Class: Opiate Agonists
VA Class: CN101
CAS Number: 437-38-7
Brands: Abstral, Actiq, Duragesic, Fentora, Ionsys, Lazanda, Sublimaze , Subsys

Introduction

Opiate agonist; a synthetic phenylpiperidine derivative.^{b c}

Uses for Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride

Pain (Acute)

Preoperatively, during surgery, and in the immediate postoperative period parenterally for its strong analgesic action.^b

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 opiate agonist such as fentanyl.^c

IM to alleviate postoperative pain and discomfort.^{b c} However, the IV route (including patient-controlled analgesia) is preferred for administration of opiate agonists after major surgery since repeated IM injections may cause pain and trauma.^c

Transdermally as fentanyl hydrochloride iontophoretic transdermal system for short-term management of acute postoperative pain in patients requiring opiate analgesia in a hospital setting.²⁴⁸ Initiate only after acceptable analgesia has been achieved using other opiate analgesics.²⁴⁸ Use only in patients who are sufficiently alert and have adequate cognitive ability to understand directions for use.²⁴⁸ Must be discontinued prior to hospital discharge.²⁴⁸

Because of the risk of life-threatening respiratory depression, fentanyl transdermal systems (e.g., Duragesic) and transmucosal immediate-release preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) are contraindicated in the management of acute or postoperative pain.^{221 225 227 230 232 245 246 247} (See Contraindications under Cautions.)

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated.^{431 432 433 435} Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain.^{411 431 434 435} Optimize concomitant use of other appropriate therapies.^{432 434 435} (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)

Malignant (Cancer) Pain

Transdermally as fentanyl transdermal system (e.g., Duragesic) in opiate-tolerant patients for the management of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic.^{209 211 225} Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended doses, and because of the greater risks of overdose and death with extended-release opiate formulations, reserve for use when alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.²²⁵

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, opiates used around-the-clock for persistent cancer pain.^{227 230 234 245 246 247} Patient must continue receiving around-the-clock opiate therapy while receiving these transmucosal immediate-release preparations for relief of breakthrough pain.^{227 230 245 246 247}

Do not use fentanyl transdermal systems or transmucosal immediate-release preparations in patients who are not opiate tolerant.^{225 227 230 232 245 246 247}

Patients are considered opiate tolerant if they have been receiving around-the-clock opiate therapy consisting of at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for at least 1 week.^{225 227 230 245 246 247}

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.^c

Although consideration of the dependence potential of opiate 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.^c

Other Chronic Pain

Transdermally as fentanyl transdermal system (e.g., Duragesic) in opiate-tolerant patients for the management of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic.^{209 211 225} Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended doses, and because of the greater risks of overdose and death with extended-release opiate formulations, reserve for use when alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.²²⁵

Patients are considered opiate tolerant if they have been receiving around-the-clock opiate therapy consisting of at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for at least 1 week.^{225 227 230 245 246 247}

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing^{410 411 412 413} ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.^{411 412 413 414 422 429}

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).^{411 412 413 422 429}

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life^{411 423 431 432 436} or is superior to other pharmacologic or nonpharmacologic treatments.⁴³² Use is associated with serious risks (e.g., opiate use disorder, overdose).^{411 431 436} (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Anesthesia

A supplement to general or regional anesthesia, including neuroleptanalgesia in which it often is used in combination with droperidol.^{b f}

For induction and maintenance of anesthesia to provide preinduction sedation and analgesia, provide analgesia for additional vascular line placement, blunt hemodynamic and stress response to laryngoscopy and intubation, reduce requirements for other anesthetics, promote perioperative hemodynamic stability, and provide postoperative analgesia.^f

As the opiate component of balanced anesthesia or total IV anesthesia (balanced anesthesia in which the IV anesthetic completely replaces the inhalation anesthetic).^{d e}

May be especially useful preoperatively before surgery of short duration or minor surgery in outpatients and in diagnostic procedures or treatments that require the patient to be awake or very lightly anesthetized.^b

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

Tachypnea and Delirium (Postoperative)

