Brand names: Actiq, Fentora, Sublimaze
Drug class: Opoid Agonists

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

Introduction

Opioid agonist; a synthetic phenylpiperidine derivative.

Uses for fentaNYL

Pain

Strong analgesic used to relieve pain.

Available in several dosage forms including buccal tablets (Fentora) and lozenges (Actiq), transdermally as fentanyl transdermal system, and as a solution for injection.

The CDC clinical guideline for prescribing opioids for pain gives recommendations for clinicians providing pain care to adults for the management of acute, sub-acute, and chronic pain. Acute pain (duration <1 month) has a sudden onset and is usually occurring after injury, trauma, or medical procedures or surgery.760 Subacute pain (duration of 1–3 months) may be the continuation of acute pain or pain with a longer duration of unresolved pain. Chronic pain has a longer duration (>3 months) and may result from an underlying medical condition or disease, injury, medical treatment, inflammation, or unknown cause.

Should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Acute pain and subacute pain, if unresolved, may evolve into chronic pain. The guideline addresses the following four areas: 1) determining whether 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. The full text of the recommendations can be accessed at https://www.cdc.gov/opioids/healthcare-professionals/prescribing/guideline/at-a-glance.html.

Acute Pain

Parenterally for pain that likely will be of short duration (e.g., that associated with diagnostic procedures, orthopedic manipulation) and can be controlled with a short-acting opioid agonist such as fentanyl.

Because of the risk of life-threatening respiratory depression, fentanyl transdermal systems (e.g., Duragesic) and transmucosal immediate-release preparations (buccal lozenges, buccal tablets, ) are contraindicated in the management of acute or postoperative pain. (See Contraindications under Cautions.)

In symptomatic treatment of acute pain, reserve opioid analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopioid alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated. Use smallest effective dosage for shortest possible duration since long-term opioid use often begins with treatment of acute pain. Optimize concomitant use of other appropriate therapies. Clinicians should not treat acute pain with ER/LA opioids (e.g., transdermal fentanyl) and clinicians should not prescribe ER/LA opioids for intermittent use because of the longer half-life and longer duration of effects.

Chronic Pain (Non-cancer)

Transdermally as fentanyl transdermal system (e.g., Duragesic) in opiate-tolerant patients for the management severe and persistent pain in opioid tolerant patients, that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Because of the risks of addiction, abuse, and misuse associated with opiods, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opiod formulations, reserve for use in patients when alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are ineffective, not tolerated or would be otherwise inadequate to provide sufficient management of pain.

Patients are considered opioid tolerant if they have been receiving around-the-clock opioid therapy consisting of at least 60 mg of 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, 60 mg oral hydrocodone daily, or an equianalgesic dosage of another opioid daily for at least 1 week.

Generally use opioids for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopioid pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.

If used for chronic pain, opioid analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities such as exercise (e.g., aerobic, aquatic, or resistance exercises) or exercise therapy (a prominent modality in physical therapy) for back pain, fibromyalgia, and hip or knee osteoarthritis; weight loss for knee osteoarthritis; manual therapies for hip osteoarthritis; psychological therapy, spinal manipulation, low-level laser therapy, massage, mindfulness-based stress reduction, yoga, acupuncture, and multidisciplinary rehabilitation for low back pain; mind-body practices (e.g., yoga, tai chi, or qigong), massage, and acupuncture for neck pain; cognitive behavioral therapy, myofascial release massage, mindfulness practices, tai chi, qigong, acupuncture, and multidisciplinary rehabilitation for fibromyalgia; and spinal manipulation for tension headache.

Available evidence insufficient to determine whether long-term opioid therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opioid use disorder [OUD], overdose). (See Managing Opioid Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Chronic Pain (Cancer-related)

Transdermally as fentanyl transdermal system (e.g., Duragesic) in opioid-tolerant patients for the management of pain that is severe enough to require long-term, daily, around-the-clock use of an opioid analgesic. Because of the risks of addiction, abuse, and misuse associated with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for use when alternative treatment options (e.g., nonopioid analgesics, immediate-release opioids) are inadequate or not tolerated.

Transmucosally as an immediate-release preparation (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) for the management of breakthrough pain only in patients who are already being treated with, and are tolerant of, opioids used around-the-clock for persistent cancer pain. Patient must continue receiving around-the-clock opioid therapy while receiving these transmucosal immediate-release preparations for relief of breakthrough pain.

