FDA label be24d79a-2287-2b3a-e053-2a95a90a8243

BOXED WARNING WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME Life-Threatening Respiratory Depression Serious, life-threatening, and/or fatal respiratory depression has occurred in patients treated with LAZANDA, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of LAZANDA or following a dose increase. The substitution of LAZANDA for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.1 )]. Due to the risk of respiratory depression, LAZANDA is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see Contraindications ( 4 )] Accidental Exposure Accidental exposure of even one dose of LAZANDA, especially in children, can result in a fatal overdose of fentanyl [see Warnings and Precautions ( 5.1 )]. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. LAZANDA must be kept out of reach of children [see Warnings and Precautions ( 5.2 )]. Cytochrome P450 3A4 Interaction The concomitant use of LAZANDA 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 LAZANDA and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 ), Clinical Pharmacology ( 12.2 )]. 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 [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. Reserve concomitant prescribing of LAZANDA 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 and sedation. Risk of Medication Errors Substantial differences exist in the pharmacokinetic profile of LAZANDA compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.5 )]. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to LAZANDA. When dispensing, do not substitute a LAZANDA prescription for other fentanyl products. Addiction, Abuse, and Misuse LAZANDA 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 LAZANDA, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.6 )]. Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose, LAZANDA 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, pharmacies, outpatients, and healthcare professionals who prescribe to outpatients must enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require LAZANDA while hospitalized [see Warnings and Precautions ( 5.7 )] Further information is available at www.TIRFREMSaccess.com or by calling 1-866-822-1483. Neonatal Opioid Withdrawal Syndrome Prolonged use of LAZANDA 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 [see Warnings and Precautions ( 5.8 )]

WARNINGS AND PRECAUTIONS 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 (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 LAZANDA, 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 LAZANDA. To reduce the risk of respiratory depression, proper dosing and titration of LAZANDA are essential [see Dosage and Administration ( 2.1 )]. Overestimating the LAZANDA dosage can result in a fatal overdose with the first dose. The substitution of LAZANDA for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.5 )]. LAZANDA could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant. Accidental ingestion of (or exposure to) even one dose of LAZANDA, especially by (in) children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions ( 5.2 )]. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )]. 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 ( 2.5 ) ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with LAZANDA. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17 )]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions ( 5.4 , 5.6 ), Patient Counseling Information ( 17 )]. 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 LAZANDA contains a medicine in an amount which can be fatal to a child. Physicians 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 LAZANDA are provided in the LAZANDA 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 LAZANDA 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 ( 5.2 )] , particularly when an inhibitor is added after a stable dose of LAZANDA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in LAZANDA treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using LAZANDA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in LAZANDA treated patients, monitor patients closely at frequent intervals and consider dosage reduction of LAZANDA until stable drug effects are achieved [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7 )]. Concomitant use of LAZANDA with CYP3A4 inducers or discontinuation of an 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 LAZANDA 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 Profound sedation, respiratory depression, coma, and death may result from the concomitant use of LAZANDA 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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. Advise both patients and caregivers about the risks of respiratory depression and sedation when LAZANDA 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 ), Patient Counseling Information ( 17 )]. 