Brand names: Actiq, Fentora
Drug class: Opioid Agonists

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

Opioid agonist; a synthetic phenylpiperidine derivative.

Uses for fentaNYL, fentaNYL Citrate

Pain

Strong analgesic used for management of severe pain.

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.

Transdermal system is indicated for management of severe and persistent pain in opioid-tolerant patients (adults and pediatric patients ≥2 years of age) who require extended treatment with a daily opioid analgesic and for which alternative treatment options are inadequate. 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. Complex absorption and pharmacodynamic properties of transdermal system can increase risk of fatal overdose if not used appropriately. Reserve use for patients in whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.

Immediate-release transmucosal formulations (buccal tablets, transmucosal lozenges) are indicated for 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. Patients are considered opioid 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. Substantial pharmacokinetic differences exist among the immediate-release transmucosal formulations and between other preparations of fentanyl; do not use interchangeably (e.g., on a mcg-per-mcg basis) or substitute with any other fentanyl products because of risk of fatal overdose.

Preservative-free injection is indicated for IV or IM use to provide short durations of analgesia prior to, during, or following surgical procedures. Administer 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.

Also has been used for management of pain in ICU patients. A multimodal analgesic approach generally is used to reduce opioid requirements and optimize patient outcomes.

Pain management should be individualized, patient-centered, and multimodal. Opioids can be essential, but associated with considerable potential harm, including opioid use disorder and overdose. Therefore, safer and more effective treatments should be considered prior to initiating opioid therapy.

Multiple nonpharmacologic treatments (e.g., exercise, physical therapy, psychological therapies) and nonopioid drugs (e.g., serotonin and norepinephrine reuptake inhibitors [SNRIs], gabapentinoids, NSAIAs) have been shown to be at least as effective as opioids for many types of common pain conditions.

If opioids are used, clinicians should carefully evaluate risk of opioid-related harms and incorporate appropriate risk-mitigation strategies into treatment plan, including offering naloxone. If opioid therapy is required, oral administration of an immediate-release preparation at the lowest effective dosage generally is preferred.

CDC guidelines provide 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. Other guidelines provide recommendations for management of specific types of pain such as postoperative pain, cancer-related pain, sickle-cell pain, and pain associated with palliative care; although specific recommendations vary across these guidelines, common elements include risk mitigation strategies, careful dosage titration, and consideration of risks versus benefits.

Anesthesia

Fentanyl citrate preservative-free injection is indicated for IV or IM use as an adjunct in the maintenance of general or regional anesthesia.

When attenuation of the response to surgical stress is especially important, fentanyl may be administered with oxygen and a skeletal muscle relaxant to provide anesthesia without the use of additional anesthetic agents.

Administer only by clinicians specifically trained in the use of IV anesthetics and management of respiratory effects of potent opioids, and in appropriate settings where resuscitative equipment and oxygen are readily available.

fentaNYL, fentaNYL Citrate Dosage and Administration

General

Pretreatment Screening

• Prior to initiation, carefully evaluate risks and benefits of opioid therapy, and assess for opioid-related harms (e.g., addiction, abuse, misuse). Incorporate risk mitigation strategies into the treatment plan, including offering naloxone. Consider a discontinuation plan in case treatment needs to be withdrawn if benefits do not outweigh risks.

• Review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or combinations that put the patient at high risk for overdose.

• Screen patients for sleep-related breathing disorders including central sleep apnea and sleep-related hypoxemia.

Patient Monitoring

• When opioids are used for subacute or chronic pain, evaluate the benefits and risks within 1–4 weeks following initiation of therapy or an increase in dosage, and re-evaluate on an ongoing basis.

• Monitor patients closely for signs of sedation and respiratory depression, particularly when initiating therapy and following dosage increases.

• Monitor and manage common adverse effects of opioid therapy (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment).

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), fentanyl is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Handling and Disposal

• Advise patients to store opioids in a secure and preferably locked location and discuss options for safe disposal of unused opioids. Accidental ingestion or exposure has resulted in fatal overdose.

Administration Precautions for Transmucosal Immediate-release Fentanyl (TIRF) Preparations

• Do not convert patients on a mcg-per-mcg basis from any other fentanyl products and do not substitute with any other fentanyl products.

Administration Precautions for Fentanyl Transdermal System

• Should be prescribed only by healthcare providers knowledgeable about the use of extended-release/long-acting opioids and how to manage associated risks.

• Exposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources.

REMS

TIRF REMS

• Because of the risk of accidental exposure, misuse, abuse, addiction, and overdosage, transmucosal immediate-release fentanyl (TIRF) preparations (transmucosal lozenges, buccal tablets) are available only through a restricted distribution program under the TIRF REMS Access program.

• Outpatients who receive TIRF preparations, clinicians who prescribe these preparations, and pharmacies, wholesalers, and distributors that dispense or distribute these preparations must enroll in the program. Prescribers must document opioid tolerance and outpatient pharmacies must verify such documentation with each prescription; inpatient pharmacies must develop policies and procedures to verify opioid tolerance in patients who require these preparations while hospitalized.

• Additional information available at [Web] or 866-822-1483.

Opioid Analgesic REMS

• FDA approved a REMS for fentanyl transdermal system under a shared REMS system (Opioid Analgesic REMS).

• The goals are to reduce the occurrence of addiction, unintentional overdosage, and death resulting from inappropriate prescribing, misuse, and abuse of opioid analgesics.