Do not use fentanyl transdermal systems or transmucosal immediate-release preparations in patients who are not opioid tolerant.

Patients are considered opioid tolerant if they have been receiving around-the-clock opioid 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 opioid daily for at least 1 week.

In the management of severe chronic pain associated with a terminal illness such as cancer, the principal goal of analgesic therapy is to make the patient relatively pain-free while maintaining as good a quality of life as possible.

Although consideration of the dependence potential of opioid agonists has often limited their effective use by many clinicians in terminally ill patients with severe chronic pain, such consideration is irrelevant in the context of terminal illness. When opioids are no longer indicated, they should be weaned or tapered in situations such as resolution of acute syndromes such as mucositis, or if anticancer therapies or interventional treatments lead to significant pain relief. Patients with cancer and their caregivers can be reassured that this is feasible at the initiation of opioid therapy.

Anesthesia

Administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.

Provide analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises..

As the opioid analgesic supplement in general or regional anesthesia.

Use as an anesthetic agent with oxygen in selected high-risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

Related/similar drugs

gabapentin, acetaminophen, trazodone, tramadol, cyclobenzaprine, hydroxyzine, naproxen

fentaNYL Dosage and Administration

General

Pretreatment Screening

• Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opioids and formulations, coexisting diseases, and concomitant drug therapy.

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

• Buccal and Transdermal Administration: Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction; establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.

• Buccal and Transdermal Administration: Some experts recommend initiating opioid therapy for chronic noncancer pain with conventional (immediate-release) opioid analgesics prescribed at lowest effective dosage. Individualize opioid selection, initial dosage, and dosage titration based on patient’s health status, prior opioid use, attainment of therapeutic goals, and predicted or observed harms. Fentanyl transdermal system should be prescribed only by clinicians familiar with absorption characteristics and dosing of this formulation.

Patient Monitoring

• Buccal and Transdermal Administration: Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment). If benefits do not outweigh harms, optimize other therapies and taper opioid to lower dosage or taper and discontinue opiate.

• Buccal and Transdermal Administration: Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase and reevaluate on ongoing basis (e.g., at least every 3 months ) throughout therapy. Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies. Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment). If benefits do not outweigh harms, optimize other therapies and taper opioid to lower dosage or taper and discontinue opioid.

• Buccal and Transdermal Administration:CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥21 mcg/hour of transdermal fentanyl) for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily (approximately ≥37.5 mcg/hour of transdermal fentanyl) or carefully justify decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily. Some states have established opioid dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended) or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).

• Parenteral Administration: Administer only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids. Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available.Individualize dosage based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved. Monitor vital signs routinely.

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.

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opioid analgesia (generally ≤3 days and rarely >7 days). Do not prescribe larger quantities for use in case pain continues longer than expected; instead, reevaluate patient if severe acute pain does not remit.

• Buccal Administration: It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.

• Buccal AdministrationTransmucosal immediate-release fentanyl (TIRF) formulations are not equivalent to other fentanyl products. Do not convert patients on a mcg per mcg basis from any other fentanyl product to a TIRF product. Other TIRF formulations and ACTIQ are not equivalent. DO NOT substitute an ACTIQ prescription for any other TIRF formulation under any circumstances.

TIRF REMS Restricted Distribution Program

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

• Outpatients who receive transmucosal immediate-release fentanyl preparations, clinicians who prescribe these preparations to outpatients, 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, and inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require these preparations while hospitalized.

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

REMS: Opioid Analgesics Used in Outpatient Setting

• FDA has approved a REMS for opioid analgesics, including fentanyl transdermal system, used in the outpatient setting and not covered by other REMS programs. (See 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 program consists of educational programs for health professionals, a patient counseling guide, and a product-specific medication guide for patients.

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

Other General Considerations

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opioid overdosage (such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose ) or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.

• Buccal AdministrationInstruct patients and caregivers to take steps to store their prescription securely and to properly dispose of unused drug as soon as no longer needed.

Administration

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

Administer by IM or IV injection or by IV infusion.

Administer transmucosally as a buccal lozenge or buccal tablet. Buccal tablets also may be administered sublingually once an effective dose has been established.

Administer percutaneously by topical application of a transdermal system.