To prevent or relieve tachypnea and postoperative emergence delirium.^b

Conscious Sedation

Previously was available for restricted use as an intrabuccal (transmucosal) premedicant (Fentanyl Oralet) prior to anesthesia or for inducing conscious sedation prior to diagnostic or therapeutic procedures in a monitored anesthesia setting.^b However, this preparation no longer is commercially available for such use in the US and the currently available buccal preparations (Actiq lozenge, Fentora tablet, generic oral transmucosal fentanyl citrate lozenge) are labeled only for management of breakthrough pain in opiate-tolerant patients with chronic cancer pain.^b

Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride Dosage and Administration

General

• FDA approved REMS programs for most fentanyl preparations; specific requirements may vary.^{227 230 245 246 247 248 249} (See REMS.)

TIRF REMS Restricted Distribution Program

• Because of the risk of misuse, abuse, addiction, and overdosage, transmucosal immediate-release fentanyl (TIRF) preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) are available only through a restricted distribution program under the TIRF REMS Access program.^{227 230 245 246 247} (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.^{227 230 245 246 247} Patient and prescriber enrollment is not required for inpatient administration (e.g., in hospitals, hospices, and long-term care facilities that prescribe for inpatient use).^{227 230 245 246 247}

• Additional information available at or 866-822-1483.^{227 230 245 246 247}

Ionsys REMS Restricted Distribution Program

• Because of the risk of respiratory depression resulting from accidental exposure, fentanyl hydrochloride iontophoretic transdermal system is available only through a restricted distribution program under the Ionsys REMS program.²⁴⁸ (See REMS.)

• Hospitals that dispense and administer the iontophoretic transdermal system must be certified and comply with the REMS requirements and must dispense this formulation for hospital use only.²⁴⁸

• Additional information available at or 877-488-6835.²⁴⁸

Extended-release/Long-acting Opiates REMS

• FDA has approved a REMS program for extended-release and long-acting opiate analgesics, including fentanyl transdermal system (e.g., Duragesic).²⁴⁹ (See REMS.)

• The REMS consists of educational programs for prescribers, information that prescribers can use when counseling patients, and a medication guide that must be dispensed with every prescription for fentanyl transdermal system.²⁴⁹

• The goals are to reduce the occurrence of addiction, unintentional overdosage, and death resulting from inappropriate prescribing, misuse, and abuse of extended-release and long-acting opiates, while maintaining patient access to these analgesics.²⁴⁹

• Additional information available at .²⁴⁹

Managing Opiate Therapy for Acute Pain

• Optimize concomitant use of other appropriate therapies.^{432 434 435}

• When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.^{411 431 434 435}

• When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.⁴³²

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).^{411 433 434 435} Do not prescribe larger quantities for use in case pain continues longer than expected;^{411 432} instead, reevaluate patient if severe acute pain does not remit.^{411 431 435}

• For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.^{430 431 432}

• Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.^{430 431}

• Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery.^{430 432} When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.^{430 431}

Managing Opiate Therapy for Chronic Noncancer Pain

• 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 opiates and formulations, coexisting diseases, and concomitant drug therapy.^{410 411 414 415 423}

• Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction;^{411 412 413 415 422 429} establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.^{411 415}

• Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.^{411 412 413}

• Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.^{411 412 413 414 415}

• Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage.^{411 415} Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.^{412 413} Fentanyl transdermal system should be prescribed only by clinicians familiar with absorption characteristics and dosing of this formulation.⁴¹¹

• Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase^{411 413} and reevaluate on ongoing basis (e.g., at least every 3 months⁴¹¹ ) throughout therapy.^{411 412 413} Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.^{412 413 422 423} Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment).^{412 413 415} If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.^{411 412 413 415}

• When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks.^{412 413} Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.^{412 413 415}

• Higher dosages require particular caution,^{410 412 415} including more frequent and intensive monitoring or referral to specialist.^{411 412 413} Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, opiate use disorder).^{411 415 423 424 425 426}

• 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.⁴¹¹ Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.^{423 431} Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended)^{411 420 421 423} or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).^{411 419 423}

• Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.^{410 411 412 413 414 415 422 423 429}

• Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion.^{412 413 415} Offer or arrange treatment for patients with opiate use disorder.^{411 412 413}