• The REMS program consists of educational programs for healthcare professionals, a patient counseling guide, and a product-specific medication guide for patients.

• Additional information available at [Web] or 1-800-503-0784.

Administration

Administer parenteral formulation by IM or IV injection.

Administer buccal tablet and transmucosal lozenge intrabuccally. Buccal tablets also may be administered sublingually once an effective dose has been established.

Apply transdermal system topically to the skin.

Preservative-free injections also have been administered epidurally^{† [off-label]}.

Intrabuccal Administration

Administer intrabuccally as a buccal tablet or transmucosal lozenge.

Carefully instruct patients on proper use and disposal of buccal dosage forms.

If signs of excessive opioid effects develop before the lozenge or buccal tablet is consumed completely, remove the remaining portion from the patient’s mouth immediately and decrease future doses.

Transmucosal Lozenges

Open lozenge package with scissors just prior to administration.

Place lozenge in patient's mouth (between the cheek and the lower gum) using the handle, and instruct patient to suck, and not bite or chew; efficacy may be reduced if the lozenge is not administered as directed. The lozenge occasionally may be moved from one side to the other using the handle.

Consume over a period of 15 minutes; longer or shorter consumption times may result in reduced efficacy.

May store partially used lozenge in a temporary storage bottle (supplied by manufacturer) out of reach of children until proper disposal is possible. Unused portions may contain sufficient amounts of fentanyl to be fatal to a child. Consult manufacturer's prescribing information for additional details on proper storage and disposal.

Buccal Tablets

Do not open the blister package until ready to administer. Bend and tear along the blister card perforations to separate a single blister unit. Peel back blister backing to expose buccal tablet; do not attempt to push the buccal tablet through the blister.

Do not split buccal tablets.

Place the buccal tablet in the patient’s mouth (above a rear molar, between the upper cheek and gum) and instruct the patient not to crush, suck, chew, or swallow the buccal tablet; efficacy may be reduced if the buccal tablet is not administered as directed. Alternate sides of the mouth with each intrabuccal dose.

Alternatively, once an effective dose has been established, the buccal tablets may be administered sublingually.

Leave the buccal tablet between the upper cheek and gum or under the tongue until it has disintegrated (generally 14–25 minutes). If the buccal tablet has not completely disintegrated after 30 minutes, the remnants may be swallowed with a glass of water. Disintegration time does not appear to affect early systemic exposure to the drug.

Consult manufacturer's prescribing information for additional details on proper storage and disposal.

IV Administration

Administer by slow (e.g., over 1–2 minutes) IV injection; also has been administered bycontinuous IV infusion^{† [off-label]} or IV via a controlled-delivery device for patient-controlled analgesia (PCA)^{† [off-label]} .

Opioid antagonist and facilities for administration of oxygen and respiratory support should be available during and immediately following IV administration of the drug.

Standardize 4 Safety

Standardized concentrations for fentanyl have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].

These concentrations are for continuous infusions not delivered by a PCA device

Babies under 500 g may require a lower concentration

IM Injection

May administer parenteral formulation by IM injection.

Transdermal Administration

Carefully instruct patients on proper use and disposal of fentanyl transdermal system.

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.

Apply the transdermal system to a dry, intact, nonirritated, nonirradiated flat surface on the chest, back, flank, or upper arm by firmly pressing the system with the palm of the hand for 30 seconds with the adhesive side touching the skin; ensure that contact is complete, particularly around the edges. In young children or individuals with cognitive impairment, place transdermal system on the upper back to reduce the risk that the system could be removed and placed in the mouth.

Clip, not shave, hair at the application site prior to application.

Use only clear water if site must be cleaned before transdermal application; do not use soaps, oils, lotions, alcohol, or any other agents that could irritate the skin or alter its characteristics.

Do not use transdermal system if seal of package is broken or if system is altered in any way (e.g., cut, damaged).

Avoid contact with unwashed or unclothed application sites; such contact can result in secondary exposure to the drug.

Patients or caregivers who apply the transdermal system should wash their hands with soap and water immediately after application.

Each transdermal system may be worn continuously for 72 hours; apply subsequent systems to a different site after removal of previous system.

If a system inadvertently falls off during the period of use, apply a new system to a different skin site and leave in place for 72 hours. May tape edges of system in place with first-aid tape if patient experiences difficulty with system adhesion. If adhesion problems persist, a transparent adhesive film dressing (e.g., Bioclusive, Askina) may be applied over the system.

Patients may bathe, shower, or swim while wearing transdermal systems, but should not engage in strenuous exercise that increases core body temperature or expose the application site and surrounding area to direct external heat sources.

Immediately following removal, fold the used system so adhesive side adheres to itself and then flush system down the toilet. Used systems may contain sufficient fentanyl to be fatal to children, pets, or other adults for whom the drug was not prescribed.

Epidural Administration

Preservative-free injections of fentanyl have been injected or infused epidurally^{† [off-label]}; specialized techniques are required for administration by this route, and such administration should be performed only by qualified individuals.

Standardize 4 Safety

Standardized epidural drug concentrations for fentanyl have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].

Dosage

Available as fentanyl and fentanyl citrate; dosage expressed in terms of fentanyl.

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

Reduced dosage is indicated initially in poor-risk patients and geriatric patients.

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy.