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

Intrabuccal Administration

Administer intrabuccally as buccal lozenge or buccal tablet.

Carefully instruct patients in the proper use and disposal of the buccal lozenges and buccal tablets.

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.

Buccal Lozenges

Cut lozenge package open with scissors just prior to administration.

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

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

If unused portions cannot be disposed of immediately, store the partially used lozenge in a temporary storage bottle (supplied by the manufacturer) according to manufacturer's instructions and dispose of these units at least once a day. Unused portions may contain sufficient amounts of fentanyl to be fatal to a child.

Buccal Tablets

Bend and tear along the blister card perforations to separate a single blister unit. Just prior to administration, bend along the indicated line on a single blister unit and peel the backing to remove the 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 crushed, sucked, chewed, or swallowed whole rather than being 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.

IV Administration

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

Administer by direct IV injection, IV infusion, or IV via a controlled-delivery device for patient-controlled analgesia (PCA).

Dilution

May give undiluted as direct IV injection.

Rate of Administration

Direct IV injection: Usually, slowly over several (e.g., 1–2) minutes.

IV injection for PCA: Self-administered intermittently as needed (“prn”) via controlled-delivery device, with usual lockout intervals (minimum time between self-administered doses programmed into device) of 6–12 minutes.

IV infusion: Usually, slowly but occasionally rapidly (e.g., for high-dose opioid anesthesia).

IV infusion, maintenance doses in anesthesia: Usually, 2–10 mcg/kg per hour.

Risk of muscular rigidity (particularly of the respiratory muscles) is related to the dose and speed of IV administration; if administered IV rapidly (particularly large doses) or even slowly by IV infusion for anesthesia, administration of a neuromuscular blocking agent prior to or simultaneously with anesthetic fentanyl therapy can reduce the risk.

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 by IM injection.

Transdermal Administration

Take steps to ensure that fentanyl transdermal systems are not administered inadvertently to opioid-naive patients or for acute pain management because of risk of potentially fatal overdosage.

Carefully instruct patients in the 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 the 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 the seal of the package is broken or if the 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 the previous system.

If a system should inadvertently come off during the period of use, apply a new system to a different skin site and leave in place for 72 hours. The edges of the system may be taped in place with first-aid tape if the 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 while wearing the system or expose the application site and surrounding area to direct external heat sources. (See Patients with Fever or Exposure to High Temperatures under Cautions.)

Immediately following removal, fold the used system so that the 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 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 familiar with the techniques of administration, dosages, and special patient management problems.

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. (See Geriatric Patients under Dosage and Administration.)

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy. (See Specific Drugs under Interactions.)

Individualize dosage of fentanyl according to the clinical status of the patient, desired therapeutic effect, and age and weight. The most important factor in determining the appropriate dose of transdermal fentanyl is the degree of existing opioid tolerance.

Pediatric Patients

Anesthesia and Analgesia

IV or IM

Children 2–12 years of age, anesthesia induction and maintenance phase: Usually, 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, 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, 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..

PCA (usually IV) via controlled-delivery device: Loading doses of 0.05–2 mcg/kg, preferably titrated by clinician or nurse at bedside, up to 0.5–4 mcg/kg total.

PCA (usually IV) via controlled-delivery device: Maintenance doses (administered intermittently by patient) of 0.25–0.5 mcg/kg, usually no more frequently than every 6–12 minutes as a device-programmed lockout period.

Chronic Malignant (Cancer) Pain and Other Chronic Pain

Initial Dose Selection in Patients Being Switched to Fentanyl Transdermal System

Transdermal (e.g., Duragesic)

Use transdermal system only in children ≥2 years of age who are opioid tolerant. (See Uses.) Risk of fatal respiratory depression when administered to patients not already opioid tolerant. (See Fentanyl Transdermal Systems in Boxed Warning.)

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 the dosage is overestimated.

Discontinue all other around-the-clock opioid analgesics 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 8 and 9).

Alternatively, to switch children ≥2 years of age who currently are receiving other opioid therapy or dosages that are not listed in Table 8 or 9 or Table 10 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 10.

The manufacturers consider the initial dosages of transdermal fentanyl in Tables 8, 19, and 10 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.

If overdosage occurs, monitor and treat patient for at least 72–96 hours because of long elimination half-life of this formulation (20–27 hours).

