FDA label ec21fe5a-b1f8-405e-9d75-6c01a24c9e51

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL RESPIRATORY DEPRESSION Fatal respiratory depression has occurred in patients treated with immediate-release transmucosal fentanyl, including following use in opioid non-tolerant patients and improper dosing. The substitution of Lazanda for any other fentanyl product may result in fatal overdose. 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) ] Lazanda must be kept out of reach of children. [see Patient Counseling Information (17.1) and How Supplied/Storage and Handling (16.1) ] The concomitant use of Lazanda with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions (7) ]. 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. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Lazanda. (2.1) When dispensing, do not substitute a Lazanda prescription for other fentanyl products. ABUSE POTENTIAL Lazanda contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Lazanda can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Lazanda in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Because of the risk for 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 Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [see Warnings and Precautions (5.10) ] Further information is available at www.TIRFREMSaccess.com or by calling 1-866-822-1483. WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL See full prescribing information for complete boxed warning . Due to the risk of fatal respiratory depression, Lazanda is contraindicated in opioid non-tolerant patients ( 1 ) and in management of acute or postoperative pain, including headache/migraines. ( 4 ) Keep out of reach of children. ( 5.3 ) Use with CYP3A4 inhibitors may cause fatal respiratory depression. ( 7 ) When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to Lazanda. ( 2.1 , 5.2 ) When dispensing, do not substitute with any other fentanyl products. ( 5.2 ) Contains fentanyl, a Schedule II controlled substance with abuse liability similar to other opioid analgesics. ( 9.1 ) Lazanda is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program. ( 5.10 )

IMPORTANT: Do not use Lazanda unless you are regularly using another opioid pain medicine around-the-clock for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant. Keep Lazanda in a safe place away from children. Get emergency medical help right away if: a child takes Lazanda. Lazanda can cause an overdose and death in any child who takes it an adult who has not been prescribed Lazanda takes it an adult who is not already taking opioids around-the-clock takes Lazanda These are medical emergencies that can cause death.

5 WARNINGS AND PRECAUTIONS Clinically significant respiratory and CNS depression can occur. Monitor patients accordingly. [ 5.1 ] Do not convert patients to Lazanda from other fentanyl products on a mcg per mcg basis, or substitute a Lazanda prescription for another fentanyl product, such substitution may result in fatal overdose. [ 5.2 ] Lazanda bottles contain medicine that can be fatal to a child. Ensure proper storage and disposal. [ 5.3 , 16.2 , 16.3 ] Use with other CNS depressants and potent CYP450 3A4 inhibitors may increase depressant effects including hypoventilation, hypotension, and profound sedation. Consider dosage adjustments if warranted. [ 5.2 , 5.4 ] Titrate Lazanda cautiously in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression and in patients susceptible to intracranial effects of CO 2 retention. [ 5.2 , 5.6 , 5.7 ] 5.1 Respiratory Depression Serious or fatal respiratory depression can occur even at recommended doses in patients using Lazanda. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. 5.2 Lazanda and other Fentanyl Products Lazanda is NOT equivalent to other fentanyl products used to treat breakthrough pain on a mcg per mcg basis. There are differences in the pharmacokinetics of Lazanda relative to other fentanyl products which could potentially result in clinically important differences in the amount of fentanyl absorbed and could result in a fatal overdose. When prescribing Lazanda to a patient, DO NOT convert from other fentanyl products. Directions for safely converting patients to Lazanda from other fentanyl products are not currently available. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid-tolerant patients starting treatment for breakthrough pain, the initial dose of Lazanda is 100 mcg. Individually titrate each patient's dose to provide adequate analgesia while minimizing side effects. [See Dosage and Administration (2.1) ] When dispensing Lazanda to a patient, DO NOT substitute it for any other fentanyl product prescription. 5.3 Information for Patients and Their Caregivers Patients and their caregivers must be instructed that Lazanda contains medicine in an amount that could be fatal to a child. Patients and their caregivers must be instructed to keep both used and unused bottles in their child-resistant container and out of the reach of children at all times. Partially used bottles represent a special risk to children. As soon as they are no longer required, all used, unopened or partially used bottles must be completely emptied of accessible fentanyl solution by spraying the remaining contents into the carbon-lined pouch. The sealed pouch and the empty bottle should be put into the child-resistant container before discarding in the trash. Hands must be washed with soap and water immediately after handling the pouch. [see Storage and Handling (16.2) , Disposal of Lazanda (16.3) , and Patient/Caregiver Instructions (17.1) ]. Physicians and dispensing pharmacists must question patients and caregivers specifically about the presence of children in the home on a full-time or visiting basis and counsel accordingly regarding the dangers to children of inadvertent exposure to Lazanda. Lazanda could be fatal to individuals for whom it is not prescribed and for those who are not opioid tolerant. 5.4 Additive CNS Depressant Effects The concomitant use of Lazanda with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Metabolic Drug Interactions (7.1) ]. Patients on concomitant CNS depressants must be monitored for a change in opioid effects and may require adjustment of the dose of Lazanda. 5.5 Effects on Ability to Drive and Use Machines Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking Lazanda of these dangers and counsel them accordingly. 5.6 Chronic Pulmonary Disease Because potent opioids can cause respiratory depression, cautiously adjust the dose of Lazanda in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of Lazanda may further decrease respiratory drive to the point of respiratory failure. 5.7 Head Injuries and Increased Intracranial Pressure Administer Lazanda with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO 2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury; only use opioids if clinically warranted. 5.8 Cardiac Disease Intravenous fentanyl may produce bradycardia. Use Lazanda with caution in patients with bradyarrhythmias. 5.9 MAO Inhibitors Lazanda is 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 Non-metabolic Drug Interactions (7.2) ]. 5.10 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk of misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence (9) ], Lazanda is available only through a restricted program under a REMS called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, 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 Lazanda, patient and prescriber enrollment is not required. Required components of the TIRF REMS Access program are: Healthcare professionals who prescribe Lazanda must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements. To receive Lazanda, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement. Pharmacies that dispense Lazanda must enroll in the program and agree to comply with the REMS requirements. Wholesalers and distributers that distribute Lazanda 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.