5.5 Risk of Medication Errors When prescribing, DO NOT convert a patient to LAZANDA from any other fentanyl product on a mcg per mcg basis as LAZANDA and other fentanyl products are not equivalent on a microgram per microgram basis. LAZANDA is NOT a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, DO NOT substitute a LAZANDA prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and LAZANDA are not equivalent. Substantial differences exist in the pharmacokinetic profile of LAZANDA 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 LAZANDA for any other fentanyl product may result in a fatal overdose. There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of LAZANDA should always be ONE 100 mcg spray. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects [see Dosage and Administration ( 2.4 )]. 5.6 Addiction, Abuse, and Misuse LAZANDA contains fentanyl a Schedule II controlled substance. As an opioid, LAZANDA 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 LAZANDA. 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 LAZANDA, and monitor all patients receiving LAZANDA 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 LAZANDA, but use in such patients necessitates intensive counseling about the risks and proper use of LAZANDA along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing LAZANDA. 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) Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.6)] , LAZANDA is available only through a restricted program under a REMS called the TIRF REMS. Under the TIRF REMS, healthcare professionals who prescribe to outpatients, the outpatients themselves, and pharmacies are required to enroll in the program. Notable requirements of the TIRF REMS are: Prescribers for outpatient use must must be certified by the TIRF REMS program by enrolling and completing training. Prescribers must document opioid tolerance with every LAZANDA prescription. Outpatients must be enrolled in the REMS program, and must be opiod tolerant to receive LAZANDA [see Dosage and Administration ( 2.1 )] Outpatient pharmacies must be certified with the REMS program and verify documentation of opioid tolerance with every LAZANDA prescription. Inpatient pharmacies must be certified with the REMS program and develop policies and procedures to verify opioid tolerance in inpatients who require LAZANDA while hospitalized. Wholesalers and distributers must enroll in the REMS program and distribute only to certified pharmacies. Further information, including a list of certified pharmacies and enrolled distributors, is available at www.tirfremsaccess.com or by calling 1-866-822-1483. 5.8 Neonatal Opioid Withdrawal Syndrome Prolonged use of LAZANDA 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 LAZANDA 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 : LAZANDA-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 LAZANDA [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 LAZANDA and when LAZANDA 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. 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 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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 LAZANDA 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 LAZANDA 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 LAZANDA. In patients with circulatory shock, LAZANDA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of LAZANDA 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), LAZANDA 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 LAZANDA. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of LAZANDA in patients with impaired consciousness or coma. 5.14 Risks of Use in Patients with Gastrointestinal Conditions LAZANDA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in LAZANDA 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 LAZANDA 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 LAZANDA therapy. 5.16 Risks of Driving and Operating Machinery LAZANDA 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 LAZANDA and know how they will react to the medication. 5.17 Cardiac Disease Intravenous fentanyl may produce bradycardia. Therefore, use LAZANDA with caution in patients with bradyarrhythmias.

