section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Notification

REMS:

FDA approved a REMS for transmucosal immediate-release fentanyl (TIRF) products under a shared REMS system (TIRF REMS) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of fentanyl and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page ([Web]

FDA approved a REMS for fentanyl transdermal systems under a shared REMS system (Opioid Analgesic REMS) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of fentanyl and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page ([Web]).

Fentanyl is a synthetic phenylpiperidine-derivative opiate agonist.230,240,256,706

Uses ⬆ ⬇

[Section Outline]

Pain !!navigator!!

Fentanyl is a strong analgesic used for the management of severe pain.230,240,256,706 The drug is commercially available in various dosage forms and formulations including immediate-release transmucosal preparations (buccal tablet, transmucosal lozenge), long-acting/extended-release transdermal systems, and a parenteral formulation; FDA-labeled indications and patient populations vary based on the specific preparation.230,240,256,706

Pain needs to be appropriately and effectively treated, regardless of whether opioids are part of the treatment regimen.760 Treatment should be individualized, patient-centered, and include multimodal approaches.760 Opioids can be essential in the management of pain but are associated with considerable potential harm, including opioid use disorder and overdose.760 Therefore, safer and more effective treatments should be considered prior to initiating opioid therapy.760 There are multiple nonpharmacologic treatments (e.g., exercise, physical therapy, psychological therapies) and nonopioid drugs (e.g., serotonin and norepinephrine reuptake inhibitors [SNRIs], gabapentinoids, nonsteroidal anti-inflammatory agents [NSAIAs]) that have been shown to be at least as effective as opioids for many types of common pain conditions.760 These nonopioid treatments are generally preferred to opioids in most situations.760 If opioids are used, clinicians should carefully evaluate the risk of opioid-related harms and work with the patient to incorporate appropriate risk-mitigation strategies into the treatment plan, including offering naloxone.760

The Centers for Disease Control and Prevention (CDC) clinical guideline for prescribing opioids for pain provides recommendations for the management of acute (duration <1 month), subacute (duration 1-3 months), and chronic (duration >3 months) pain in adults in the outpatient setting.760 The CDC guideline addresses the following areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use.760

Other clinical practice guidelines provide recommendations for the management of specific types of pain including postoperative pain, cancer-related pain, sickle-cell pain, and pain associated with palliative care; although specific recommendations for the management of opioid therapy vary across the guidelines, common elements include risk mitigation strategies, careful dosage titration, and consideration of risks and benefits.174,430,431,432,433,434,761

Acute Pain

Fentanyl citrate preservative-free injection is indicated for IV or IM use to provide short durations of analgesia prior to, during, or following surgical procedures.706 The drug should be administered only by clinicians specifically trained in the use of IV anesthetics and management of the respiratory effects of potent opioids, and in appropriate settings where an opiate antagonist, resuscitative equipment, and oxygen are readily available.706

Because of the risk of life-threatening respiratory depression, fentanyl transdermal systems and transmucosal immediate-release preparations (buccal tablets, transmucosal lozenges) are contraindicated in the management of acute or postoperative pain.230,240,256

CDC guidelines state that nonopioid therapies are at least as effective as opioids for many common types of acute pain (e.g., low back pain, neck pain, pain related to other musculoskeletal injuries).760 Use of nonpharmacologic therapies (e.g., ice, heat, elevation, rest, immobilization, exercise) and nonopioid pharmacologic therapies (e.g., topical or oral NSAIAs, acetaminophen) should be maximized as appropriate for the specific condition and patient.760

Chronic Pain

Fentanyl transdermal system is used for the management of severe and persistent pain in opioid-tolerant patients (adults and pediatric patients 2 through 18 years of age) who require extended treatment with a daily opioid analgesic and for which alternative treatment options are inadequate.209,240 Patients are considered opioid-tolerant if they have been receiving at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid for at least 1 week.240 Fentanyl transdermal system is a long-acting (extended-release) formulation of fentanyl with complex absorption and pharmacodynamic properties, which can increase the risk of fatal overdose if not used appropriately.240,760 Because of the greater risks of overdose and death with extended-release opiate formulations, therapy with fentanyl transdermal system should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.240 Fentanyl transdermal system is contraindicated in patients who are not opiate tolerant, in those who require opiate analgesia for a short period of time, and for the management of acute, mild, intermittent, or postoperative pain.240 Fentanyl transdermal systems should be prescribed only by qualified clinicians who are experienced in the use of extended-release/long-acting opioids and management of associated risks.240,760

