Healthcare professionals who prescribe LAZANDA for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of

LAZANDA [see Warnings and Precautions ( 5.7)].

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
• 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.
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with LAZANDA and adjust the dosage accordingly [see Warnings and Precautions ( 5.1)].
• Instruct patients and caregivers to take steps to store LAZANDA securely and to properly dispose of unused LAZANDA as soon as no longer needed [see Warnings and Precautions ( 5.2, 5.6), Patient Counseling Information ( 17)].
• LAZANDA is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products (Note: This includes oral, transdermal, or parenteral formulations of fentanyl) [see Warnings and Precautions ( 5.5)].
• LAZANDA is NOT a generic version of any other oral transmucosal fentanyl product [see Warnings and Precautions ( 5.5)].

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 [see Warnings and Precautions (5.1), Patient Counseling Information ( 17)].

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).

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 [see Warnings and Precautions ( 5.1, 5.4, 5.6)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

Initiate treatment with LAZANDA for all patients (including those switching from another fentanyl product) using ONE 100 mcg spray of LAZANDA (1 spray in one nostril).

Repeat Dosing

• If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg single spray, treat subsequent episodes of breakthrough pain with this dose.
• If adequate analgesia is not achieved with the first 100 mcg dose, dose escalate in a step-wise manner over consecutive episodes of breakthrough pain until adequate analgesia with tolerable side effects is achieved.
• Patients MUST wait at least 2 hours before treating another episode of breakthrough cancer pain with LAZANDA.

Titration

The objective of dose titration is to identify an effective and tolerable maintenance dose for ongoing management of breakthrough cancer pain episodes. The effective and tolerable dose of LAZANDA will be determined by dose titration in individual patients.

Titration steps: If adequate analgesia is not achieved with the first 100 mcg dose, dose escalate in a step-wise manner over consecutive episodes of breakthrough pain until adequate analgesia with tolerable side effects is achieved.

Patients MUST wait at least 2 hours before treating another episode of breakthrough cancer pain with LAZANDA.

The titration steps should be:

Patients should confirm the dose of LAZANDA that works for them with a second episode of breakthrough pain and review their experience with their physicians to determine if that dose is appropriate, or whether a further adjustment is warranted.

The safety and efficacy of doses higher than 800 mcg have not been evaluated in clinical studies. Avoid the use of a combination of dose strengths to treat an episode as this may cause confusion and dosing errors.

LAZANDA TITRATION PROCESS

In order to minimize the risk of LAZANDA-related adverse reactions and to identify the appropriate dose, it is imperative that patients be supervised closely by health professionals during the titration process.

Maintenance Therapy

Once an appropriate dose has been established, instruct patients to use that dose for each subsequent breakthrough cancer pain episode. Limit LAZANDA use to four or fewer doses per day.

Patients MUST wait at least 2 hours before treating another episode of breakthrough cancer pain with LAZANDA.

During any episode of breakthrough cancer pain, if there is inadequate pain relief after 30 minutes following LAZANDA dosing or if a separate episode of breakthrough cancer pain occurs before the next dose of LAZANDA is permitted (i.e., within 2 hours), the patients may use a rescue medication as directed by their healthcare provider.

If the response (analgesia or adverse reactions) to the titrated LAZANDA dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained.

If more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the long-acting opioid used for persistent underlying cancer pain. If the long-acting opioid or dose of long-acting opioid is changed, re-evaluate and re-titrate the LAZANDA dose as necessary to ensure the patient is on an appropriate dose.

Limit the use of LAZANDA to treat four or fewer episodes of breakthrough pain per day.

It is imperative that any dose re-titration is monitored carefully by a healthcare professional.

Instruct patients on the proper use of LAZANDA.

• Prime the device before use by spraying into the pouch (4 sprays in total). If the product has not been used for 5 days, re-prime by spraying once. For priming, follow the instructions provided [See Medication Guide].
• Insert the nozzle of the LAZANDA bottle a short distance (about ½ inch or 1 cm) into the nose and point towards the bridge of the nose, tilting the bottle slightly.
• Press down firmly on the finger grips until they hear a “click” and the number in the counting window advances by one.