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

Additional intermediate strengths 37.5 mcg/hr, 62.5 mcg/hr, and 87.5 mcg/hr fentanyl transdermal systems are available and may be considered during conversion from prior opioids or dose titration. For example, the 37.5 mcg/hr system could be used before converting or titrating to a 50 mcg/hr system. Similarly, a 62.5 mcg/hr system is available for use as an intermediate strength between the 50 mcg/hr and the 75 mcg/hr system, and an 87.5 mcg/hr system is available as an intermediate strength between the 75 mcg/hr system and the 100 mcg/hr system.

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

Dosage Adjustment to Achieve Adequate Analgesia

Transdermal (e.g., Duragesic)

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 12.5-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.

Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.

Maintenance Therapy

Transdermal (e.g., Duragesic)

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.

Discontinuance of Transdermal Fentanyl Therapy

Transdermal (e.g., Duragesic)

To switch to another opioid, remove the fentanyl transdermal system and titrate the dosage of the other opioid according to patient response.

Substantial amounts of fentanyl continue to be absorbed from the skin for ≥24 hours after removal of the transdermal system. It generally takes 20–27 hours for serum fentanyl concentrations to decline by 50% following removal of the system.

Symptoms of withdrawal (e.g., nausea, vomiting, diarrhea, anxiety, shivering) may occur in some patients after switching to another opioid agonist or following discontinuance of the fentanyl transdermal system.

When transdermal fentanyl is discontinued and another opioid analgesic is not initiated, withdraw fentanyl gradually (e.g., reduce dosage by 50% every 6 days) to avoid precipitation of withdrawal symptoms. Dosage level at which transdermal fentanyl may be discontinued without producing withdrawal symptoms is not known.

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.

PCA (usually IV) via controlled-delivery device: Loading doses of 25–50 mcg every 5 minutes, preferably titrated by clinician or nurse at bedside, up to 50–300 mcg total.

PCA (usually IV) via controlled-delivery device: Maintenance doses (self-administered intermittently by patient) of 10–30 mcg, usually no more frequently than every 6–12 minutes as a device-programmed lockout period.

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.

IV Infusion

Initial loading dose: Usually, 4–20 mcg/kg titrated to effect over several minutes.

Maintenance dose: Usually, 2–10 mcg/kg per hour; additional supplemental IV doses of 25–100 mcg as needed.

Maintenance dose: Alternatively after usual loading dose, variable-rate infusion titrated to maintain targeted plasma and effect site fentanyl concentrations:

Supplemental IV doses also can be used as needed with the alternative maintenance dose.

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.

Postoperative Pain, Restlessness, Tachypnea, and Emergence Delirium

IM

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

Breakthrough Malignant (Cancer) Pain in Opioid-tolerant Patients

Intrabuccal (Lozenges [Actiq, generic oral transmucosal fentanyl citrate lozenges])

Because of differences in pharmacokinetic properties, do not switch patients on a mcg-per-mcg basis from any other fentanyl preparation, including fentanyl citrate buccal tablets (Fentora), to the buccal lozenges; buccal lozenges are not equivalent to other fentanyl preparations and are not a generic version of the buccal tablets. (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opioid tolerant. (See Malignant [Cancer] Pain under Uses.) Patients must continue receiving around-the-clock opioid analgesic therapy while receiving the buccal lozenges for breakthrough pain.

Initially, 200 mcg for breakthrough episode in all patients.

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

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

May be necessary to use >1 lozenge per episode of breakthrough cancer pain until the appropriate dose is attained; an additional lozenge may be administered 15 minutes after the previous lozenge has been consumed (i.e., 30 minutes after the first lozenge initially was placed in the mouth).

Maximum of 2 lozenges per breakthrough pain episode may be given, if necessary, during dosage titration phase.

Increase dose to the next higher available strength after several consecutive breakthrough pain episodes require the use of >1 lozenge per episode; again, prescribe only 6 lozenges of the new strength.

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

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

Once titrated to an adequate dose (average breakthrough pain episode is treated with a single lozenge), the patient should use a maximum of 4 lozenges daily.

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 opioids 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, buccal lozenges can usually be discontinued immediately.