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 (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 LAZANDA, 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 LAZANDA. To reduce the risk of respiratory depression, proper dosing and titration of LAZANDA are essential [see Dosage and Administration ( 2.1 )]. Overestimating the LAZANDA dosage can result in a fatal overdose with the first dose. The substitution of LAZANDA for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.5 )]. LAZANDA could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant. Accidental ingestion of (or exposure to) even one dose of LAZANDA, especially by (in) children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions ( 5.2 )]. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )]. 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 ( 2.5 ) ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with LAZANDA. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17 )]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions ( 5.4 , 5.6 ), Patient Counseling Information ( 17 )].

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 LAZANDA contains a medicine in an amount which can be fatal to a child. Physicians 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 LAZANDA are provided in the LAZANDA 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 LAZANDA 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 ( 5.2 )] , particularly when an inhibitor is added after a stable dose of LAZANDA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in LAZANDA treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using LAZANDA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in LAZANDA treated patients, monitor patients closely at frequent intervals and consider dosage reduction of LAZANDA until stable drug effects are achieved [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7 )]. Concomitant use of LAZANDA with CYP3A4 inducers or discontinuation of an 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 LAZANDA 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 )].

ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug product 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 LAZANDA has been evaluated in a total of 523 opioid-tolerant patients with breakthrough cancer pain. The average duration of therapy in patients in the long-term study was 73 days, with 153 patients being treated for over 3 months. Patients continuing into the open-label extension period of the safety study have been treated for up to 26 months. The clinical trials of LAZANDA were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone, or transdermal fentanyl, for their persistent cancer pain. The adverse reaction data presented in Table 1 reflect the actual percentage of patients experiencing each adverse effect among patients who received LAZANDA for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of LAZANDA therapy, or cancer-related symptoms. Adverse events are included regardless of causality or severity. Table 1 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 LAZANDA a dose-response relationship to these adverse events is limited by the titration schemes used in these studies. Table 1: Adverse Reactions That Occurred During Titration at a Frequency of > 5% System Organ Class MedDRA preferred term, n (%) 100 mcg (N=483) 200 mcg (N=380) 400 mcg (N=301) 800 mcg (N=161) Total (N=516) Gastrointestinal disorders Nausea 19 (4) 6 (2) 6 (2) 5 (3) 35 (7) Vomiting 14 (3) 10 (3) 9 (3) 1 (1) 33 (6) Nervous system disorders Dizziness 14 (3) 11 (3) 6 (2) 4 (2) 31 (6) Table 2 lists, by dose, adverse reactions with an overall frequency of ≥5% within the total population that occurred after a final titrated dose had been determined. Table 2: Adverse Reactions That Occurred During Maintenance Treatment at a Frequency of ≥5% System Organ Class MedDRA preferred term, n (%) 100 mcg (N=61) 200 mcg (N=68) 400 mcg (N=109) 800 mcg (N=108) Total (N=346) Gastrointestinal disorders Vomiting 8 (13) 5 (7) 9 (8) 12 (11) 34 (10) Nausea 4 (7) 6 (9) 4 (4) 9 (8) 23 (7) Constipation 6 (10) 1 (1) 8 (7) 5 (5) 20 (6) General disorders and administration site conditions Pyrexia 3 (5) 5 (7) 8 (7) 6 (6) 22 (6) The adverse reactions listed below represent those that occurred in ≥1% of patients from clinical trials while receiving LAZANDA. Events are classified by system organ class. Eye disorders: dry eye, swelling, ptosis, strabismus Blood and Lymphatic System Disorders: anemia, neutropenia Cardiac Disorders: cardiorespiratory arrest Gastrointestinal Disorders: vomiting, nausea, constipation, diarrhea, abdominal pain, gastritis, ascites, dry mouth, dyspepsia, mouth ulcer, proctalgia General Disorders and Administration Site Conditions: pyrexia, fatigue, edema peripheral, asthenia, edema Hepatobiliary Disorders: jaundice Immune System Disorders: hypersensitivity Infections and Infestations: urinary tract infection, pneumonia, nasopharyngitis, infection, rhinitis, upper respiratory tract infection, bronchitis Injury, Poisoning and Procedural Complications: fall Investigations: weight decreased, blood alkaline phosphatase increased Metabolism and Nutrition Disorders: dehydration, decreased appetite, hyperglycemia, anorexia Musculoskeletal and Connective Tissue Disorders: back pain, pain in extremity, arthralgia Nervous System Disorders: dizziness, somnolence, headache, dysgeusia Psychiatric Disorders: anxiety, insomnia, depression, confusional state, disorientation, agitation Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, cough, pharyngolaryngeal pain, nasal discomfort, rhinorrhea, nasal congestion, postnasal drip, pulmonary embolism Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, decubitus ulcer, mouth ulceration Vascular Disorders: hypertension, deep vein thrombosis 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in LAZANDA. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )].