CDC guidelines state that in patients with chronic or subacute pain not associated with active cancer treatment, palliative care, or end-of-life care (also referred to as chronic noncancer pain), nonopioid therapies are preferred.760 There is insufficient evidence to determine the long-term benefits of opioid therapy for chronic pain, and there is an increased risk for serious harms related to long-term opioid therapy that appears to be dose dependent.760 Use of opioid analgesics for the management of chronic noncancer pain increased four-fold in the US from 1999 to 2010, along with a parallel increase in overdose deaths, despite uncertainty over the long-term benefits of such therapy.760 In addition, evidence that opioid analgesics are superior to other pharmacologic or nonpharmacologic treatments for chronic pain generally is lacking.760 Opioid analgesics should be considered only if other pain management strategies (nonpharmacologic [e.g., exercise, physical therapy] and nonopioid drugs [e.g., NSAIAs, select antidepressants or anticonvulsants, gabapentinoids, lidocaine and capsaicin patches for neuropathic pain]) have been maximized as appropriate for the specific condition and patient, and the expected benefits of opioid analgesics are anticipated to outweigh the risks.760 If opioid analgesics are used, they should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies.760 The lowest-effective dosage of an immediate-release preparation should be used.760 Clinicians should work with patients to establish treatment goals and also consider how opioid therapy wll be discontinued if the benefits do not outweigh the risks.760

The benefits and risks of opioid analgesic therapy should be evaluated within 1-4 weeks following initiation of therapy or an increase in dosage, and reevaluated on an ongoing basis throughout therapy.760 Monitoring should include documentation of pain intensity and level of functioning, assessment of progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.760 Common opioid-related adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment) should be anticipated and appropriately managed.760

Patients should be closely monitored for adverse effects and other risks of therapy, including opioid use disorder.760 Various strategies for managing risks associated with opioid therapy for chronic noncancer pain have been recommended, including written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state prescription drug monitoring program (PDMP) data, and risk assessment and monitoring tools.414,415,422,423,760 Clinicians should offer or arrange treatment for patients with opioid use disorder.760

Cancer Pain

The American Society of Clinical Oncology (ASCO) states that opioids should be offered to patients with moderate-to-severe pain associated with cancer or active cancer treatment, unless contraindicated.759 Prior to initiating opioid therapy, it is useful to assess the mechanism for the pain syndrome (imaging may be required), the response to nonopioid analgesics (e.g., acetaminophen or NSAIAs), and the presence of risk factors such as a history of misuse of alcohol, recreational substances, or prescription drugs.759 Opioids should be initiated as an immediate-release formulation and as needed to establish an effective dosage.759 The lowest possible dosage should be used to achieve acceptable analgesia and patient goals, and patients should be assessed early with frequent dosage titration.759 In patients receiving opioids around the clock, an immediate-release opioid at a dose of 5-20% of the regular morphine equivalent daily dose should be prescribed for breakthrough pain.759 Evidence remains insufficient to recommend a specific, short-acting opioid for breatkthrough pain.759

Fentanyl transdermal system is indicated for the management of severe and persistent pain in opioid tolerant patients (adults and pediatric patients 2 through 18 years of age) who require extended treatment with a daily opioid analgesic, and has been used for pain control in patients with cancer.209,240,759 (See Chronic Pain under Uses.) In clinical studies in patients with cancer, fentanyl transdermal system was administered at dosages of 25-600 mcg/hour for variable periods of time (i.e., periods exceeding 30 days, 4 months, or 1 year in 56, 28, or 10% of patients, respectively, and extending up to 866 days in individual patients).240 At 1 month following initiation of transdermal fentanyl therapy, pain intensity generally was less than that reported with the oral morphine regimen used prior to the study.240

Fentanyl citrate immediate-release transmucosal formulations (buccal tablets, transmucosal lozenges) are indicated for the management of breakthrough pain in cancer patients who are already being treated with, and are tolerant of, opiates used around the clock for persistent cancer pain.230,256 The fentanyl preparation labeled as Fentora® is indicated for use in adults 18 years of age or older, and the fentanyl preparation labeled as Actiq® is labeled for use in patients 16 years of age or older.230,256 Patients are considered opiate tolerant if they have been receiving around-the-clock opiate therapy consisting of at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for at least 1 week.230,256 Patients must continue around-the-clock opiate analgesic therapy while receiving these transmucosal immediate-release preparations for the relief of breakthrough pain.230,256 Because of the risk of fatal or life-threatening respiratory depression, fentanyl citrate buccal tablets and transmucosal lozenges are contraindicated in the management of acute or postoperative pain and in patients who are not opiate tolerant.230 In addition, these formulations should be administered only under the supervision of qualified clinicians who are trained in the use of IV anesthetics and management of respiratory effects of potent opioids.230,256 Substantial pharmacokinetic differences exist among these transmucosal immediate-release formulations of fentanyl, and between these formulations and other preparations of the drug; these differences could result in clinically important differences in the rate and extent of absorption. 230,256 Therefore, these fentanyl products should not be used interchangeably (e.g., on a mcg-per-mcg basis) or substituted with any other fentanyl products. 230,256 Fatal overdosage may occur if these formulations are substituted on a mcg-per-mcg basis for any other fentanyl preparation.230,256