Intrabuccal (Buccal tablets [Fentora])

Because of differences in pharmacokinetic properties, do not switch on a mcg-per-mcg basis from any other fentanyl preparation to the buccal tablets; buccal tablets are not equivalent to other fentanyl preparations. (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opioid tolerant. (See Malignant [Cancer] Pain under Uses.) 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 fentanyl citrate buccal lozenges.

In patients being switched from the buccal lozenges to the buccal tablets, base the initial buccal tablet dose on the current buccal lozenge dose (see Table 7). Instruct patients to discontinue use of the buccal 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.

In patients who initiated buccal tablet therapy with the 200-mcg tablets (i.e., those who were transferred from fentanyl citrate buccal lozenge dosages of ≥600 mcg (see Table 7), titrate buccal tablet 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 opioidrelated 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 forpersistent pain but no longer require treatment for breakthrough pain, therapy with the buccal tablets can usually be discontinued immediately

Chronic Malignant (Cancer) Pain and Other Chronic Pain

Initial Dose Selection in Patients Being Switched to Fentanyl Transdermal System

Transdermal (e.g., Duragesic)

Use transdermal system only in patients who are opioid tolerant. (See Uses.) Risk of fatal respiratory depression when administered to patients not already opioid tolerant. (See Fentanyl Transdermal Systems in Boxed Warning.)

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 around-the-clock opioid analgesics when therapy with fentanyl transdermal system is initiated.

The manufacturers provide specific dosage recommendations for switching opioid-tolerant patients from certain oral or parenteral opioids to fentanyl transdermal system (see Table 8 and 9).

Alternatively, to switch patients who currently are receiving other opioid therapy or dosages that are not listed in Table 8 or 9 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 10.

The manufacturers consider the initial dosages of transdermal fentanyl in Tables 8, 9, and 10 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 overdosage occurs, monitor patient for at least 72–96 hours because of long elimination half-life of this formulation (20–27 hours).

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

Additional intermediate strengths 37.5 mcg/hr, 62.5 mcg/hr, and 87.5 mcg/hr fentanyl transdermal systems are available and may be considered during conversion from prior opioids or dose titration. For example, the 37.5 mcg/hr system could be used before converting or titrating to a 50 mcg/hr system. Similarly, a 62.5 mcg/hr system is available for use as an intermediate strength between the 50 mcg/hr and the 75 mcg/hr system, and an 87.5 mcg/hr system is available as an intermediate strength between the 75 mcg/hr system and the 100 mcg/hr system.

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

Dosage Adjustment to Achieve Adequate Analgesia

Transdermal (e.g., Duragesic)

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 12.5-mcg/hour delivery from the fentanyl transdermal system.

Most patients are maintained adequately with transdermal systems applied at 72-hour intervals; however, some may require application of the systems at 48-hour intervals to maintain adequate analgesia. Before shortening the dosing interval for inadequate response to a given dose, evaluate a dose increase so that patients can be maintained on a 72-hour regimen if possible.

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 appropriatebalance between management of pain and opioid-related adverse reactions.

Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.

Maintenance Therapy

Transdermal (e.g., Duragesic)

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.

Discontinuance of Transdermal Fentanyl Therapy

Transdermal (e.g., Duragesic)

To switch to another opioid, remove the fentanyl transdermal system and titrate the dosage of the other opioid according to patient response.

Substantial amounts of fentanyl continue to be absorbed from the skin for ≥24 hours after removal of the transdermal system. It generally takes 20–27 hours or serum fentanyl concentrations to decline by 50% following removal of the system.

Symptoms of withdrawal (e.g., nausea, vomiting, diarrhea, anxiety, shivering) may occur in some patients after switching to another opioid agonist or following discontinuance of the fentanyl transdermal system.

When transdermal fentanyl is discontinued and another opioid analgesic is not initiated, withdraw fentanyl gradually (e.g., reduce dosage by 50% every 6 days) to avoid precipitation of withdrawal symptoms. Dosage level at which transdermal fentanyl may be discontinued without producing withdrawal symptoms is not known.

Prescribing Limits

Adults

Acute Pain:For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opioid analgesia (generallya few days or less).

Chronic Noncancer Pain: CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily (approximately ≥21 mcg/hour of transdermal fentanyl) for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily (approximately ≥37.5 mcg/hour of transdermal fentanyl) or carefully justify their decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).

Special Populations

Hepatic Impairment

Parenteral fentanyl: Administer with caution. Reduce initial dosage and monitor closely for signs of respiratory depression, sedation, andhypotension.