Pediatric Patients

Anesthesia and Analgesia

IV or IM

Children 2–12 years of age, for anesthesia induction and maintenance: Manufacturer recommends 2–3 mcg/kg IV. Other experts suggest a 2–3 mcg/kg IV bolus, followed by a 1-3 mcg/kg/hour continuous IV infusion.

Children <50 kg, for analgesia: Usually, 0.5–1 mcg/kg IV or IM, repeated every 1–2 hours as needed, or continuous IV infusion of 0.5–1.5 mcg/kg per hour.

Children >50 kg, for analgesia: 0.5–1 mcg/kg IV or IM, repeated every 1–2 hours as needed, or continuous IV infusion of 0.5–1.5 mcg/kg per hour.

Chronic Pain

Fentanyl Transdermal System

Transdermal

Use transdermal system only in children ≥2 years of age who are opioid tolerant. Risk of fatal respiratory depression when administered to patients not already opioid tolerant.

Individualize initial dosage, taking into account the patient's prior analgesic use and risk factors for addiction, abuse, and misuse. Fatal overdosage possible with the first transdermal dose if dosage is overestimated.

Discontinue all other opioid analgesics other than those used on an as-needed basis for breakthrough pain when therapy with fentanyl transdermal system is initiated.

The manufacturers provide specific dosage recommendations for switching opioid-tolerant children ≥2 years of age from certain oral or parenteral opioids to fentanyl transdermal system (see Table 7 and Table 8).

Alternatively, to switch children ≥2 years of age who currently are receiving other opioid therapy or dosages that are not listed in Table 7 or Table 8 to fentanyl transdermal system, calculate the opioid analgesic requirements during the previous 24 hours. Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using a reliable source. Finally, calculate the equivalent dosage of fentanyl transdermal system using Table 9.

The manufacturers consider the initial dosages of transdermal fentanyl in Tables 7, 8, and 9 to be conservative estimates. Do not use the dosage conversion guidelines in these tables to switch patients from fentanyl transdermal system to oral or parenteral opioids, since dosage of oral or parenteral opioids may be overestimated.

For transdermal dosages >100 mcg/hour, apply multiple systems at different sites simultaneously.

Dosing intervals <72 hours have not been evaluated in children and adolescents and cannot be recommended in this population.

Because of substantial interpatient variability in relative potency of opioid analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opioid requirements and provide “rescue” therapy with an immediate-release opioid analgesic than to overestimate the requirements and manage an adverse reaction.

Administer supplemental doses of a short-acting opioid as needed during initial application period and subsequently thereafter as necessary to relieve breakthrough pain.

If analgesia is inadequate after initial application of a fentanyl transdermal system, dosage may be increased after 3 days based on the daily dose of supplemental opioids during the second or third day after initial application.

Because subsequent equilibrium with an increased dosage may require up to 6 days to achieve, make further increases in dosage based on supplemental opioid requirements no more frequently than every 6 days (i.e., after two 72-hour application periods with a given dosage).

To convert supplemental opioid requirements to transdermal dosage, use a ratio of 45 mg of oral morphine sulfate (during a 24-hour period) to each 12 mcg/hour delivery from the fentanyl transdermal system.

If unacceptable adverse effects are observed (including an increase in pain after dosage increase), decrease subsequent dosage. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the fentanyl transdermal system dosage. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Continually assess adequacy of pain control and reevaluate for adverse effects, as well as for development of addiction, abuse, or misuse. During long-term therapy, continually reevaluate need for continued opioid therapy.

When a decision is made to decrease dose or discontinue therapy, consider the total daily dose of opioid (including fentanyl transdermal system) the patient has been using, duration of treatment, type of pain being treated, and the physical and psychological attributes of the patient. There are no standard opioid tapering schedules that are suitable for all patients; individualize taper plan. For patients on fentanyl transdermal system who are physically opioid-dependent, initiate the taper by a small increment (e.g., no greater than 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks.

Adults

Analgesia

IM or IV

Preoperatively: 50–100 mcg IM 30–60 minutes prior to surgery.

Postoperatively: 50–100 mcg IM every 1–2 hours in the recovery room as needed.

Anesthesia

Adjunct to General Anesthesia

IV or IM

May be given in low-dose, moderate-dose, or high-dose regimens.

Low-dose, used for minor but painful surgical procedures: Usually, 2 mcg/kg IV; additional doses usually not necessary.

Moderate-dose, used in more major surgical procedures: Initially, 2–20 mcg/kg IV; additional doses of 25–100 mcg IV or IM as necessary.

High-dose, used during open heart surgery or certain complicated neurosurgical or orthopedic procedures where surgery is more prolonged: Initially, 20–50 mcg/kg IV; additional doses ranging from 25 mcg to one-half the initial dose IV as necessary.

General Anesthesia without Additional Anesthetic Agent

IV

Attenuation of the response to surgical stress: 50–100 mcg/kg in conjunction with oxygen and a skeletal muscle relaxant; doses up to 150 mcg/kg may be required.

Adjunct to Regional Anesthesia

IV or IM

50–100 mcg IM or by slow IV injection over 1–2 minutes when additional analgesia is required.

Breakthrough Cancer Pain in Opioid-tolerant Patients

Transmucosal Lozenges

Because of differences in pharmacokinetic properties, do not switch on a mcg-per-mcg basis from any other fentanyl preparation to the transmucosal lozenges; the lozenges are not equivalent to other fentanyl preparations and are not a generic version of the buccal tablets.

Use only in patients who are opioid tolerant. Patients must continue receiving around-the-clock opioid analgesic therapy while receiving the transmucosal lozenges for breakthrough pain.