In clinical studies in opiate-tolerant adults with breakthrough cancer pain, transmucosal immediate-release fentanyl formulations have been shown to provide substantially more pain relief than placebo.228,230,231 In studies with fentanyl citrate buccal tablets and transmucosal lozenges, approximately 65-70% of patients successfully achieved an adequate dose during the titration period.230,256 Fentanyl doses evaluated in these studies ranged from 100-800 mcg as the buccal tablets and 200-1600 mcg as the transmucosal lozenges.230,256

Pain in Critically Ill Patients

Fentanyl also has been used for the management of pain in critically ill patients in the intensive care unit (ICU).174,712 Opioid agonists may be used in combination with sedative agents to maintain an optimal level of comfort and safety in patients in a critical care setting.174,712 To ensure consistent analgesic therapy, a therapeutic plan and goal of analgesia should be established for each patient.174 There are important safety concerns with opioids, such as sedation, delirium, respiratory depression, ileus, and immunosuppression, that should be considered in ICU patients.712 A multimodal analgesic approach generally is used to reduce opioid requirements and optimize patient outcomes and has included the use of nonopioid analgesics such as acetaminophen, ketamine, lidocaine, neuropathic agents, and NSAIAs.712

Anesthesia !!navigator!!

Fentanyl citrate preservative-free injection is indicated for IV or IM use as an adjunct in the maintenance of general or regional anesthesia.706 When attenuation of the response to surgical stress is especially important, fentanyl citrate may be administered with oxygen and a skeletal muscle relaxant to provide anesthesia without the use of additional anesthetic agents.706 Fentanyl citrate injection should be administered only by clinicians specifically trained in the use of IV anesthetics and management of the respiratory effects of potent opioids, and in appropriate settings where resuscitative equipment and oxygen are readily available.706

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Dispensing and Administration Precautions

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Addiction, Abuse, and Misuse

As an opioid, fentanyl exposes users to the risks of addiction, abuse, and misuse.230,240,256,706 A boxed warning about this risk is including in the prescribing information for fentanyl.230,240,256,706 Although the risk of addiction in any individual is unknown, it can occur in patients with appropriate prescribing.230,240,256 Addiction can occur at recommended dosages and if the drug is misused or abused.230,240,256

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing, and reassess all patients receiving the drug for the development of these behaviors and conditions.230,240,256 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).230,240,256 The potential for these risks should not, however, prevent the proper management of pain in any given patient.230,240,256 Patients at increased risk may be prescribed opioids but use in such patients necessitates intensive counseling about the risks and proper use along with frequent reevaluation for signs of addiction, abuse, and misuse. 230,240,256

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.230,240,256 Consider these risks when prescribing or dispensing.230,240,256 Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during treatment and proper disposal of unused drug.230,240,256 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.230,240,256

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.230,240,256,706 A boxed warning about this risk is included in the prescribing information for fentanyl.230,240,256,706 Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.230,240,256,706

While serious, life-threatening, or fatal respiratory depression can occur at any time during fentanyl use, the risk is greatest during the initiation of therapy or following a dosage increase.230,240,256 To reduce the risk of respiratory depression, proper dosing and titration of fentanyl is essential.230,240,256

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of parenteral fentanyl.706

Transmuccosal immediate-release fentanyl and fentanyl transdermal systems could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.230,240,256

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 fentanyl overdose. 230,240,256

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia.230,240,256,706 Opioid use increases the risk of CSA in a dose-dependent fashion.230,240,256,706 In patients who present with CSA, consider decreasing fentanyl dosage using best practices for tapering the drug.230,240,256,706

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.230,240,256

Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.230,256 Death and other serious problems also have been reported when children and adults were accidentally exposed to fentanyl transdermal system.240 A boxed warning about this risk is included in the prescribing information for fentanyl transmucosal products.230,256

Patients and their caregivers must be informed that transmucosal immediate-release fentanyl products contains a medicine in an amount which can be fatal to a child.230,256 Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children.230,256 While all units should be disposed of immediately after use, partially consumed units represent a special risk to children.230,256 If a unit is not completely consumed it must be properly disposed as soon as possible.230,256

Placing a fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.240 A boxed warning about this risk has been included in the prescribing information for fentanyl transdermal system.240 Improper disposal of fentanyl transdermal system in the trash has resulted in accidental exposures and deaths as a considerable amount of active fentanyl remains in fentanyl transdermal system even after use as directed.240 Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to fentanyl transdermal system.240

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).230,240,256,706 A boxed warning about this risk has been included in the prescribing information for fentnayl.230,240,256,706 Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.230,240,256,706