Fentanyl 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 (buccal lozenges, buccal tablets): Insufficient information available to support recommendations regarding use; if used, caution advised.

Renal Impairment

Parenteral fentanyl: Reduce initial dosage and monitor closely for signs of respiratory depression, sedation, andhypotension.

Fentanyl 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 of this formulation, avoid use in patients with severe renal impairment.

Transmucosal immediate-release preparations (buccal lozenges, buccal tablets): Insufficient information available to support recommendations regarding use; if used, caution advised.

Geriatric Patients

Titrate fentanyl dosage carefully.

Parenteral fentanyl: Reduce initial doses; response to initial dosing should be considered in determining subsequent incremental doses.

Fentanyl transdermal system: Select dosage with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Buccal lozenges: Doses in patients >65 years of age generally are about 200 mcg lower than those required in younger adults. Titrate the dose slowly and frequentlyreevaluate the patient for signs of central nervous system and respiratory depression.

Buccal tablets: Doses in patients >65 years of age are slightly lower than those required in younger adults. Titrate the dose slowly and frequently reevaluate the patient for signs of central nervous system and respiratory depression.

Cautions for fentaNYL

Contraindications

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

• Significant respiratory depression.

• Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.

• 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.

Warnings/Precautions

Warnings

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression can occur even when used as recommended. If not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.

Even therapeutic doses of fentanyl may decrease respiratory drive to the point of apnea in patients with COPD or cor pulmonale, and in those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. Monitor closely, particularly when initiating therapy or titrating dosage and when given concomitantly with other drugs that depress respiration.

Serious, life-threatening, or fatal respiratory depression can occur at any time during therapy with fentanyl transdermal system or transmucosal immediate-release preparations, but risk is greatest during initiation of therapy and following dosage increases. To reduce the risk of respiratory depression, proper dosing and titration is 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.

Do not switch patients from one transmucosal immediate-release fentanyl preparation (buccal lozenges, buccal tablets) on a mcg-per-mcg basis to another such preparation or to any other fentanyl preparation; do not dispense one such preparation as a substitute for another. Such substitution may result in fatal overdosage. (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related 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.

Consider prescribing naloxone for patients receiving opioid analgesics who are at increased risk of opioid overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opioid or substance use disorder, those with medical conditions that could increase sensitivity to opioid effects, those who have experienced a prior opioid overdose) or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opioid analgesic, consider prescribing naloxone if the patient is at increased risk of opioid overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opioid overdose).

Addiction, Abuse, and Misuse

As an opioid, exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients with appropriate prescribing. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing, 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 (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids, 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. Consider prescribing naloxone for the emergency treatment of opioid overdose. 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.

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing. 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 the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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 (e.g., transfer of a transdermal system from an adult to a child while hugging, exposure of individuals sharing the same bed, inadvertently sitting on a transdermal system, exposure of the caregiver’s skin to the drug during application or removal of the transdermal system, exposure to systems that were disposed of improperly). If accidental exposure occurs, remove system and wash area of contact with water.

Risk of choking or potentially fatal overdosage of fentanyl if transdermal system is placed in the mouth, chewed or swallowed, or used in other unintended ways.

Risk of fatal overdosage if transmucosal immediate-release preparations are ingested by non-opioid-tolerant individuals or individuals for whom drug was not prescribed. If accidental exposure to solid transmucosal dosage forms occurs, attempt to remove dosage form from mouth.

Accidentally exposed individuals should seek medical attention immediately.

Proper storage, handling, and disposal are essential to prevent accidental exposure. (See Advice to Patients, Administration under Dosage and Administration, and Storage under Stability.)

Interactions with CYP3A4 Inhibitors

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

Patients with Fever or Exposure to High Temperatures

Closely observe patients who develop a fever during therapy with fentanyl transdermal system for manifestations of opioid toxicity and adjust dosage accordingly; drug release from the system and percutaneous permeability of the drug are temperature dependent. Serum fentanyl concentrations theoretically could increase by approximately one-third when body temperature increases to 40°C.

Patients should avoid strenuous exertion that leads to increased core body temperature while wearing the transdermal system.

Application of heat over the fentanyl transdermal system increases mean exposure and peak plasma concentrations by 120 and 61%, respectively; fatal overdosage reported. 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 the transdermal system is being worn.