Initially, 200 mcg for breakthrough episode in all patients.

Prescribe 6 lozenges initially for titration supply; use all 6 lozenges for various breakthrough episodes before increasing to a higher dose. To reduce risk of overdosage, patient should have only one strength of lozenges available for use at any one time.

If breakthrough cancer pain not relieved after 15 minutes of consuming 1 lozenge (30 minutes after the first lozenge initially was placed in the mouth), patient may take only 1 additional dose using the same strength for that episode. Maximum of 2 lozenges per episode of breakthrough pain episode may be given, if necessary, during dosage titration phase.

During titration phase, evaluate each new dose over several breakthrough pain episodes to determine efficacy and tolerability.

After treating one episode of breakthrough pain, wait ≥4 hours before treating a subsequent episode.

Once an appropriate dose has been achieved, patients generally should use only 1 lozenge of the appropriate strength per episode of breakthrough pain. On occasion during maintenance therapy, when breakthrough pain is not relieved within 15 minutes after a single lozenge was consumed (i.e., 30 minutes after the first lozenge initially was placed in the mouth), the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.

During maintenance therapy, generally increase dosage only if several consecutive episodes require >1 lozenge of the current dose for pain relief.

If patient experiences >4 breakthrough pain episodes daily, reevaluate dosage of maintenance opioid used around the clock for chronic cancer pain.

When opioid therapy is discontinued, gradually taper the opioid dosage to avoid manifestations associated with abrupt withdrawal. In patients who continue to take their chronic opioid therapy for persistant pain but no longer require treatment for breakthrough pain, transmucosal lozenges can usually be discontinued immediately.

Buccal Tablets

Because of differences in pharmacokinetic properties, do not switch on a mcg-per-mcg basis from any other fentanyl preparation to the buccal tablets; the buccal tablets are not equivalent to other fentanyl preparations.

Use only in patients who are opioid tolerant. Patients must continue receiving around-the-clock opioid analgesic therapy while receiving the buccal tablets for breakthrough pain.

Initially, 100 mcg for breakthrough episode in all patients except those being switched from lozenges.

In patients being switched from the transmucosal lozenges to the buccal tablets, base the initial buccal tablet dose on the current lozenge dose (see Table 6). Instruct patients to discontinue use of the lozenges and to dispose of any remaining lozenges.

Manufacturer states that these doses should be considered starting doses for the buccal tablets and are not intended to represent equianalgesic doses.

If breakthrough pain is not relieved within 30 minutes after the initial buccal tablet dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain. After treating one episode of breakthrough pain with the buccal tablets, the patient must wait ≥4 hours before treating a subsequent episode of breakthrough pain with the buccal tablets.

Titrate dosage with close monitoring to a level that provides adequate analgesia with acceptable adverse effects.

Instruct patients to record use of buccal tablets over several episodes of breakthrough pain and to discuss their experience with their clinician to decide whether dosage adjustment is warranted.

During dosage titration, 1 dose may include administration of 1–4 tablets of the same strength. Administer no more than 4 tablets simultaneously. Manufacturer states that the only time patients should take >1 tablet as a single dose (e.g., two 100-mcg tablets for a single 200-mcg dose) is during dosage titration.

Patients receiving an initial dose of 100 mcg who require titration to a higher dosage level may increase buccal tablet dosage to 200 mcg (two 100-mcg tablets, with one tablet placed on each side of the mouth in the buccal cavity) with the next episode of breakthrough pain. Those who require a further increase in dosage may place two 100-mcg tablets on each side of the mouth in the buccal cavity (total of four 100-mcg tablets). If doses >400 mcg (i.e., doses of 600 or 800 mcg) are required, titrate dosage using multiples of 200-mcg tablets.

During dosage titration period, if breakthrough pain is not relieved within 30 minutes after the initial dose of buccal tablets, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain. Manufacturer states that no more than 2 doses may be given during a single episode of breakthrough pain, even if the patient continues to experience pain after the second dose is administered.

To reduce the risk of overdosage during titration, strongly advise patients to use or discard all the buccal tablets of one strength prior to obtaining tablets of a different strength.

During titration phase, evaluate each new dose over several breakthrough pain episodes to determine efficacy and tolerability.

Once titrated to an adequate dose, breakthrough pain episodes generally should be treated effectively with 1 buccal tablet. On occasion during maintenance therapy, when a breakthrough pain episode is not relieved within 30 minutes after the first intrabuccal dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.

Some patients may require adjustment of the intrabuccal fentanyl dosage to maintain effective analgesia for breakthrough pain episodes; however, dosage generally should be increased only if several consecutive episodes require administration of >1 intrabuccal dose for pain relief. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

After treating one episode of breakthrough pain with the buccal tablets, patient must wait ≥4 hours before treating a subsequent episode of breakthrough pain with the buccal tablets.

If patient experiences >4 breakthrough pain episodes daily, reevaluate dosage of opioids used around the clock for chronic cancer pain.

Presence of grade 1 mucositis does not appear to substantially alter absorption or adverse effects of the buccal tablets.

When opioid therapy is discontinued, gradually taper the opioid dosage to avoid manifestations associated with abrupt withdrawal. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, therapy with the buccal tablets can usually be discontinued immediately.

Chronic Pain

Fentanyl Transdermal System

Transdermal

Use transdermal system only in patients who are opioid tolerant. Risk of fatal respiratory depression when administered to patients not already opioid tolerant.