Clinical studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increased the risk of drug-related mortality compared to use of opioid analgesics alone.230,240,256,706 Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.230,240,256,706

If concomitant use of a benzodiazepine or other CNS depressant with fentanyl is necessary, prescribe the lowest effective dosages and minimum durations of concomitant use.230,240,256,706 In patients already receiving fentanyl, 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. 230,240,256,706 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 such as fentanyl, and titrate based on clinical response. 230,240,256,706 Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).230,240,256,706 If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.230,240,256,706

Advise both patients and caregivers about the risks of respiratory depression and sedation when fentanyl transdermal system is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).230,240,256,706 Also 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.230,240,256,706

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of fentanyl with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole antifungals (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 the inhibitor is added after a stable dose is achieved.230,240,256,706 Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions.230,240,256,706 A boxed warning about these risks has been included in the prescribing information for fentanyl.230,240,256,706 When using fentanyl with CYP3A4 inhibitors or discontinuing CYP3A4 inducers, evaluate patients at frequent intervals and consider dosage reduction of fentanyl until stable drug effects are achieved.230,240,256,706 Concomitant use of fentanyl 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.230,240,256,706 When using fentanyl with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.230,240,256,706

Risk of Medication Errors

Do not convert patients to transmucosal immediate-release fentanyl (TIRF) preparations from any other fentanyl product based on dosage amounts as these products are not equivalent on a mcg-per-mcg basis.230,256 A boxed warning about this risk is included in the prescribing information for fentanyl transmucosal products.230,256

TIRF preparations are not generic versions of other TIRF formulations.230,256 When dispensing, do not substitute these prescriptions for any other TIRF formulation under any circumstances as substantial differences exist in the pharmacokinetic profile compared to other fentanyl products, including other TIRF formulations.230 Differences in the rate and extent of absorption of fentanyl may result in a fatal overdose.230

There are no safe conversion directions available for patients on any other fentanyl products (e.g., oral, transdermal, or parenteral formulations of fentanyl) except the conversion of Actiq® to Fentora®.230 Therefore, for opioid-tolerant patients, the initial starting dose should be prescribed and dosage should be titrated to provide adequate analgesia while minimizing side effects.230

Neonatal Opioid Withdrawal Syndrome

Use of fentanyl transdermal system and transmucosal immediate release products for an extended period of time during pregnancy can result in withdrawal in the neonate.230,256 A boxed warning about this risk has been included in the prescribing information for fentanyl.230,240,256 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.230,240,256

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.230,240,256 Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.230,240,256

Risk of Increased Fentanyl Absorption with Application of External Heat

Exposure to heat may increase fentanyl absorption from transdermal systems and there have been reports of overdose and death from exposure to heat.240 A boxed warning about this risk has been included in the prescribing information for fentanyl transdermal system.240 A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased fentanyl exposure.240

Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources.240

Other Warnings and Precautions

Risks of Muscle Rigidity and Skeletal Muscle Movement

Fentanyl citrate injection may cause muscle rigidity, particularly involving the muscles of respiration.706 The incidence and severity of muscle rigidity are dose-related and also related to the speed of injection.706 Skeletal muscle rigidity has been reported to occur or recur infrequently in the extended postoperative period, usually following high dose administration.706 In addition, skeletal muscle movements of various groups in the extremities, neck, and external eye have been reported during induction of anesthesia with fentanyl citrate injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.706 These effects can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a nondepolarizing neuromuscular blocking agent just prior to administration of fentanyl citrate injection; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when fentanyl citrate injection is used in anesthetic doses titrated by slow IV infusion; or, 3) simultaneous administration of fentanyl citrate injection and a full paralyzing dose of a neuromuscular blocking agent when fentanyl citrate injection is used in rapidly administered anesthetic dosages.706

Severe Cardiovascular Depression

Fentanyl citrate injection may cause severe bradycardia, severe hypotension, including orthostatic hypotension, and syncope.706 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 depressants (e.g., phenothiazines or general anesthetics).706 In patients with circulatory shock, fentanyl citrate injection may cause vasodilation that can further reduce cardiac output and blood pressure. 706 Monitor these patients for signs of hypotension after initiating or titrating the dosage.706

Opioid-Induced Hyperalgesia and Allodynia

Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.230,240,256,706 This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.230,240,256,706 Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia) if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.230,240,256,706 Cases of OIH have been reported, both with short- and longer-term use of opioid analgesics.230,240,256,706

If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety). 230,240,256,706

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl with serotonergic drugs.230,240,256,706 Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazadone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and IV methylene blue).230,240,256,706 This may occur within the recommended dosage range.230,240,256,706 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 GI symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal.230,240,256,706 The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later.230,240,256,706 Discontinue fentanyl citrate injection if serotonin syndrome is suspected.230,240,256,706