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids, including fentanyl, and 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. Substantial proportion of fatal opioid overdoses involve concurrent benzodiazepine use.

Reserve concomitant use of fentanyl and other CNS depressants for patients in whom alternative treatment options are inadequate. (See Specific Drugs and Foods under Interactions.)

Other Warnings/Precautions

Supervised Administration

Administer only under the supervision of qualified clinicians who are experienced in the use of opioids for anesthesia or the management of pain (depending on use) and in the management of respiratory effects of potent opioids.

Opioid antagonist and facilities for administration of oxygen and controlled respiration should be available during and immediately following IV administration.

Use transmucosal immediate-release formulations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) only under the supervision of qualified clinicians who are experienced in the use of schedule II (C-II) opioids for the management of cancer pain.

Use fentanyl transdermal system only under the supervision of clinicians who are experienced in continuous administration of potent opioids for the management of chronic pain.

Serotonin Syndrome

Serotonin syndrome reported during concurrent use of opioid agonists, including fentanyl, and serotonergic drugs or drugs that impair serotonin metabolism (e.g., MAO inhibitors). (See Interactions.)

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).

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opioid agonists or opioid partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opioid agonist or partial agonist to allow recovery of adrenal function. If the opioid agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opioid improved symptoms.

Head Injury and Increased Intracranial Pressure

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

May obscure the clinical course in patients with head injuries; use only if clinically warranted.

Use with extreme caution in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention or who are especially prone to respiratory depression (e.g., comatose patients; those with head injury, brain tumor, impaired consciousness, or elevated CSF pressure); monitor closely for signs of sedation and respiratory depression, particularly during initiation of therapy.

Avoid use of extended-release fentanyl (fentanyl transdermal system) in those who may be particularly susceptible to intracranial effects of carbon dioxide retention; monitor patients with brain tumors who may be susceptible to such effects for signs of sedation and respiratory depression, particularly during initiation of therapy.

Musculoskeletal Effects

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.

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.

Hypotension

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

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

Cardiac Arrhythmia

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

Interactions with MAO Inhibitors

Severe and unpredictable potentiation by MAO inhibitors may occur. Avoid use in patients who are receiving or have received MAO inhibitors within 14 days.

Seizure Disorders

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

May induce or aggravate seizures in some clinical settings.

Debilitated and Special Risk Patients

Increased risk of life-threatening respiratory depression in geriatric, cachectic, or debilitated patients because of altered pharmacokinetics. Monitor closely, especially when initiating therapy, titrating dosage, or using other respiratory depressants concomitantly.

Use with caution in patients with pulmonary disease. (See Respiratory Depression under Cautions.)

Pancreatic and Biliary Disease

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.

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opioid agonist or opioid partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.

Dental Decay

Dental decay, including caries, tooth loss, and gum line erosion, has occurred in patients receiving fentanyl citrate buccal lozenges, despite routine oral hygiene in some patients. (See Transmucosal Immediate-release Fentanyl Preparations under Advice to Patients.) Each fentanyl citrate buccal lozenge contains 2 g of sugar.

Diabetes Mellitus

Each buccal lozenge contains 2 g of sugar.

Local Reactions

Application site reactions (e.g., paresthesia, pain, ulceration, irritation, bleeding) reported in patients receiving fentanyl citrate buccal tablets; tend to occur early during treatment and generally are self-limited.

Specific Populations

Pregnancy

Category C.

Analysis of data from the National Birth Defects Prevention Study (large population-based, case-control study) suggests therapeutic use of opioids in pregnant women during organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.

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

Use of opioids during late pregnancy can result in neonatal respiratory depression.

Prolonged maternal use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts. Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity vary depending on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.

Lactation

Distributed into milk. Limited data suggest breast-fed infants receive an estimated 0.38% of the maternal weight-adjusted dosage. Potential risk (sedation, respiratory depression) to nursing infants.

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.

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

Pediatric Use

Safety and efficacy of parenteral fentanyl citrate and fentanyl transdermal systems not established in children <2 years of age.

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

Safety and efficacy of buccal tablets, sublingual tablets, sublingual spray, and nasal spray not established in patients <18 years of age.

To reduce potential for accidental ingestion, carefully select application site in young children receiving transdermal fentanyl therapy and monitor the system for proper adhesion over the period of application.

