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.
ACTIQ (NDA-020747)
(FENTANYL CITRATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/15/2023 (SUPPL-62)
11/22/2022 (SUPPL-56)
03/04/2021 (SUPPL-53)
Boxed Warning
Risk Evaluation and Mitigation Strategy (REMS)
Additions and/or revisions underlined:
Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose, ACTIQ 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 ACTIQ 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 ACTIQ, 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 ACTIQ. 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 ACTIQ, but use in such patients necessitates intensive counseling about the risks and proper use of ACTIQ 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 Warnings and Precautions (5.6)], ACTIQ 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 are:
Prescribers for outpatient use must be certified with the REMS program by enrolling and completing training. Prescribers must document opioid tolerance with every ACTIQ prescription.
Outpatients must be enrolled in the REMS program and must be opioid tolerant to receive ACTIQ [see Dosage and Administration (2.1)].
Outpatient pharmacies must be certified with the REMS program and verify documentation of opioid tolerance with every ACTIQ prescription.
Inpatient pharmacies must be certified with the REMS program and develop policies and procedures to verify opioid tolerance in inpatients who require ACTIQ 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 3: Clinically Significant Drug Interactions with ACTIQ
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 ACTIQ:
Additions and/or revisions underlined:
Get emergency help or call 911 right away if you take too much ACTIQ (overdose). When you first start taking ACTIQ, 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.
ACTIQ is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS). To receive ACTIQ, you must:
Sign the Patient Enrollment Form
Before taking ACTIQ, 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 ACTIQ. 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
ACTIQ 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 ACTIQ.
ACTIQ 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 ACTIQ while hospitalized [see Warnings and Precautions (5.7)].
10/07/2019 (SUPPL-49)
12/16/2016 (SUPPL-43)
Boxed Warning
Additions and/or revisions underlined:
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
Life-Threatening
Respiratory Depression
Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ACTIQ, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ACTIQ or following a dose increase …
Accidental Ingestion
Accidental ingestion of even one dose of ACTIQ, especially by children, can result in a fatal overdose of fentanyl …
Cytochrome P450 3A4 Interaction
The concomitant use of ACTIQ 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 ACTIQ 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 ACTIQ 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 …
Addiction, Abuse, and Misuse
ACTIQ 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 ACTIQ, and monitor all patients regularly for the development of these behaviors and conditions.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of ACTIQ 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:
ACTIQ 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 to fentanyl or components of ACTIQ (e.g., anaphylaxis, hypersensitivity)
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 ACTIQ, 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 ACTIQ.
To reduce the risk of respiratory depression, proper dosing and titration of ACTIQ are essential. Overestimating the ACTIQ dosage can result in a fatal overdose with the first dose. The substitution of ACTIQ for any other fentanyl product may result in fatal overdose.
ACTIQ 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 ACTIQ, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
(Newly added subsection)
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ACTIQ 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) [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 ACTIQ if serotonin syndrome is suspected.
(Newly added subsection)
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 subsection)
ACTIQ 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 ACTIQ. In patients with circulatory shock, ACTIQ may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ACTIQ in patients with circulatory shock.
Additions and/or revisions underlined:
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), ACTIQ 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 ACTIQ.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ACTIQ in patients with impaired consciousness or coma.
(Newly added subsection)
ACTIQ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in ACTIQ 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.
(Newly added subsection)
The fentanyl in ACTIQ 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 ACTIQ therapy.
… Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ACTIQ and know how they will react to the medication.
(Additions and/or revisions underlined)
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ACTIQ are provided in the ACTIQ Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.
Concomitant use of ACTIQ 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 ACTIQ is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ACTIQ-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using ACTIQ with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ACTIQ-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ACTIQ until stable drug effects are achieved.
Concomitant use of ACTIQ 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 ACTIQ 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 ACTIQ 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 ACTIQ 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:
ACTIQ is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute an ACTIQ prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and ACTIQ are not equivalent. Substantial differences exist in the pharmacokinetic profile of ACTIQ compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl.
Newly added subsection:
ACTIQ contains fentanyl, a Schedule II controlled substance. As an opioid, ACTIQ 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 ACTIQ. 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 ACTIQ, and monitor all patients receiving ACTIQ 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 ACTIQ, but use in such patients necessitates intensive counseling about the risks and proper use of ACTIQ 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 ACTIQ. 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 subsection)
Prolonged use of ACTIQ 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.
Newly added subsection:
The use of ACTIQ 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: ACTIQ-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 ACTIQ.
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 ACTIQ and when ACTIQ 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)
The safety of ACTIQ has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of ACTIQ use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days …
Following table 1:
… The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.
Nervous: Hypesthesia, migraine
Following table 2:
The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.
Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder, migraine
(Newly added subsection)
The following adverse reactions have been identified during post approval use of ACTIQ. 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.
Digestive:
Dental decay: Dental decay, including dental caries, tooth loss, and gum line erosion. Nervous System Disorders:
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 ACTIQ.
General Disorders and Administration Site Conditions:
Application site reactions including irritation, pain, and ulcer, and drug withdrawal syndrome.
7 Drug Interactions
Table 3 includes clinically significant drug interactions with ACTIQ.
Table 3: Clinically Significant Drug Interactions with ACTIQ
(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 ACTIQ 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. ACTIQ is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ACTIQ, 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 …
Animal Data
Fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 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 >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 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 (0.2 times the 1600 mcg dose of ACTIQ on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of ACTIQ 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 3 times the human dose of 1600 mcg ACTIQ per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean Cmax observed following administration of 1600 mcg dose of ACTIQ in humans.
In a postnatal development study, pregnant rats were treated from GD 6 through Lactation Day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 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 ACTIQ.