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of fentanyl transdermal systems and transmucosal immediate release products in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.230,240,256 Patients with chronic pulmonary disease such as those 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.230,240,256 Additionally, 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.230,240,256

Regularly evaluate patients, particularly when initiating and titrating fentanyl and when given concomitantly with other drugs that depress respiration.230,240,256 Alternatively, consider the use of non-opioid analgesics in these patients.230,240,256

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.230,240,256,706 Presentation of adrenal insufficiency may include nonspecific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.230,240,256,706 If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.230,240,256,706 If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.230,240,256,706 Taper the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.230,240,256,706 Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency; however, available information does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.230,240,256,706

Severe Hypotension

Fentanyl transdermal systems and transmucosal immediate release products may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.230,240,256 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 depressants (e.g. phenothiazines or general anesthetics).230,240,256 Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage.230,240,256 May cause vasodilation in patients with circulatory shock that can further reduce cardiac output and blood pressure; avoid use in patients with circulatory shock.230,240,256

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury

In patients who may be susceptible to the intracranial effects of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure or brain tumors), fentanyl may reduce respiratory drive, and the resultant carbon dioxide retention can further increase intracranial pressure.230,240,256,706 Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy.230,240,256,706

Opioids may also obscure the clinical course in a patient with a head injury.230,240,256,706 Avoid use in patients with impaired consciousness or coma.230,240,256,706

Risks of Use in Patients with GI Conditions

Fentanyl is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.230,240,256,706 Fentanyl may cause spasm of the sphincter of Oddi.230,240,256,706 Opioids may cause increases in serum amylase.230,240,256,706 Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.230,240,256,706

Seizures

Fentanyl 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.230,240,256,706 Regularly evaluate patients with a history of seizure disorders for worsened seizure control during therapy.230,240,256,706

CNS Effects

May impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.230,240,256,706 Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects and know how they will react to the medication.230,240,256,706

Application Site Reactions

Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding in patients using fentanyl transdermal systems.230

Risks due to Interaction with Neuroleptic Agents

Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of fentanyl citrate injection combined with a neuroleptic.706 This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.706

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with fentanyl citrate injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.706 When used with a neuroleptic and an EEG is used for postoperative monitoring, the EEG pattern may return to normal slowly.706

Risk of Increased Fentanyl Absorption with Elevated Body Temperature

Pharmacokinetic modeling suggests that serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability.240 Monitor patients wearing fentanyl transdermal systems who develop fever closely for sedation and respiratory depression and reduce the fentanyl transdermal system dose, if necessary.240

Withdrawal

Do not abruptly discontinue fentanyl transdermal system in a patient physically dependent on opioids.240 When discontinuing fentanyl transdermal system in a physically dependent patient, gradually taper the dosage.240 Rapid tapering of fentanyl transdermal system in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.240

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients receiving a full opioid agonist analgesic, including fentanyl transdermal system.240 In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.240

Specific Populations

Pregnancy

Available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.230,240,256,706

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing and when administered during gestation through lactation resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing.230,240,256 No evidence of malformations noted in animal studies completed to date.230,240,256

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates.230,240,256,706 There are insufficient data to support the use of fentanyl in labor or delivery and therefore such use is not recommended.706

Transient neonatal muscular rigidity reported in infants whose mothers received IV fentanyl during labor.230,240,256

Prolonged maternal use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome; withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts.230,240,256,706 Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.230,240,256,706

Lactation

Fentanyl is distributed into human milk.230,240,256,706

Manufacturers of fentanyl transdermal system and transmucosal immediate-release fentanyl preparations (used only in opioid-tolerant patients) state these preparations should not be used in nursing women because of the potential for serious adverse effects in nursing infants.230,240,256

There is a potential risk of sedation and respiratory depression in nursing infants; monitor breastfeeding infants for excess sedation and respiratory depression.230,240,256,706 Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.230,240,256,706

Females and Males of Reproductive Potential

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential.230,240,256,706 It is not known whether these effects on fertility are reversible.230,240,256,706

Pediatric Use

Safety and efficacy of parenteral fentanyl citrate and fentanyl transdermal systems have not been established in pediatric patients <2 years of age.240,706

Safety and efficacy of transmucosal lozenges have not been established in pediatric patients <16 years of age.256 Safety and efficacy of buccal tablets have not been established in pediatric patients <18 years of age.230

To reduce the potential for accidental ingestion, carefully select application sites in young children receiving transdermal fentanyl therapy and monitor the system for proper adhesion over the period of application.240 Transdermal systems and transmucosal immediate-release preparations (transmucosal lozenges, buccal tablets) contain fentanyl in amounts that can be fatal to a child.230,256 Fatal respiratory depression can occur if a transdermal system is accidentally or deliberately applied or ingested by a child or adolescent; choking can occur if the system is ingested.240 There is a high risk of respiratory depression if a child accidentally ingests a transmucosal immediate-release preparation.230,256