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

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. High risk of respiratory depression if a child accidentally ingests a transmucosal immediate-release preparation. (See Advice to Patients and see Accidental Exposure under Cautions.)

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. (See Geriatric Patients under Dosage and Administration.)

Clearance of IV fentanyl may be reduced. Geriatric patients may be more sensitive to effects of IV fentanyl.

Pharmacokinetics of fentanyl transdermal system in geriatric patients 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.

Dosage of buccal lozenges (following titration) generally about 200 mcg lower in geriatric patients than in younger adults. Median dosage of sublingual tablets (following titration) similar to that in younger adults. Dosage of buccal tablets (following titration) slightly lower in geriatric patients than in younger adults.

Increased frequency of certain adverse effects (e.g., vomiting, constipation, abdominal pain) reported in geriatric patients compared with younger adults receiving buccal tablets. Safety profiles of buccal lozenges, sublingual tablets, sublingual spray, and nasal spray in geriatric patients generally similar to those observed in younger adults.

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 the long half-life of this formulation, avoid use in patients with severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

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 the long half-life of this formulation, avoid use in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

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

Common Adverse Effects

Headache, nausea, vomiting, constipation, diarrhea, somnolence, confusion, asthenia, fatigue, dizziness, insomnia, anxiety, dyspnea, peripheral edema, dehydration, anemia.

IV administration: Skeletal and thoracic muscle rigidity also occur frequently.

Transdermal system: Erythema (may persist for ≥6 hours after removal of the system), papules, pruritus, and edema at application site also occur frequently.

Buccal tablets: Application site reactions (e.g., paresthesia, pain, bleeding, ulceration, irritation) also occur frequently.

Drug Interactions

Metabolized by CYP3A4.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors (macrolide antibiotics [e.g., erythromycin, troleandomycin, 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 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 selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (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), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). May occur at usual dosages. 230,240,256,704,706 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 Pharmacokinetics

Absorption

Bioavailability

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

Substantial pharmacokinetic differences exist among the transmucosal immediate-release fentanyl preparations (buccal lozenges, buccal tablets); these preparations must not be substituted on a mcg-for-mcg basis. (See Risk of Medication Errors under Cautions.)

Buccal 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.

Buccal lozenge versus buccal tablet: When administered as a buccal tablet rather than a buccal 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 patientts 65 years of age and older did not differ significantly from young 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, peak plasma concentration and AUC increased by 35 and 73%, respectively, compared with values in control patients after application of fentanyl transdermal system.

Distribution

Extent

Fentanyl is highly lipophilic.

Large single or repeated doses can result in substantial accumulation, potentially resulting in an extended duration of effect.

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

Buccal 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

Buccal Lozenges

To dispose of lozenges that are no longer needed, manufacturers recommend removing the lozenges from their 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. Do not flush handles down the toilet.

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

If unused portions cannot be disposed of immediately, store the partially used lozenge in a temporary storage bottle (supplied by the manufacturer) according to manufacturer's instructions 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 that are no longer needed, the manufacturer recommends removing the tablets from their blister packages and flushing them down the 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 the μ-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 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. 256 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 https://www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opioids, either therapeutically or illicitly;r700 r703 importance of informing patients that fentanyl should not be combined with alcohol and should not be used concomitantly with other CNS depressants (e.g., sedatives/hypnotics, tranquilizers) unless such use is supervised by clinician.

• 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 permittedby 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 while using any drugs that inhibit monoamine oxidase. 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 lifethreatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

• 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 their fentanyl preparation. Advise patients how to recognize such a reaction and when to seek medical attention.

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

• Importance of women informing 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 signs.

• 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Transmucosal Immediate-release Fentanyl Preparations

• Importance of understanding the requirements of the TIRF REMS Access program and of signing the patient-prescriber agreement mandated by the program. (See TIRF REMS Restricted Distribution Program under Dosage and Administration.)

• Importance of using transmucosal immediate-release preparations (buccal lozenges, buccal tablets) exactly as prescribed and only if opioid tolerant. 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 buccal 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 occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk. Consult your 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 andgum above a molar tooth or under the tongue and allowed to dissolve. After 30minutes if remnants of the tablet still remain, patients may swallow it with a glass ofwater.

• 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. 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.

* 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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Frequently asked questions

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