Individualize initial dosage, taking into account the patient's prior analgesic use and risk factors for addiction, abuse, and misuse. Fatal overdose possible with the first transdermal dose if the dosage is overestimated.

Discontinue all other opioid analgesics other than those used on an as-needed basis for breakthrough pain when therapy with fentanyl transdermal system is initiated.

The manufacturer provides specific dosage recommendations for switching opioid-tolerant patients from certain oral or parenteral opioids to fentanyl transdermal system (see Table 7 and Table 8).

Alternatively, to switch patients who currently are receiving other opioid therapy or dosages that are not listed in Table 7 or Table 8 to fentanyl transdermal system, calculate the opioid analgesic requirements during the previous 24 hours. Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using a reliable source. Finally, calculate the equivalent dosage of fentanyl transdermal system using Table 9.

The manufacturers consider the initial dosages of transdermal fentanyl in Tables 7, 8, and 9 to be conservative estimates. Do not use the dosage conversion guidelines in these tables to switch patients from fentanyl transdermal system to oral or parenteral opioids, since dosage of oral or parenteral opioids may be overestimated.

For transdermal dosages >100 mcg/hour, apply multiple systems at different sites simultaneously.

Because of substantial interpatient variability in relative potency of opioid analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opioid requirements and provide “rescue” therapy with an immediate-release opioid analgesic than to overestimate the requirements and manage an adverse reaction.

If analgesia is inadequate after initial application, dosage may be titrated upward after 3 days (and every 6 days thereafter).

Administer supplemental doses of a short-acting opioid as needed during the initial application period and subsequently thereafter as necessary to relieve breakthrough pain.

Special Populations

Hepatic Impairment

Transdermal system: Reduce initial dosage by 50% in patients with mild to moderate hepatic impairment; monitor closely for sedation and respiratory depression, including after each increase in dosage. Because of long half-life of this formulation, avoid use in patients with severe hepatic impairment.

Transmucosal immediate-release preparations (transmucosal lozenges, buccal tablets): Insufficient information available; if used, caution advised.

Renal Impairment

Transdermal system: Reduce initial dosage by 50% in patients with mild to moderate renal impairment; monitor closely for sedation and respiratory depression, including after each increase in dosage. Because of long half-life, avoid use in patients with severe renal impairment.

Transmucosal immediate-release preparations (transmucosal lozenges, buccal tablets): Insufficient information available; if used, caution advised.

Geriatric Patients

May have increased sensitivity to fentanyl. In general, use caution when selecting a dosage, usually starting at the low end of dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Cautions for fentaNYL, fentaNYL Citrate

Contraindications

• Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose.

• Significant respiratory depression.

• Patients with substantial respiratory depression, especially in settings where adequate monitoring and equipment for resuscitation are not available; in patients with acute or severe bronchial asthma; and in those with known or suspected paralytic ileus.

• Known hypersensitivity to fentanyl or any ingredient or component of the respective formulation.

• Fentanyl Transdermal Systems:: Managment of mild pain, acute or intermittent pain, or in patients that require analgesia for a short period of time.

• Fentanyl Transdermal Systems, Transmucosal Lozenges, and Buccal Tablets: Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

Risks of addiction, abuse, and misuse. Addiction can occur at recommended dosages and if the drug is misused or abused. (see Boxed Warning.)

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.

Risks are increased in patients with a personal or family history of substance abuse (e.g., drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent proper management of pain in any given patient. Patients at increased risk may be prescribed opioid agonists, but use necessitates intensive counseling about the risks and proper use of the drug along with frequent reevaluation for signs of addiction, abuse, and misuse.

Strategies to reduce these risks include prescribing the smallest appropriate quantity and advising patient on careful storage of the drug during treatment and proper disposal of unused drug. Contact a state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion.

Respiratory Depression

Risk of serious life-threatening, or fatal respiratory depression can occur even when used as recommended. Can occur at any time, but risk is greatest during initiation of therapy or following a dosage increase. (see Boxed Warning.)

To reduce risk of respiratory depression, proper dosing and titration are essential.

Use of fentanyl transdermal system or transmucosal immediate-release preparations in non-opioid-tolerant patients may result in fatal respiratory depression and is contraindicated.

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

Routinely discuss availability of the opioid antagonist naloxone with all patients receiving new or reauthorized prescriptions for opioid analgesics, including fentanyl.

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

Risk of serious or fatal adverse effects following accidental exposure to fentanyl transdermal systems. (see Boxed Warning.)

Risk of fatal overdosage if transmucosal immediate-release preparations are ingested by non-opioid-tolerant individuals or individuals for whom drug was not prescribed. (see Boxed Warning.)

Proper storage, handling, and disposal are essential to prevent accidental exposure.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use with benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioid agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death. (see Boxed Warning.)

Reserve concomitant prescribing of these drugs for patients in whom alternative treatment options are inadequate.

If a benzodiazepine or other CNS depressant is used concomitantly with an opioid analgesic, prescribe lowest effective dosages and minimum durations of concomitant use.

In patients are already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant, 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.

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

Concomitant use with CYP3A4 inhibitors may increase plasma fentanyl concentrations, increasing or prolonging opioid effects and potentially resulting in fatal respiratory depression. (see Boxed Warning.)

Discontinuation of a CYP3A4 inducer in fentanyl-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions.