Geriatric Use

Pharmacokinetics of fentanyl may be altered in geriatric patients, increasing risk of life-threatening respiratory depression.230,240 Monitor closely for sedation and respiratory depression, particularly during initiation or titration of therapy and when other respiratory depressants are used concomitantly.230,240,256

Use caution when titrating dosage.230,240,256,706 Renal clearance of fentanyl may be reduced.230,240,256,706 Geriatric patients may be more sensitive to effects of fentanyl. 230,240,256,706

Clinical studies of fentanyl transdermal system did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger subjects.240 However, a study reported that the pharmacokinetics of fentanyl transdermal system in geriatric patients are not substantially different than that in younger adults, although peak serum concentrations tended to be lower and mean half-life was prolonged in geriatric patients.240 Dosages of transmucosal lozenges (following titration) are generally about 200 mcg lower in geriatric patients than in younger adults.256 Dosages of buccal tablets (following titration) are slightly lower in geriatric patients than in younger adults.230 Increased frequency of certain adverse effects (e.g., vomiting, constipation, abdominal pain) reported in geriatric patients compared with younger adults receiving buccal tablets.230

Hepatic Impairment

Exercise caution and reduce initial parenteral dosage and monitor closely for signs of respiratory depression, sedation, and hypotension.706 Reduce initial dosage of fentanyl transdermal system by one-half in patients with mild to moderate hepatic impairment; monitor closely for sedation and respiratory depression, including after each increase in dosage.240 Because of the long half-life of transdermal systems, avoid use in patients with severe hepatic impairment.240 Insufficient information is available to support recommendations regarding use of transmucosal immediate-release preparations; if used, caution advised.230,256

Renal Impairment

Exercise caution and reduce initial parenteral dosage and monitor closely for signs of respiratory depression, sedation, and hypotension.706 Reduce initial dosage of fentanyl transdermal system by one-half in patients with mild to moderate renal impairment; monitor closely for sedation and respiratory depression, including after each increase in dosage.240 Because of the long half-life of this formulation, avoid use in patients with severe renal impairment.240 Insufficient information is available to support recommendations regarding use of transmucosal immediate-release preparations; if used, caution advised.230,256

Patients with Cardiac Diseases

IV administered fentanyl may produce bradycardia.230,240,256 Use fentanyl transdermal systems and transmucosal immediate release products with caution in patients with bradyarrhythmias.230,240,256

Common Adverse Effects !!navigator!!

The most common adverse effects reported with parenteral administration of fentanyl include respiratory depression, apnea, rigidity, and bradycardia.706

The most common adverse effects reported with use of fentanyl transdermal system (≥5% incidence) include nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, anorexia, headache, and diarrhea.240

The most common adverse effects reported with use of fenanyl buccal tablets (≥10% incidence) include nausea, dizziness, vomiting, fatigue, anemia, constipation, peripheral edema, asthenia, dehydration, and headache.230

The most common adverse effects reported with use of fentanyl transmucosal lozenges (≥5% incidence) include nausea, dizziness, somnolence, vomiting, asthenia, headache, dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia.256

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes !!navigator!!

Because fentanyl undergoes metabolism via cytochrome P-450 (CYP) isoenzyme 3A4 in the liver and the intestinal mucosa, concomitant use of inhibitors of CYP3A4 (e.g., macrolide antibiotics [e.g., erythromycin, clarithromycin], azole-antifungal agents [e.g., ketoconazole, itraconazole, fluconazole], protease inhibitors [e.g., nelfinavir, ritonavir, fosamprenavir], amiodarone, amprenavir, diltiazem, nefazodone, verapamil, grapefruit juice) may increase plasma concentrations of fentanyl, possibly resulting in increased or prolonged opiate effects, including potentially fatal respiratory depression.230,234

Conversely, concomitant use of drugs that induce CYP3A4 (e.g., rifampin, carbamazepine, phenytoin) may reduce plasma concentrations of fentanyl, possibly resulting in decreased analgesic efficacy 230,234 and/or development of opiate withdrawal.230,240,256,706 If concomitant use of fentanyl with CYP3A4 inducers is necessary, patients should be monitored for opiate withdrawal and dosage adjustments should be considered until stable drug effects are achieved.230,240,256,706 Discontinuance of a concomitantly used CYP3A4 inducer may result in increased plasma concentrations of fentanyl, possibly resulting in increased or prolonged therapeutic or adverse effects, including sedation or potentially fatal respiratory depression.230,240,256,706 Patients receiving fentanyl who discontinue therapy with, or decrease the dosage of, a CYP3A4 inducer should be monitored for increased opiate effects and the fentanyl dosage should be adjusted as necessary.230,240,256,706

Benzodiazepines and Other CNS Depressants !!navigator!!