Clinical Considerations
Monitor infants exposed to ACTIQ 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)
… 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 ACTIQ 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 throughout this subsection:
Both male and female opioid-tolerant cancer patients 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).
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ACTIQ 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.
Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)
Inform patients and caregivers that potentially fatal additive effects may occur if ACTIQ is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.
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 physicians if they are taking, or plan to take serotonergic medications.
MAOI Interaction
Inform patients to avoid taking ACTIQ while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ACTIQ.
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 ACTIQ 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 ACTIQ during pregnancy 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 ACTIQ can cause fetal harm and to inform their 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 ACTIQ 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.
Other
Prior label already in PLR Format; further revision to incorporate the opioid analgesic template language; please refer to label.
12/16/2016 (SUPPL-44)
Boxed Warning
Additions and/or revisions underlined:
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
Life-Threatening
Respiratory Depression
Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ACTIQ, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ACTIQ or following a dose increase …
Accidental Ingestion
Accidental ingestion of even one dose of ACTIQ, especially by children, can result in a fatal overdose of fentanyl …
Cytochrome P450 3A4 Interaction
The concomitant use of ACTIQ 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 ACTIQ 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 ACTIQ 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 …
Addiction,
Abuse, and Misuse
ACTIQ 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 ACTIQ, and monitor all patients regularly for the development of these behaviors and conditions.
Neonatal Opioid Withdrawal
Syndrome
Prolonged use of ACTIQ 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:
ACTIQ 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 to fentanyl or components of ACTIQ (e.g., anaphylaxis, hypersensitivity)
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 ACTIQ, 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 ACTIQ.
To reduce the risk of respiratory depression, proper dosing and titration of ACTIQ are essential. Overestimating the ACTIQ dosage can result in a fatal overdose with the first dose. The substitution of ACTIQ for any other fentanyl product may result in fatal overdose.
ACTIQ 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 ACTIQ, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
(Newly added subsection)
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ACTIQ 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) [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 ACTIQ if serotonin syndrome is suspected.
(Newly added subsection)
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 subsection)
ACTIQ 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 ACTIQ. In patients with circulatory shock, ACTIQ may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ACTIQ in patients with circulatory shock.
Additions and/or revisions underlined:
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), ACTIQ 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 ACTIQ.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ACTIQ in patients with impaired consciousness or coma.
(Newly added subsection)
ACTIQ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in ACTIQ 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.
(Newly added subsection)
The fentanyl in ACTIQ 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 ACTIQ therapy.
… Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ACTIQ and know how they will react to the medication.
(Additions and/or revisions underlined)
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ACTIQ are provided in the ACTIQ Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.
(Additions and/or revisions underlined)
Concomitant use of ACTIQ 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 ACTIQ is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ACTIQ-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using ACTIQ with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ACTIQ-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ACTIQ until stable drug effects are achieved.
Concomitant use of ACTIQ 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 ACTIQ 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.
Additions and/or revisions underlined:
ACTIQ is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute an ACTIQ prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and ACTIQ are not equivalent. Substantial differences exist in the pharmacokinetic profile of ACTIQ compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl.
Newly added subsection:
ACTIQ contains fentanyl, a Schedule II controlled substance. As an opioid, ACTIQ 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 ACTIQ. 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 ACTIQ, and monitor all patients receiving ACTIQ 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 ACTIQ, but use in such patients necessitates intensive counseling about the risks and proper use of ACTIQ 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 ACTIQ. 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 subsection)
Prolonged use of ACTIQ 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.
Newly added subsection:
The use of ACTIQ 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: ACTIQ-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 ACTIQ.
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 ACTIQ and when ACTIQ 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)
The safety of ACTIQ has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of ACTIQ use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days …
Following table 1:
… The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.
Nervous: Hypesthesia, migraine
Following table 2:
The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.
Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder, migraine
(Newly added subsection)
The following adverse reactions have been identified during post approval use of ACTIQ. 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.
Digestive:
Dental decay: Dental decay, including dental caries, tooth loss, and gum line erosion. Nervous System Disorders:
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 ACTIQ.
General Disorders and Administration Site Conditions:
Application site reactions including irritation, pain, and ulcer, and drug withdrawal syndrome.
7 Drug Interactions
Table 3 includes clinically significant drug interactions with ACTIQ.
Table 3: Clinically Significant Drug Interactions with ACTIQ
(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 ACTIQ 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. ACTIQ is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ACTIQ, 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 …
Animal Data
Fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 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 >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 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 (0.2 times the 1600 mcg dose of ACTIQ on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of ACTIQ 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 3 times the human dose of 1600 mcg ACTIQ per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean Cmax observed following administration of 1600 mcg dose of ACTIQ in humans.
In a postnatal development study, pregnant rats were treated from GD 6 through Lactation Day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 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 ACTIQ.
Clinical Considerations
Monitor infants exposed to ACTIQ 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)
… 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 ACTIQ 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 throughout this subsection:
Both male and female opioid-tolerant cancer patients 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)
5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol)Newly added subsection:
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ACTIQ 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 ACTIQ 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.
(Extensively revised; please refer to label)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ACTIQ 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.
Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)
Inform patients and caregivers that potentially fatal additive effects may occur if ACTIQ is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.
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 physicians if they are taking, or plan to take serotonergic medications.
MAOI Interaction
Inform patients to avoid taking ACTIQ while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ACTIQ.
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 ACTIQ 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 ACTIQ during pregnancy 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 ACTIQ can cause fetal harm and to inform their 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 ACTIQ 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.
Other
Prior label already in PLR Format; further revision to incorporate the opioid analgesic template language; please refer to label.