Drug Safety-related Labeling Changes (SrLC)
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Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
FENTORA (NDA-021947)
(FENTANYL CITRATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/15/2023 (SUPPL-43)
11/22/2022 (SUPPL-38)
03/04/2021 (SUPPL-34)
Boxed Warning
Additions and/or revisions underlined:
Risk Evaluation and Mitigation Strategy (REMS)
Because
of the risk for accidental exposure, misuse, abuse, addiction, and
overdose, FENTORA 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
FENTORA while hospitalized [see
Warnings and Precautions (5.7)]. Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483
5 Warnings and Precautions
5.1 Life-Threatening Respiratory Depression
Additions and/or revisions underlined:
… Accidental ingestion of even one dose of FENTORA, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
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 (2.7)].
Newly added information:
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 FENTORA. 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)].
5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol)
Additions and/or revisions underlined:
… 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)].
5.6 Addiction, Abuse, and Misuse
Additions and/or revisions underlined:
… Patients at increased risk may be prescribed opioids such as FENTORA, but use in such patients necessitates intensive counseling about the risks and proper use of FENTORA 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)].
5.7 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS)
Additions and/or revisions underlined:
Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence (9)], FENTORA is available only through a restricted program 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 include the following:
Prescribers for outpatient use must be certified with the REMS program by enrolling and completing training. Prescribers must document opioid tolerance with every FENTORA prescription.
Outpatients must be enrolled in the REMS program and must be opioid-tolerant to receive FENTORA [see Dosage and Administration (2.1)].
Outpatient pharmacies must be certified with the REMS program and verify documentation of opioid tolerance with every FENTORA prescription.
Inpatient pharmacies must be certified with the REMS program and develop policies and procedures to verify opioid tolerance in inpatients who require FENTORA while hospitalized.
Wholesalers and distributors 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.
7 Drug Interactions
Table 4: Clinically Significant Drug Interactions with FENTORA
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Under Intervention, the following language is added:
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, 5.4, 5.6)].
Muscle Relaxants
Under Intervention, the following language is added:
Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.4)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEImportant information about FENTORA:
Additions and/or revisions underlined:
Get emergency help or call 911 right away if you take too much FENTORA (overdose). When you first start taking FENTORA, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.
FENTORA is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS). To receive FENTORA, you must:
Sign the Patient Enrollment Form
Before taking FENTORA, tell your healthcare provider if you have a history of:
abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.
Tell your healthcare provider if you are:
living in a household where there are small children or someone who has abused street or prescription drugs
Get emergency medical help or call 911 right away if you have: …
Life-Threatening Respiratory Depression
Newly added information:
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 Warnings and Precautions (5.1)].
Newly added information:
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with FENTORA. 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) [see Dosage and Administrations (2.2), Warnings and Precautions (5.1)].
Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.
Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].
If naloxone is prescribed, also advise patients and caregivers:
How to treat with naloxone in the event of an opioid overdose
To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.
Additions and/or revisions underlined:
Transmucosal Immediate-Release Fentanyl (TIRF) REMS
FENTORA is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:
Outpatients must be enrolled in the REMS program
Patients must be opioid-tolerant to receive FENTORA
FENTORA is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.
Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require FENTORA while hospitalized [see Warnings and Precautions (5.7)].
10/07/2019 (SUPPL-29)
12/16/2016 (SUPPL-24)
Boxed Warning
WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME
Additions and/or revisions underlined:
Life-Threatening Respiratory
Depression
Serious life-threatening and/or fatal respiratory depression has occurred in patients treated with FENTORA, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of FENTORA or following a dose increase. The substitution of FENTORA for any other fentanyl product may result in fatal overdose …
Accidental Ingestion
Accidental ingestion of even one dose of FENTORA, especially by children, can result in a fatal overdose of fentanyl.
Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. FENTORA must be kept out of reach of children.
Cytochrome P450 3A4 Interaction
The concomitant use of FENTORA 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 FENTORA and any CYP3A4 inhibitor or inducer.
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.
Reserve concomitant prescribing of FENTORA 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 …
Addiction, Abuse, and Misuse
FENTORA 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 FENTORA, and monitor all patients regularly for the development of these behaviors or conditions.
Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction …
Neonatal Opioid Withdrawal Syndrome
Prolonged use of FENTORA 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.
4 Contraindications
Additions and/or revisions underlined:
FENTORA is contraindicated in:
Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.
Significant respiratory depression.
Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
Known or suspected gastrointestinal obstruction, including paralytic ileus.
Known hypersensitivity (e.g. anaphylaxis) to fentanyl or components of FENTORA (e.g., anaphylaxis).
5 Warnings and Precautions
5.1 Life-Threatening Respiratory Depression(Additions and/or revisions underlined)
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. 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 FENTORA, 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 FENTORA.