Concomitant use of opiate agonists and benzodiazepines or other CNS depressants, including other opiate agonists, anxiolytics, sedatives, hypnotics, muscle relaxants, general anesthetics, antipsychotics, and alcohol, may result in hypotension, profound sedation, respiratory depression, coma, and death.230,240,256,416,417,418,700,701,702,703,706

Concomitant use of parenteral fentanyl and benzodiazepines or other CNS depressants also may result in decreased pulmonary arterial pressure; even relatively small dosages of diazepam may cause cardiovascular depression when used with high or anesthetic dosages of fentanyl.706 Clinicians should consider the potential for such concomitant therapy to decrease pulmonary arterial pressure when performing diagnostic or surgical procedures where interpretation of pulmonary arterial pressure measurements might determine patient management.706 If hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate fluid therapy.706 When operative conditions permit, repositioning of the patient to improve venous return to the heart should be considered.706 Because of the potential for orthostatic hypotension, care should be exercised when moving and repositioning the patient.706 If volume expansion and other countermeasures do not correct hypotension, administration of a pressor agent (other than epinephrine, which may cause a reduction in blood pressure in patients receiving a neuroleptic with alpha-adrenergic blocking activity) should be considered.706 If used parenterally for postoperative analgesia in conjunction with a benzodiazepine or other CNS depressant, fentanyl should be initiated at a reduced dosage and titrated based on clinical response, and the patient should be monitored closely for respiratory depression, sedation, and hypotension.700,703,706 Fluids or other measures to counteract hypotension should be available.706

Drugs Associated with Serotonin Syndrome !!navigator!!

Serotonin syndrome has occurred in patients receiving opiate agonists, including fentanyl, in conjunction with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT3 receptor antagonists, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid and methylene blue).230,240,256,706 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.230,240,256,706 Manifestations of serotonin syndrome 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 GI symptoms (e.g., nausea, vomiting, diarrhea).230,240,256,706 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.230,240,256,706

If concurrent therapy with opiate agonists and serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.230,240,256,706 If serotonin syndrome is suspected, treatment with fentanyl, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.230,240,256,706

Anticholinergic Agents !!navigator!!

Concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus 230,240,256,706 Patients should be monitored for signs of urinary retention or decreased GI motility when fentanyl preparations are used concomitantly with anticholinergic drugs.230,240,256,706

Diuretics !!navigator!!

Concomitant use of opioids with diuretics may decrease diuretic efficacy by inducing the release of antidiuretic hormone.230,240,256,706 Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.230,240,256,706

Mixed Agonist/Antagonist and Partial Agonist Opioids !!navigator!!

The use of mixed agonist/antagonist and partial agonist opioid analgesics (e.g., butorphanol, nalbuphine, pentazocine, buprenorphine) may reduce the analgesic effect of fentanyl and/or precipitate withdrawal symptoms.230,240,256,706 Concomitant use should be avoided.230,240,256,706

Monoamine Oxidase Inhibitors (MAOIs) !!navigator!!

Monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) may interact with opioids and manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).230,240,256,706 The use of fentanyl preparations is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.230,240,256,706

Muscle Relaxants !!navigator!!

Concomitant use may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.230,240,256,706 Use with parenteral fentanyl may decrease pulmonary arterial pressure and cause hypotension.706

Because respiratory depression may be greater than otherwise expected, decrease the dosage of fentanyl and/or the muscle relaxant as necessary.230,240,256 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.230,240,256

Other Information ⬆ ⬇

Description

Fentanyl is a potent analgesic that shares the actions of the opiate agonists.230,240,256,706 Fentanyl interacts predominately with the opioid mu receptor; mu receptor binding sites are distributed in the human brain, spinal cord, and other tissues.230,240,256,706 The agonist activity of fentanyl at the mu receptor can also result in suppression of opioid withdrawal (and antagonist activity can result in precipitation of withdrawal).230,240,256

Fentanyl mediates respiratory depression by direct action on brain stem respiratory centers.230,240,256 Fentanyl also causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum.230,240,256 Other opioid-related effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.230,240,256 Cardiovascular effects of fentanyl include peripheral vasodilation, which may result in orthostatic hypotension or syncope.230,240,256 Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.230,240,256 Opioid agonists have been shown to have a variety of effects on the secretion of hormones including adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), prolactin, growth hormone (GH), insulin, glucagon, and thyroid stimulating hormone (TSH).230,240,256 Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.230,240,256

