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 )]

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.

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>