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug product 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 LAZANDA has been evaluated in a total of 523 opioid-tolerant patients with breakthrough cancer pain. The average duration of therapy in patients in the long-term study was 73 days, with 153 patients being treated for over 3 months. Patients continuing into the open-label extension period of the safety study have been treated for up to 26 months. The clinical trials of LAZANDA were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone, or transdermal fentanyl, for their persistent cancer pain. The adverse reaction data presented in Table 1 reflect the actual percentage of patients experiencing each adverse effect among patients who received LAZANDA for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of LAZANDA therapy, or cancer-related symptoms. Adverse events are included regardless of causality or severity. Table 1 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 LAZANDA a dose-response relationship to these adverse events is limited by the titration schemes used in these studies. Table 1: Adverse Reactions That Occurred During Titration at a Frequency of > 5% System Organ Class MedDRA preferred term, n (%) 100 mcg (N=483) 200 mcg (N=380) 400 mcg (N=301) 800 mcg (N=161) Total (N=516) Gastrointestinal disorders Nausea 19 (4) 6 (2) 6 (2) 5 (3) 35 (7) Vomiting 14 (3) 10 (3) 9 (3) 1 (1) 33 (6) Nervous system disorders Dizziness 14 (3) 11 (3) 6 (2) 4 (2) 31 (6) Table 2 lists, by dose, adverse reactions with an overall frequency of ≥5% within the total population that occurred after a final titrated dose had been determined. Table 2: Adverse Reactions That Occurred During Maintenance Treatment at a Frequency of ≥5% System Organ Class MedDRA preferred term, n (%) 100 mcg (N=61) 200 mcg (N=68) 400 mcg (N=109) 800 mcg (N=108) Total (N=346) Gastrointestinal disorders Vomiting 8 (13) 5 (7) 9 (8) 12 (11) 34 (10) Nausea 4 (7) 6 (9) 4 (4) 9 (8) 23 (7) Constipation 6 (10) 1 (1) 8 (7) 5 (5) 20 (6) General disorders and administration site conditions Pyrexia 3 (5) 5 (7) 8 (7) 6 (6) 22 (6) The adverse reactions listed below represent those that occurred in ≥1% of patients from clinical trials while receiving LAZANDA. Events are classified by system organ class. Eye disorders: dry eye, swelling, ptosis, strabismus Blood and Lymphatic System Disorders: anemia, neutropenia Cardiac Disorders: cardiorespiratory arrest Gastrointestinal Disorders: vomiting, nausea, constipation, diarrhea, abdominal pain, gastritis, ascites, dry mouth, dyspepsia, mouth ulcer, proctalgia General Disorders and Administration Site Conditions: pyrexia, fatigue, edema peripheral, asthenia, edema Hepatobiliary Disorders: jaundice Immune System Disorders: hypersensitivity Infections and Infestations: urinary tract infection, pneumonia, nasopharyngitis, infection, rhinitis, upper respiratory tract infection, bronchitis Injury, Poisoning and Procedural Complications: fall Investigations: weight decreased, blood alkaline phosphatase increased Metabolism and Nutrition Disorders: dehydration, decreased appetite, hyperglycemia, anorexia Musculoskeletal and Connective Tissue Disorders: back pain, pain in extremity, arthralgia Nervous System Disorders: dizziness, somnolence, headache, dysgeusia Psychiatric Disorders: anxiety, insomnia, depression, confusional state, disorientation, agitation Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, cough, pharyngolaryngeal pain, nasal discomfort, rhinorrhea, nasal congestion, postnasal drip, pulmonary embolism Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, decubitus ulcer, mouth ulceration Vascular Disorders: hypertension, deep vein thrombosis

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in LAZANDA. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )].

<table border="1" cellpadding="0" cellspacing="0"><tbody><tr><td><paragraph><content styleCode="bold">System Organ Class MedDRA preferred term, n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">100 mcg</content></paragraph><paragraph><content styleCode="bold">(N=483)</content></paragraph></td><td><paragraph><content styleCode="bold">200 mcg</content></paragraph><paragraph><content styleCode="bold">(N=380)</content></paragraph></td><td><paragraph><content styleCode="bold">400 mcg</content></paragraph><paragraph><content styleCode="bold">(N=301)</content></paragraph></td><td><paragraph><content styleCode="bold">800 mcg</content></paragraph><paragraph><content styleCode="bold">(N=161)</content></paragraph></td><td><paragraph><content styleCode="bold">Total</content></paragraph><paragraph><content styleCode="bold">(N=516)</content></paragraph></td></tr><tr><td colspan="6"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td><paragraph>19 (4)</paragraph></td><td><paragraph>6 (2)</paragraph></td><td><paragraph>6 (2)</paragraph></td><td><paragraph>5 (3)</paragraph></td><td><paragraph>35 (7)</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>14 (3)</paragraph></td><td><paragraph>10 (3)</paragraph></td><td><paragraph>9 (3)</paragraph></td><td><paragraph>1 (1)</paragraph></td><td><paragraph>33 (6)</paragraph></td></tr><tr><td colspan="6"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td></tr><tr><td><paragraph>Dizziness</paragraph></td><td><paragraph>14 (3)</paragraph></td><td><paragraph>11 (3)</paragraph></td><td><paragraph>6 (2)</paragraph></td><td><paragraph>4 (2)</paragraph></td><td><paragraph>31 (6)</paragraph></td></tr></tbody></table>