Advise patients that the fine mist spray is not always felt on the nasal mucosal membrane and to rely on the audible click and the advancement of the dose counter to confirm a spray has been administered.

For patients no longer requiring opioid therapy, consider discontinuing LAZANDA along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, LAZANDA therapy can usually be discontinued immediately [see Drug Abuse and Dependence ( 9.3)].

Instruct patients and caregivers to properly dispose of all unused, partially used and used LAZANDA bottles. The remaining liquid in all bottles must be sprayed into the pouch, provided in the pack, for safe disposal as soon as possible.

Instruct the patient how to do this correctly. If there are any unwanted therapeutic sprays remaining in the bottle, instruct the patient to spray these into the pouch until the number “8” appears in the counting window and there are no more full therapeutic sprays obtainable from the bottle. After the counter has advanced to “8”, the patient should continue to push down on the finger grips a total of four times in order to expel any residual medicine from the bottle. After the 8 therapeutic sprays have been emitted, the patient will not hear a click and the counter will not advance beyond “8”; further sprays emitted will not be full sprays and should always be trapped in the pouch, not used therapeutically.

Instruct the patient and caregiver to seal the pouch and place both it and the empty bottle into the child-resistant storage container. Patients must wash their hands with soap and water immediately after handling the pouch.

The patient must discard the child-resistant container containing the pouch and the bottle in the trash.

The patient or caregiver must continue to store the LAZANDA bottle in the specially provided child-resistant container and the pouch out of the reach of children until proper disposal, as described above, is possible.

Instruct the patient to dispose of the LAZANDA bottle and start a new one if it has been 60 days or more since they first used the bottle of LAZANDA.

In the event that caregivers or patients require additional assistance with the disposal of LAZANDA bottles, call the West Therapeutic Development, LLC toll-free number (1-844-452-9263).

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)].

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.

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 )].

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)].

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)].

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.

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.

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)].

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.

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.

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.

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.

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.

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.

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.

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.

Intravenous fentanyl may produce bradycardia. Therefore, use LAZANDA with caution in patients with bradyarrhythmias.

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%

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%

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

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 )].

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with LAZANDA in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing for LAZANDA. No evidence of malformations were noted in animal studies completed to date [ see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. LAZANDA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including LAZANDA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of LAZANDA on a mg/m ² basis) and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of LAZANDA based on a mg/m ² basis). There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg LAZANDA per pain episode on a mg/m ² basis and produced mean steady-state plasma levels that are 3 times higher than the mean C _max observed following administration of 800 mcg dose of LAZANDA in humans.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with LAZANDA.

Clinical Considerations

Monitor infants exposed to LAZANDA through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.2 ), Nonclinical Toxicology( 13.1 )].

The safety and efficacy of LAZANDA have not been established in patients below the age of 18 years.

Of the 523 opioid tolerant cancer patients with breakthrough cancer pain in clinical studies of LAZANDA, 148 (28%) were aged 60 years and over. No clinically meaningful difference was noted in the safety profile of the group aged over 60 years versus that of younger patients in LAZANDA clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously compared with the younger population. Therefore, exercise caution when individually titrating LAZANDA in elderly patients to provide adequate efficacy while minimizing risk.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of LAZANDA slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.1)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Insufficient information exists to make recommendations regarding the use of LAZANDA in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, it is to be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

It is recommended that LAZANDA be titrated to clinical effect for all patients with special care taken in patients with severe renal or hepatic disease.

Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were observed in adverse events.

The pharmacokinetic and safety profiles of LAZANDA in individuals with known allergic (seasonal) rhinitis showed no clinically meaningful differences in rate or extent of exposure to fentanyl, or in local tolerability of LAZANDA when compared to Asymptomatic (Unchallenged) state. However, when treated for their rhinitis with oxymetazoline, LAZANDA absorption was compromised [see Pharmacokinetics ( 12.3)].