Risk of Medication Errors

Do not convert patients to transmucosal immediate-release fentanyl (TIRF) preparations (Actiq, Fentora) from any other fentanyl product based on dosage amounts; these products are not equivalent on a mcg-per-mcg basis. (see Boxed Warning.)

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. Differences in the rate and extent of absorption of fentanyl may result in a fatal overdose.

Neonatal Opioid Withdrawal Syndrome

Use of fentanyl for an extended period during pregnancy can result in withdrawal in the neonate. (see Boxed Warning.)

Risk of Increased Fentanyl Absorption with Application of External Heat

Exposure to heat may increase fentanyl absorption from transdermal systems; overdose and death have occurred. (see Boxed Warning.) Avoid such exposure.

Other Warnings and Precautions

Risks of Muscle Rigidity and Skeletal Muscle Movement

Parenteral administration may cause muscle rigidity, particularly involving the respiratory muscles. Use of neuromuscular blocking agents before or simultaneous with anesthetic use of fentanyl can reduce the risk.

Severe Cardiovascular Depression

Because of cholinergic effects, may cause bradycardia after parenteral administration. Caution in patients with cardiac bradyarrhythmias; monitor closely for changes in heart rate, particularly during initiation of therapy.

Opioid-Induced Hyperalgesia and Allodynia

Opioid-induced hyperalgesia (OIH) may occur when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. Symptoms may include 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 OIH is suspected, carefully consider decreasing dose of the current opioid analgesic or switch to a different opioid.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Serotonin syndrome reported during concurrent use of opioid agonists, including fentanyl, and serotonergic drugs.

Serotonin syndrome may occur at usual dosages. Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

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

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.

Patients with chronic pulmonary disease such as those with significant COPD or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, even at recommended dosages.

Life-threatening respiratory depression is also more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Adrenal Insufficiency

Adrenal insufficiency reported with opioid use, usually with longer duration of use.

If adrenal insufficiency is suspected, confirm diagnosis. If diagnosed, treat with physiologic replacement doses of corticosteroids. Wean patient from the opioid to allow adrenal function to recover and continue corticosteroid treatment until recovery.

Severe Hypotension

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.

Increased risk of severe hypotension in patients whose ability to maintain BP is compromised by depleted blood volume or concomitant use of certain drugs (e.g., phenothiazines, general anesthetics). Monitor these patients for hypotension after initiation of therapy or dosage titration.

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

May reduce respiratory drive; the resultant carbon dioxide retention can further increase intracranial pressure.

May obscure the clinical course in patients with head injuries; avoid use in patients with impaired consciousness or coma.

Risks of Use in Patients with GI Conditions

May cause spasm of the sphincter of Oddi and increase serum amylase concentrations. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Seizures

May aggravate preexisting seizure disorder. Monitor for worsened seizure control.

May induce or aggravate seizures in some clinical settings.

CNS Effects

May impair mental alertness and/or physical coordination needed to perform potentially hazardous activities such as driving or operating machinery; warn patient about possible adverse CNS effects of opioid agonists.

Application Site Reactions

Application site reactions reported in patients using fentanyl transdermal systems.

Risks due to Interaction with Neuroleptic Agents

Elevated BP, with and without pre-existing hypertension, reported following administration of fentanyl injection combined with a neuroleptic.

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with fentanyl injection as an anesthetic premedication, for induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

Risk of Increased Fentanyl Absorption with Elevated Body Temperature

Serum fentanyl concentrations can 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.

Monitor patients wearing fentanyl transdermal systems who develop fever closely for sedation and respiratory depression and reduce the fentanyl transdermal system dose, if necessary.

Withdrawal

Do not abruptly discontinue fentanyl transdermal system in a patient physically dependent on opioids; gradually taper dosage.

Avoid 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. May reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Specific Populations

Pregnancy

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

Opioids cross placenta and may produce respiratory depression and psychophysiologic effects in neonates. Insufficient data to support the use of fentanyl in labor or delivery and therefore such use is not recommended.

Transient neonatal muscular rigidity reported in infants whose mothers received IV fentanyl during labor.

Prolonged maternal use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome; may be life-threatening and requires management according to protocols developed by neonatology experts.

Lactation

Distributed into human milk. Potential risk (sedation, respiratory depression) to nursing infants.

Manufacturers of transdermal system and transmucosal immediate-release preparations state these preparations should not be used in nursing women because of potential for serious adverse effects in nursing infants.

Symptoms of withdrawal can occur in opioid-dependent infants upon cessation of breast-feeding by women receiving fentanyl.

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. Not known whether these effects on fertility are reversible.

Pediatric Use

Safety and efficacy of parenteral formulation and transdermal system not established in pediatric patients <2 years of age.

Safety and efficacy of lozenges not established in pediatric patients <16 years of age.

Safety and efficacy of buccal tablets not established in patients <18 years of age.

Transdermal systems and transmucosal immediate-release preparations (transmucosal lozenges, buccal tablets) contain fentanyl in amounts that can be fatal to a child.

Fatal respiratory depression can occur if transdermal system is accidentally or deliberately applied or ingested by a child or adolescent; choking can occur if the system is ingested. High risk of respiratory depression if a child accidentally ingests a transmucosal immediate-release preparation.

Geriatric Use

Pharmacokinetics may be altered, increasing risk of life-threatening respiratory depression. Monitor closely for sedation and respiratory depression, particularly during initiation or titration of therapy and when other respiratory depressants are used concomitantly. Use caution when titrating dosage

Renal clearance of fentanyl may be reduced.