To reduce the risk of respiratory depression, proper dosing and titration of FENTORA are essential. Overestimating the FENTORA dosage can result in a fatal overdose with the first dose. The substitution of FENTORA for any other fentanyl product may result in fatal overdose. FENTORA could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.
Accidental ingestion of even one dose of FENTORA, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
(Newly added section)
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of FENTORA 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), 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). 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 FENTORA if serotonin syndrome is suspected.
(Newly added section)
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.
(Newly added section)
FENTORA 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). Monitor these patients for signs of hypotension after initiating or titrating the dosage of FENTORA. In patients with circulatory shock, FENTORA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of FENTORA in patients with circulatory shock.
(Newly added section)
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), FENTORA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with FENTORA.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of FENTORA in patients with impaired consciousness or coma.
(Newly added section)
FENTORA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in FENTORA 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 FENTORA 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 FENTORA therapy.
FENTORA 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 FENTORA and know how they will react to the medication.
Additions and/or revisions underlined:
Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.
Patients and their caregivers must be informed that FENTORA contains a medicine in an amount which can be fatal to a child. Healthcare providers 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.
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.
Newly added subsection:
Concomitant use of FENTORA 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, particularly when an inhibitor is added after a stable dose of FENTORA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in FENTORA-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using FENTORA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in FENTORA-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of FENTORA until stable drug effects are achieved.
Concomitant use of FENTORA with CYP3A4 inducers or discontinuation of a 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 FENTORA 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.
Newly added subsection:
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of FENTORA 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.
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.
Advise both patients and caregivers about the risks of respiratory depression and sedation when FENTORA 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.
Additions and/or revisions underlined:
When prescribing, do not convert a patient to FENTORA from any other fentanyl product on a mcg per mcg basis as FENTORA and other fentanyl products are not equivalent on a microgram per microgram basis.
FENTORA is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a FENTORA prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and FENTORA are not equivalent. Substantial differences exist in the pharmacokinetic profile of FENTORA 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 FENTORA or any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ (Note: This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid tolerant patients, the initial dose of FENTORA should always be 100 mcg. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects.
Additions and/or revisions underlined:
FENTORA contains fentanyl, a Schedule II controlled substance. As an opioid, FENTORA exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed FENTORA. 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 FENTORA, and monitor all patients receiving FENTORA for the development of these behaviors or 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 FENTORA, but use in such patients necessitates intensive counseling about the risks and proper use of FENTORA along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing FENTORA. 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. 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.
(Newly added section)
Prolonged use of FENTORA 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.
Additions and/or revisions underlined:
The use of FENTORA 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: FENTORA-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 FENTORA.
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.
Monitor such patients closely, particularly when initiating and titrating FENTORA and when FENTORA is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
6 Adverse Reactions
Addition of the following line listing:
The following serious adverse reactions are described, or described in greater detail, in other sections:
Life-Threatening Respiratory Depression
Interactions with Benzodiazepines and Other CNS Depressants
Addiction, Abuse, and Misuse
Neonatal Opioid Withdrawal Syndrome
Serotonin Syndrome
Adrenal Insufficiency
Severe Hypotension
Gastrointestinal Adverse Reactions
Seizures
(Additions and/or revisions underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug 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 FENTORA has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months …
(Following table 3, additional information is underlined)
… Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesias to ulceration and bleeding. Application site reactions occurring in greater than or equal to 1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.
(Newly added section)
The following adverse reactions have been identified during post approval use of 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.
Nervous System Disorders:
- Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
- Endocrine Disorders:
- Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
- Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.
Immune System Disorders:
- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in FENTORA.
- General Disorders and Administration Site Conditions: Drug withdrawal syndrome
7 Drug Interactions
(Additions and/or revisions underlined)
Table 4 includes clinically significant drug interactions with FENTORA.
Table 4: Clinically Significant Drug Interactions with FENTORA.
Information converted to table format; please refer to label.
8 Use in Specific Populations
8.1 PregnancyPLLR conversion:
Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with FENTORA 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. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date.
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 of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.
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. FENTORA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including FENTORA, 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 (25, 50, or 100 mcg/kg) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses greater than or equal to 100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison).
Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of FENTORA on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of FENTORA based on a mg/m2 basis). No evidence of teratogenicity was 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 FENTORA per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean Cmax observed following administration of 800 mcg dose of FENTORA in humans.
In a postnatal development study, pregnant rats were treated … which is approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.
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 FENTORA.
Clinical Considerations
Monitor infants exposed to FENTORA nursing 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.
PLLR conversion:
Infertility
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.
(Additions and/or revisions underlined)
Therefore, caution should be exercised in individually titrating FENTORA 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 FENTORA slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.
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.