6 ADVERSE REACTIONS Most common (frequency ≥5%): vomiting, nausea, dizziness, pyrexia, and constipation. [ 6.1 ] To report SUSPECTED ADVERSE REACTIONS, contact Archimedes Pharma at 1-866-435-6775 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 most commonly observed adverse events seen with Lazanda are typical of opioid side effects, such as nausea, constipation, somnolence, and headache. Expect opioid side effects and manage them accordingly. 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 MeDRA 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 MeDRA 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. Adverse Events (≥1%) 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

<table width="100%"> <caption>Table 1: Adverse Reactions That Occurred During Titration at a Frequency of &#x2265;5%</caption> <col width="25%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">System Organ Class MeDRA preferred term, n (%)</th> <th styleCode="Rrule">100 mcg (N=483)</th> <th styleCode="Rrule">200 mcg (N=380)</th> <th styleCode="Rrule">400 mcg (N=301)</th> <th styleCode="Rrule">800 mcg (N=161)</th> <th styleCode="Rrule">Total (N=516)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td colspan="6" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">19 (4)</td> <td styleCode="Rrule">6 (2)</td> <td styleCode="Rrule">6 (2)</td> <td styleCode="Rrule">5 (3)</td> <td styleCode="Rrule">35 (7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">14 (3)</td> <td styleCode="Rrule">10 (3)</td> <td styleCode="Rrule">9 (3)</td> <td styleCode="Rrule">1 (1)</td> <td styleCode="Rrule">33 (6)</td> </tr> <tr styleCode="Botrule"> <td colspan="6"> <content styleCode="bold">Nervous system disorders</content> </td> </tr> <tr> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">14 (3)</td> <td styleCode="Rrule">11 (3)</td> <td styleCode="Rrule">6 (2)</td> <td styleCode="Rrule">4 (2)</td> <td styleCode="Rrule">31 (6)</td> </tr> </tbody> </table>

<table width="100%"> <caption>Table 2: Adverse Reactions That Occurred During Maintenance Treatment at a Frequency of &#x2265;5% </caption> <col width="25%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <col width="15%" align="left" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">System Organ Class MeDRA preferred term, n (%)</th> <th styleCode="Rrule">100 mcg (N=61)</th> <th styleCode="Rrule">200 mcg (N=68)</th> <th styleCode="Rrule">400 mcg (N=109)</th> <th styleCode="Rrule">800 mcg (N=108)</th> <th styleCode="Rrule">Total (N=346)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td colspan="6" styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">8 (13)</td> <td styleCode="Rrule">5 (7)</td> <td styleCode="Rrule">9 (8)</td> <td styleCode="Rrule">12 (11)</td> <td styleCode="Rrule">34 (10)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">4 (7)</td> <td styleCode="Rrule">6 (9)</td> <td styleCode="Rrule">4 (4)</td> <td styleCode="Rrule">9 (8)</td> <td styleCode="Rrule">23 (7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Constipation</td> <td styleCode="Rrule">6 (10)</td> <td styleCode="Rrule">1 (1)</td> <td styleCode="Rrule">8 (7)</td> <td styleCode="Rrule">5 (5)</td> <td styleCode="Rrule">20 (6)</td> </tr> <tr styleCode="Botrule"> <td colspan="6" styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> </td> </tr> <tr> <td styleCode="Lrule Rrule"> Pyrexia</td> <td styleCode="Rrule">3 (5)</td> <td styleCode="Rrule">5 (7)</td> <td styleCode="Rrule">8 (7)</td> <td styleCode="Rrule">6 (6)</td> <td styleCode="Rrule">22 (6)</td> </tr> </tbody> </table>