Geriatric patients may be more sensitive to effects of fentanyl.

Hepatic Impairment

Exercise caution and reduce initial parenteral dosage.

Reduce initial dosage of fentanyl transdermal system in patients with mild to moderate hepatic impairment; monitor closely for sedation and respiratory depression, including after each increase in dosage. Because of long half-life of this formulation, avoid use in patients with severe hepatic impairment.

Insufficient information available to support recommendations regarding use of transmucosal immediate-release preparations; if used, caution advised.

Renal Impairment

Exercise caution and reduce initial parenteral dosage.

Reduce initial dosage of fentanyl transdermal system in patients with mild to moderate renal impairment; monitor closely for sedation and respiratory depression, including after each increase in dosage. Because of long half-life of this formulation, avoid use in patients with severe renal impairment.

Insufficient information available to support recommendations regarding use of transmucosal immediate-release preparations; if used, caution advised.

Patients with Cardiac Disease

IV fentanyl may cause bradycardia. Use fentanyl transdermal systems and transmucosal immediate release products with caution in patients with bradyarrhythmias.

Common Adverse Effects

Most common adverse effects reported with parenteral administration include respiratory depression, apnea, rigidity, bradycardia.

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

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

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

Drug Interactions

Metabolized by CYP3A4.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors (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): Possible increased plasma fentanyl concentrations with concomitant use; may result in increased or prolonged opioid effects, including sedation and potentially fatal respiratory depression. If concomitant use is necessary, monitor frequently and consider dosage reduction. Following initiation or increase in dosage of a CYP3A4 inhibitor, carefully monitor patient for increased opioid effects. If a CYP3A4 inhibitor is discontinued, consider increasing dosage of fentanyl until stable drug effects are achieved and monitor for signs of opioid withdrawal.

CYP3A4 inducers (rifampin, carbamazepine, phenytoin): Possible decreased plasma fentanyl concentrations with concomitant use; may result in decreased analgesic efficacy and/or development of opioid withdrawal. If concomitant use is necessary, monitor for signs of opioid withdrawal and consider dosage adjustments until drug effects are stable. If the CYP3A4 inducer is discontinued, fentanyl concentrations may increase, possibly resulting in increased or prolonged therapeutic or adverse effects, including sedation and potentially fatal respiratory depression. If CYP3A4 inducer is discontinued or dosage is reduced, monitor for increased opioid effects and decrease fentanyl dosage as necessary.

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs such as SSRIs, SNRIs, tricyclic antidepressants (TCAs), triptans, 5-HT₃ receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), MAO inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and methylene blue). May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use but may occur later. If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases. If serotonin syndrome is suspected, discontinue fentanyl, other opioid therapy, and/or any concurrently administered serotonergic agents.

Specific Drugs and Foods

fentaNYL, fentaNYL Citrate Pharmacokinetics

Absorption

Bioavailability

Well absorbed percutaneously following topical application of transdermal system or transmucosally following administration as transmucosal lozenge or buccal tablet.

Substantial pharmacokinetic differences exist among the transmucosal immediate release preparations (transmucosal lozenges, buccal tablets); these preparations must not be substituted on a mcg-for-mcg basis.

Transmucosal lozenge: Bioavailability averages about 50%. Generally, approximately 25% absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with saliva and then absorbed slowly from the GI tract.

Buccal tablet: Bioavailability averages about 65%. Generally, approximately 50% absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with saliva and then absorbed slowly from the GI tract. The time required for the buccal tablet to fully disintegrate does not appear to affect early systemic drug exposure.

Transmucosal lozenge versus buccal tablet: When 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.

Fentanyl transdermal systems: Amount of fentanyl released from the system is proportional to the surface area of the system; however, actual amount of drug delivered to the skin exhibits interindividual variation. Peak concentration attained within 20–72 hours after initial application. 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. Application of heat over the transdermal system increases mean exposure and peak plasma concentrations by 120 and 61%, respectively.

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.

Onset

IV administration: Rapid, with peak analgesia occurring within several minutes.

IM administration: About 7–15 minutes.

Duration

IV administration, analgesia: 0.5–1 hours.

IM administration, analgesia: 1–2 hours.

Respiratory depressant effects may persist longer than analgesia.

Special Populations

Buccal tablets in patients with mucositis: Presence of grade 1 mucositis does not appear to substantially alter absorption.

Pharmacokinetics of fentanyl transdermal system in patients ≥ 65 years of age did not differ significantly from younger adult patients, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.

In patients with cirrhosis receiving fentanyl transdermal system, peak plasma concentration and AUC increased by 35 and 73%, respectively.

Distribution

Extent

Fentanyl is highly lipophilic.

Fentanyl crosses the placenta and is distributed into breast milk.

Plasma Protein Binding

80–85% bound.

Elimination

Metabolism

Metabolized extensively in the liver and the intestinal mucosa via CYP3A4 to norfentanyl and other inactive metabolites.

Transdermally administered fentanyl does not appear to be metabolized in the skin.

Elimination Route

Principally in urine, as inactive metabolites and to a lesser extent (<10%) as unchanged drug.

Half-life

Transmucosal lozenges: terminal half-life of about 7 hours.

Parenteral: terminal elimination half-life is 219 minutes.

Stability

Storage

Store in a secure place to prevent access by children and pets.

Properly dispose of used or partially used dosage forms immediately after use.