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increase in carbon dioxide tension and electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals.

The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1, 2.5)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1, 2.2, 2.3)].

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of transmucosal fentanyl citrate product administration and may persist for several hours.

Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with oral or nasal transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration. [see Warnings and Precautions ( 5.1), Adverse Reactions ( 6), Overdosage ( 10)].

Absorption

In a study that compared the relative bioavailability of LAZANDA and an oral transmucosal fentanyl citrate product, the bioavailability of fentanyl from LAZANDA was approximately 20% higher. Fentanyl is absorbed from the nasal mucosa following intranasal administration of LAZANDA, with median T _max values ranging from 15-21 min after administration of a single dose. C _max and AUC values for fentanyl following administration of LAZANDA increase linearly over the 100- to 800-mcg dose range.

Mean plasma concentration versus time profiles are presented in Figure 1. Mean pharmacokinetic parameters are presented in Table 4.

Figure 1.

Mean Plasma Fentanyl Concentration (pg/mL) in Normal Subjects Receiving 100, 200, 400 and 800 mcg Lazanda or 200 mcg OTFC

Clin Pharm Fig 1

Table 4. Pharmacokinetic Parameters in Normal Subjects Receiving 100, 200, 400, and 800 mcg of LAZANDA or 200 mcg OTFC

A pharmacokinetic study evaluated the cerebrospinal fluid (CSF) concentrations of fentanyl administered via the intranasal (LAZANDA) route. As presented in Table 5, the maximum concentration of fentanyl in the CSF as delivered by LAZANDA was reached at 1.0 hour. Values for the C _max and AUC _0-6h of fentanyl are also presented in Table 5.

Table 5 Cerebrospinal Pharmacokinetic Parameters in Normal Subjects Receiving 200 mcg of LAZANDA

In a pharmacokinetic study that evaluated multiple-dose pharmacokinetics of LAZANDA when two doses of LAZANDA are administered in the same nostril and are separated by a 1, 2 or 4 h time lapse, C _max2 (C _max after second administration) was greater than C _max1 (C _max after first administration), by 30% when LAZANDA was administered 1 h apart, by 25% when LAZANDA was administered 2 h apart and by 10% when LAZANDA was administered 4 h apart. Based on these results and based on T _max range of LAZANDA observed across pharmacokinetic studies, and frequency of breakthrough pain episodes in a cancer population, a waiting period of 2 h between two consecutive doses of LAZANDA is recommended [see Dosage and Administration ( 2.3 , 2.4 )].

In a pharmacokinetic study to evaluate differences in LAZANDA absorption in individuals with induced allergic (seasonal) rhinitis using Ragweed, no clinically meaningful differences were observed in rate or extent of exposure to fentanyl, when compared to the Asymptomatic (Unchallenged) state, indicating that presence of allergic rhinitis does not affect LAZANDA absorption. This study also assessed differences in Lazanda absorption, if any, when co-administered with oxymetazoline, a nasal decongestant in subjects undergoing treatment for seasonal allergic rhinitis. The mean C _max and AUC _t values for Treated arm (Rhinitis treated with oxymetazoline) were about 32% and 10% lower , respectively compared to the Asymptomatic arm. In addition, mean T _max of LAZANDA in the Treated arm was 0.75 h (range 0.08-3 h) as compared to 0.25 h (0.17-1 h) for the Asymptomatic arm. These results indicate that co-administration with oxymetazoline in rhinitis leads to lower peak plasma concentrations and delayed T _max of LAZANDA [see Drug Interactions ( 7 )].

Distribution

Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean volume of distribution at steady state (Vss) was 4 L/kg.

Elimination

The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

Metabolism

The metabolic pathways following intranasal administration of LAZANDA have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active.

Excretion

The disposition of fentanyl following intranasal administration of LAZANDA has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.