titration, patients should have only one strength of OTFC available at any one time. titration-process 2.5 Maintenance Dosing Once titrated to an effective dose, patients should generally use ONLY ONE OTFC unit of the appropriate strength per breakthrough pain episode. On those occasions when the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit, patient may take ONLY ONE additi

WARNINGS AND PRECAUTIONS • Risks of Skeletal Muscle Rigidity and Skeletal Muscle Movement : Manage with neuromuscular blocking agent. See full prescribing information for more detail on managing these risks. ( 5.5 ) • Severe Cardiovascular Depression : Monitor during dosage initiation and titration. ( 5.6 ) • Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.7 ) • Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected. ( 5.8 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury : Monitor for sedation and respiratory depression. ( 5.10 ) 5.1 Addiction, Abuse, and Misuse Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance. As an opioid, Fentanyl Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling Fentanyl Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. 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. 5.2 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. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Fentanyl Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. 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. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential. As with other potent opioids, the respiratory depressant effect of Fentanyl Citrate Injection may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia. Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves. Through other mechanisms [see Clinical Pharmacology ( 12.2 )] Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl Citrate Injection is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved and be prepared to manage them in the patients selected for these forms of anesthesia. 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 Citrate Injection. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression. Monitor such patients closely including vital signs, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration ( 2.1 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.1 )]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants When benzodiazepines or other CNS depressants are used with Fentanyl Citrate Injection, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Fentanyl Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression. When Fentanyl Citrate Injection is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity. Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Fentanyl Citrate Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 manage postoperative pain with Fentanyl Citrate Injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions ( 7 )]. 5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Fentanyl Citrate Injection 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 exacerbate respiratory depression [see Warnings and Precautions ( 5.2 )] , particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved . Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fen

CONTRAINDICATIONS Fentanyl transdermal system is contraindicated in: • patients who are not opioid-tolerant. • the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time. • the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies). • the management of mild pain. • patients with significant respiratory depression [see Warnings and Precautions (5.12) ] . • in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.12) ] . • in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.19) ] . • in patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the transdermal system [see Adverse Reactions (6.2) ] . • Opioid non-tolerant patients. ( 4 ) • Acute or intermittent pain, postoperative pain, mild pain. ( 4 ) • Significant respiratory depression. ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) • Known hypersensitivity to fentanyl or any of the components of the transdermal system. ( 4 )

Mechanism of Action Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.