Intrabuccal

Transmucosal Lozenges

20–25°C (excursions permitted between 15–30°C).

To dispose of lozenges, manufacturer recommends removing lozenges from blister packages using scissors, then cutting the drug matrix from the handles with wire-cutting pliers over a toilet bowl and flushing them twice down the toilet.

After consumption of a lozenge and drug matrix is totally dissolved, discard the handle in a trash container out of reach of children; remove any drug matrix remaining on handle by placing under hot running tap water until drug matrix is completely dissolved.

If unused portions cannot be disposed of immediately, store partially used lozenge in a temporary storage bottle (supplied by manufacturer) and dispose of these units at least once a day.

Buccal Tablets

20–25°C (excursions permitted between 15–30°C). Protect from freezing and moisture. Administer immediately after removal from blister package; do not store for use at a later time since tablet integrity may be compromised or accidental exposure may occur.

To dispose of tablets, manufacturer recommends removing tablets from their blister packages and flushing down toilet.

Parenteral

Injection

20–25°C (excursions permitted between 15–30°C); protect from light.

Topical

Fentanyl Transdermal Systems

Store at 20–25°C.

To dispose of unused fentanyl transdermal systems that are no longer needed, the manufacturers recommend removing the systems from their packaging, folding them carefully so that the adhesive side adheres to itself, and then flushing them down the toilet.

To dispose of used system, fold the system so that the adhesive side adheres to itself and then flush system down the toilet.

Actions

• A potent analgesic; shares the actions of the opioid agonists.

• Interacts predominantly with the opioid mu receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

• Agonist activity at mu receptor can also result in suppression of opioid withdrawal (and antagonist activity can result in precipitation of withdrawal).

• Respiratory depression may be mediated by direct action on brain stem respiratory centers.

• Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum.

• Opioid agonists have been shown to have a variety of effects on the secretion of hormones.

• 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.

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

Advice to Patients

• Inform patients that the use of fentanyl, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share the drug with others and to take steps to protect it from theft or misuse.

• Inform patients that the risk of life-threatening respiratory depression is most likely to occur following initiation of therapy or an increase in dosage; may also occur at recommended dosages. 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.

• Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain.

• Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome 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 after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications.

• Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

• Strongly warn patients and/or caregivers to keep new, used, and partially used preparations in a secure location out of the reach of children and to strictly adhere to instructions for storage, handling, and disposal of unused and partially or fully used fentanyl preparations. Inform patients that leaving preparations unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that they can visit [Web] for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

• Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment. 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 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.

• Inform patients that potentially fatal additive effects may occur if used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.

• Inform patients to avoid taking fentanyl while using any drugs that inhibit monoamine oxidase (MAO). Patients should not start MAOIs while taking fentanyl preparations.

• Inform patients that fentanyl 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.

• 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 these symptoms.

• Inform patients that fentanyl 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).

• Inform patients that anaphylaxis has been reported with ingredients contained in fentanyl preparations. Advise patients how to recognize such a reaction and when to seek medical attention.

• Advise women to inform their clinicians if they are or plan to become pregnant. Inform women that long-term use during pregnancy may result in neonatal opioid withdrawal syndrome, which can be life-threatening if not recognized and treated.

• Advise women to inform their clinicians if they are or plan to breast-feed. Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these symptoms.

• Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Transmucosal Immediate-release Fentanyl Preparations

• Inform patients of the importance of understanding the requirements of the TIRF REMS Access program and of signing the patient-prescriber agreement mandated by the program.

• Inform patients on the importance of using transmucosal immediate-release preparations (transmucosall lozenges, buccal tablets) exactly as prescribed and only if opioid tolerant. Inform patients of the importance of not using these preparations for acute, postoperative, or short-term pain. Advise patients that if around-the-clock therapy with opioid analgesics is discontinued, they must stop taking transmucosal immediate-release fentanyl preparations for management of breakthrough pain.

• Advise patients with diabetes mellitus that fentanyl citrate transmucosal lozenges contain approximately 2 g of sugar per lozenge. Frequent consumption may also increase the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk. Advise patients to consult their dentist to ensure appropriate oral hygiene. Inform patients that buccal tablets are not to be swallowed whole; this will reduce the effectiveness of the medication. Tablets are to be placed between the cheek and gum above a molar tooth or under the tongue and allowed to dissolve. If remnants of the tablet still remain after 30 minutes, patients may swallow it with a glass of water.

• Advise patients to talk to their healthcare provider if breakthrough pain is not alleviated or worsens after taking their medicine as directed.

Fentanyl Transdermal Systems

• Inform patients that accidental exposure, especially in children, may result in respiratory depression or death. Fentanyl transdermal system can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children. Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water, and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems.

• Advise patients never to change the dose of fentanyl transdermal system or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional.

• Advise patients to avoid strenuous exertion that can increase core body temperature and to avoid exposing the application site or surrounding area to direct external heat sources (e.g., heating pads, electric blankets, heat or tanning lamps, saunas, hot tubs, hot baths, heated water beds, sunbathing) while wearing the transdermal system since temperature-dependent increases in percutaneous absorption of fentanyl from the system are possible under such conditions. Stress importance of contacting clinician if a high fever occurs during transdermal fentanyl therapy.

• Instruct patients not to discontinue fentanyl transdermal system without first discussing a tapering plan with the prescriber, in order to avoid developing withdrawal symptoms.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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.

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

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

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