Fentanyl is well absorbed percutaneously following topical application of fentanyl transdermal system to a flat surface on the upper torso.201,202,203,240 The amount of fentanyl released from the system is proportional to the surface area of the system; however, the actual amount of drug delivered to the skin exhibits interindividual variation.240 Peak concentration is attained within 20-72 hours after initial application.240 Serum concentrations increase with the first 2 transdermal system applications; steady state is reached by the end of the second 72-hour application and is maintained during continued use at the same dosage.240 Application of heat over the transdermal system increases mean exposure and peak plasma concentrations by 120 and 61%, respectively.240 Following use of fentanyl transdermal system in non-opioid-tolerant children, plasma fentanyl concentrations in children 1.5-5 years of age were about twice the concentrations achieved in adults; however, pharmacokinetic parameters in older children were similar to those in adults.240

Fentanyl is well absorbed transmucosally following intrabuccal administration as fentanyl citrate transmucosal lozenge or buccal tablet.214,230,256 Substantial pharmacokinetic differences exist among the transmucosal immediate-release preparations; these preparations must not be substituted on a mcg-for-mcg basis.230,256 Bioavailability of the transmucosal lozenge averages about 50%; generally, approximately 25% of the drug is absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with saliva and then absorbed slowly from the GI tract.256 Bioavailability of the buccal tablet averages about 65%.230 Generally, approximately 50% of the drug is absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with saliva and then absorbed slowly from the GI tract.230 The time required for the buccal tablet to fully disintegrate does not appear to affect early systemic drug exposure.230 When fentanyl is administered as a buccal tablet rather than a transmucosal lozenge, a larger fraction of the administered dose is absorbed transmucosally (48% versus 22%), peak plasma concentration is achieved earlier (47 versus 91 minutes), and systemic exposure is approximately 30-50% greater.230

The onset of action following IV administration of fentanyl is rapid; peak analgesia occurs within several minutes and the duration of analgesia is 30-60 minutes after a single dose of up to 100 mcg.706 Following IM administration of fentanyl citrate, the onset of action occurs within about 7-15 minutes and the duration of action is 1-2 hours.706 Respiratory depressant effects may persist longer than analgesia.706 Residual effects of one dose of fentanyl citrate may potentiate the effects of subsequent doses.706 It has been suggested that redistribution is the main cause of the brief analgesic effect of fentanyl.706

Fentanyl is highly lipophilic.230,256 Fentanyl crosses the placenta and is distributed into breast milk.230,240,256,706 Approximately 80-85% of the drug is protein-bound, principally to α1-acid glycoprotein.230 Fentanyl is metabolized extensively in the liver and the intestinal mucosa via cytochrome P-450 (CYP) 3A4 to norfentanyl and other inactive metabolites.230,240,256,706 Transdermally administered fentanyl does not appear to be metabolized in the skin.230 Fentanyl is principally eliminated in urine, as inactive metabolites and to a lesser extent (<10%) as unchanged drug.230,240,256,706 The terminal half-life of the transmucosal lozenges is about 7 hours.256 The terminal elimination half-life of parenteral fentanyl is 219 minutes.706

Advice to Patients

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Fentanyl and fentanyl citrate preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.

Distribution of transmucosal immediate-release fentanyl preparations is restricted.230,256

fentaNYL

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Transdermal System

12 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System ( C-II )

25 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

37.5 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

50 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

62.5 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

75 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

87.5 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

100 mcg/hour (total fentanyl content and transdermal system size may vary by manufacturer)*

fentaNYL Transdermal System (C-II)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

fentaNYL Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Buccal (Transmucosal)

Transmucosal Lozenge (solid drug matrix on a handle)

200 mcg (of fentanyl)*

Actiq® (C-II)

Cephalon

Oral Transmucosal fentaNYL Citrate ( C-II )

400 mcg (of fentanyl)*

Actiq® (C-II)

Cephalon

Oral Transmucosal fentaNYL Citrate ( C-II )

600 mcg (of fentanyl)*

Actiq® (C-II)

Cephalon

Oral Transmucosal fentaNYL Citrate ( C-II )

800 mcg (of fentanyl)*

Actiq® (C-II)

Cephalon

Oral Transmucosal fentaNYL Citrate ( C-II )

1200 mcg (of fentanyl)*

Actiq® (C-II)

Cephalon

Oral Transmucosal fentaNYL Citrate ( C-II )

1600 mcg (of fentanyl)*

Actiq® (C-II)

Cephalon

Oral Transmucosal fentaNYL Citrate ( C-II )

Tablet

100 mcg (of fentanyl)

Fentora® ( C-II )

Cephalon

200 mcg (of fentanyl)

Fentora® ( C-II )

Cephalon

400 mcg (of fentanyl)

Fentora® ( C-II )

Cephalon

600 mcg (of fentanyl)

Fentora® ( C-II )

Cephalon

800 mcg (of fentanyl)

Fentora® ( C-II )

CephalonTeva

Parenteral

Injection

50 mcg (of fentanyl) per mL*

fentaNYL Citrate Injection (C-II)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

Only references cited for selected revisions after 1984 are available electronically.

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