(Sex replaces gender in all instances in this section)
Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Exensively revised; please refer to label)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addition of the following:
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting FENTORA or when the dosage is increased, and that it can occur even at recommended dosages. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Increased Risk of Overdose and Death in Children Due to Accidental Ingestion
Healthcare providers 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.
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.
Instruct patients to take steps to store FENTORA securely and to dispose of unused FENTORA.
Instruct patients and caregivers to keep both used and unused FENTORA out of the reach of children.
Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)
Inform patients that potentially fatal additive effects may occur if FENTORA is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.
Addiction, Abuse, and Misuse
Inform patients that the use of FENTORA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share FENTORA with others and to take steps to protect FENTORA from theft or misuse.
Transmucosal Immediate-Release Fentanyl (TIRF) REMS
Advise patients of the following information pertaining to the TIRF REMS …
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications.
MAOI Interaction
Inform patients to avoid taking FENTORA while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking FENTORA.
Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.
Hypotension
Inform patients that FENTORA may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Anaphylaxis
Inform patients that anaphylaxis have been reported with ingredients contained in FENTORA. Advise patients how to recognize such a reaction and when to seek medical attention.
Pregnancy
Neonatal Opioid Withdrawal Syndrome
Inform patients that prolonged use of FENTORA can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that FENTORA can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy.
Lactation
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs.
Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.
Driving or Operating Heavy Machinery
Inform patients that FENTORA may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
… In the event that a caregiver requires additional assistance in disposing of excess unusable tablets that remain in the home after a patient has expired, instruct them to call the Teva Pharmaceuticals toll-free number (1-888-483-8279) or seek assistance from their local DEA office.
Other
Prior label already in PLR Format; further revision to incorporate the opioid analgesic template
language; please refer to label.
12/16/2016 (SUPPL-25)
Boxed Warning
WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME
Additions and/or revisions underlined:
Life-Threatening Respiratory
Depression
Serious life-threatening and/or fatal respiratory depression has occurred in patients treated with FENTORA, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of FENTORA or following a dose increase. The substitution of FENTORA for any other fentanyl product may result in fatal overdose …
Accidental Ingestion
Accidental ingestion of even one dose of FENTORA, especially by children, can result in a fatal overdose of fentanyl.
Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. FENTORA must be kept out of reach of children.
Cytochrome P450 3A4 Interaction
The concomitant use of FENTORA 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 FENTORA and any CYP3A4 inhibitor or inducer.
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.
Reserve concomitant prescribing of FENTORA 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 …
Addiction, Abuse, and Misuse
FENTORA 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 FENTORA, and monitor all patients regularly for the development of these behaviors or conditions.
Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction …
Neonatal Opioid Withdrawal Syndrome
Prolonged use of FENTORA 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.
4 Contraindications
Additions and/or revisions underlined:
FENTORA is contraindicated in:
Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.
Significant respiratory depression.
Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
Known or suspected gastrointestinal obstruction, including paralytic ileus.
Known hypersensitivity (e.g. anaphylaxis) to fentanyl or components of FENTORA (e.g., anaphylaxis).
5 Warnings and Precautions
5.1 Life-Threatening Respiratory Depression(Additions and/or revisions underlined)
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. 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 FENTORA, 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 FENTORA.
To reduce the risk of respiratory depression, proper dosing and titration of FENTORA are essential. Overestimating the FENTORA dosage can result in a fatal overdose with the first dose. The substitution of FENTORA for any other fentanyl product may result in fatal overdose. FENTORA could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.
Accidental ingestion of even one dose of FENTORA, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
(Newly added section)
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of FENTORA 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), 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). 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 FENTORA if serotonin syndrome is suspected.
(Newly added section)
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.
(Newly added section)
FENTORA 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). Monitor these patients for signs of hypotension after initiating or titrating the dosage of FENTORA. In patients with circulatory shock, FENTORA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of FENTORA in patients with circulatory shock.
(Newly added section)
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), FENTORA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with FENTORA.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of FENTORA in patients with impaired consciousness or coma.
(Newly added section)
FENTORA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in FENTORA 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 FENTORA 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 FENTORA therapy.
FENTORA 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 FENTORA and know how they will react to the medication.
Additions and/or revisions underlined:
Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.
Patients and their caregivers must be informed that FENTORA contains a medicine in an amount which can be fatal to a child. Healthcare providers 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.
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.
Newly added subsection:
Concomitant use of FENTORA 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, particularly when an inhibitor is added after a stable dose of FENTORA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in FENTORA-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using FENTORA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in FENTORA-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of FENTORA until stable drug effects are achieved.
Concomitant use of FENTORA with CYP3A4 inducers or discontinuation of a 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 FENTORA 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.
Newly added subsection:
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of FENTORA 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.
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.
Advise both patients and caregivers about the risks of respiratory depression and sedation when FENTORA 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.
Additions and/or revisions underlined:
When prescribing, do not convert a patient to FENTORA from any other fentanyl product on a mcg per mcg basis as FENTORA and other fentanyl products are not equivalent on a microgram per microgram basis.
FENTORA is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a FENTORA prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and FENTORA are not equivalent. Substantial differences exist in the pharmacokinetic profile of FENTORA 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 FENTORA or any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ (Note: This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid tolerant patients, the initial dose of FENTORA should always be 100 mcg. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects.
Additions and/or revisions underlined:
FENTORA contains fentanyl, a Schedule II controlled substance. As an opioid, FENTORA exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed FENTORA. 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 FENTORA, and monitor all patients receiving FENTORA for the development of these behaviors or 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 FENTORA, but use in such patients necessitates intensive counseling about the risks and proper use of FENTORA along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing FENTORA. 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. 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.
(Newly added section)
Prolonged use of FENTORA 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.
Additions and/or revisions underlined:
The use of FENTORA 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: FENTORA-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 FENTORA.
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.
Monitor such patients closely, particularly when initiating and titrating FENTORA and when FENTORA is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
6 Adverse Reactions
Addition of the following line listing:
The following serious adverse reactions are described, or described in greater detail, in other sections:
Life-Threatening Respiratory Depression
Interactions with Benzodiazepines and Other CNS Depressants
Addiction, Abuse, and Misuse
Neonatal Opioid Withdrawal Syndrome
Serotonin Syndrome
Adrenal Insufficiency
Severe Hypotension
Gastrointestinal Adverse Reactions
Seizures
(Additions and/or revisions underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug 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 FENTORA has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months …
(Following table 3, additional information is underlined)
… Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesias to ulceration and bleeding. Application site reactions occurring in greater than or equal to 1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.
(Newly added section)
The following adverse reactions have been identified during post approval use of 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.
Nervous System Disorders:
- Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
- Endocrine Disorders:
- Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
- Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.
Immune System Disorders:
- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in FENTORA.
- General Disorders and Administration Site Conditions: Drug withdrawal syndrome
7 Drug Interactions
(Additions and/or revisions underlined)
Table 4 includes clinically significant drug interactions with FENTORA.
Table 4: Clinically Significant Drug Interactions with FENTORA.
Information converted to table format; please refer to label.
8 Use in Specific Populations
8.1 PregnancyPLLR conversion:
Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with FENTORA 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. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date.
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 of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.
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. FENTORA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including FENTORA, 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 (25, 50, or 100 mcg/kg) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses greater than or equal to 100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison).
Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of FENTORA on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of FENTORA based on a mg/m2 basis). No evidence of teratogenicity was 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 FENTORA per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean Cmax observed following administration of 800 mcg dose of FENTORA in humans.
In a postnatal development study, pregnant rats were treated … which is approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.
PLLR conversion:
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 FENTORA.
Clinical Considerations
Monitor infants exposed to FENTORA nursing 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.
PLLR conversion:
Infertility
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.
(Additions and/or revisions underlined)
Therefore, caution should be exercised in individually titrating FENTORA 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 FENTORA slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.
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.
(Sex replaces gender in all instances in this section)
Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Extensively revised; please refer to label)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addition of the following:
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting FENTORA or when the dosage is increased, and that it can occur even at recommended dosages. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Increased Risk of Overdose and Death in Children Due to Accidental Ingestion
Healthcare providers 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.
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.
Instruct patients to take steps to store FENTORA securely and to dispose of unused FENTORA.
Instruct patients and caregivers to keep both used and unused FENTORA out of the reach of children.
Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)
Inform patients that potentially fatal additive effects may occur if FENTORA is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.
Addiction, Abuse, and Misuse
Inform patients that the use of FENTORA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share FENTORA with others and to take steps to protect FENTORA from theft or misuse.
Transmucosal Immediate-Release Fentanyl (TIRF) REMS
Advise patients of the following information pertaining to the TIRF REMS …
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications.
MAOI Interaction
Inform patients to avoid taking FENTORA while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking FENTORA.
Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.
Hypotension
Inform patients that FENTORA may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Anaphylaxis
Inform patients that anaphylaxis have been reported with ingredients contained in FENTORA. Advise patients how to recognize such a reaction and when to seek medical attention.
Pregnancy
Neonatal Opioid Withdrawal Syndrome
Inform patients that prolonged use of FENTORA can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that FENTORA can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy.
Lactation
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs.
Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.
Driving or Operating Heavy Machinery
Inform patients that FENTORA may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
… In the event that a caregiver requires additional assistance in disposing of excess unusable tablets that remain in the home after a patient has expired, instruct them to call the Teva Pharmaceuticals toll-free number (1-888-483-8279) or seek assistance from their local DEA office.
Other
Prior label already in PLR Format; further revision to incorporate the opioid analgesic template
language; please refer to label.