• Consider providing concomitant naloxone for patients at increased risk of opiate overdosage (e.g., those with history of overdose or substance use disorder, those receiving ≥50 mg of morphine sulfate [or equivalent] daily, those receiving benzodiazepines concomitantly, those with medical conditions that could increase sensitivity to opiate effects).^{411 431}

Administration

Administer by IM or IV injection or by IV infusion.^{b d f}

Administer transmucosally as a buccal lozenge, buccal tablet, sublingual tablet, sublingual spray, or nasal spray.^{227 230 245 246 247 b}

Administer percutaneously by topical application of a transdermal system or iontophoretic transdermal system.^{225 248}

Preservative-free injections have been administered epidurally†.^b

Intrabuccal Administration

Administer intrabuccally as buccal lozenge or buccal tablet.^{227 230}

Carefully instruct patients in the proper use and disposal of the buccal lozenges and buccal tablets.^{227 230} (See Storage under Stability and see Advice to Patients.)

If signs of excessive opiate 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.^{227 230}

Buccal Lozenges

Cut lozenge package open with scissors just prior to administration.²²⁷

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.²²⁷ The lozenge occasionally may be moved from one side to the other using the handle.²²⁷

Usually consumed over a period of 15 minutes; longer or shorter consumption times may result in reduced efficacy.²²⁷

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.²²⁷ Unused portions may contain sufficient amounts of fentanyl to be fatal to a child.²²⁷

Buccal Tablets

Bend and tear along the blister card perforations to separate a single blister unit.²³⁰ 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.²³⁰

Do not split buccal tablets.²³⁰

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.^{230 234} Alternate sides of the mouth with each intrabuccal dose.²³⁰

Alternatively, once an effective dose has been established, the buccal tablets may be administered sublingually.²³⁰

Leave the buccal tablet between the upper cheek and gum or under the tongue until it has disintegrated (generally 14–25 minutes).^{230 234} If the buccal tablet has not completely disintegrated after 30 minutes, the remnants may be swallowed with a glass of water.^{230 234} Disintegration time does not appear to affect early systemic exposure to the drug.²³⁰

Sublingual Administration

Administer sublingually as sublingual tablets or sublingual spray.^{245 247}

Carefully instruct patients in the proper use and disposal of the sublingual tablets and sublingual spray.^{245 247} (See Storage under Stability and see Advice to Patients.)

Manufacturer states that buccal tablets also may be administered sublingually once an effective dose has been established.²³⁰ (See Intrabuccal Administration under Dosage and Administration.)

Sublingual Tablets

Immediately prior to administration, separate a single blister unit from the blister card and then peel the backing to gently remove the tablet; do not push the sublingual tablet through the blister.²⁴⁵

Place the sublingual tablet on the floor of the mouth directly under the tongue as far back as possible.²⁴⁵ If >1 tablet is required, spread the tablets around the floor of the mouth under the tongue.²⁴⁵

Allow the sublingual tablet(s) to dissolve completely in the sublingual cavity; tablets should not be chewed, sucked, or swallowed.²⁴⁵ Patients should not eat or drink until dissolution is complete.²⁴⁵

Patients with a dry mouth may moisten the buccal mucosa with water before administering the sublingual tablets.²⁴⁵

Sublingual Spray

Immediately prior to administration, open a blister package containing a single-use spray unit with scissors.²⁴⁷ Carefully spray the contents of the unit (100, 200, 400, 600, or 800 mcg of fentanyl) into the mouth underneath the tongue.²⁴⁷ Patient should hold the drug under the tongue for 30–60 seconds.²⁴⁷ Patient should not spit out the drug or rinse the mouth.²⁴⁷ The spray unit will remain locked after use.²⁴⁷

Immediately after use, properly dispose of the used spray unit.²⁴⁷ (See Sublingual Spray under Stability.) Consumed units may contain sufficient amounts of fentanyl to be fatal to a child.²⁴⁷

Consult patient instructions in the medication guide for additional information about administration.²⁴⁷

Intranasal Administration

Administer by nasal inhalation as an aqueous solution using a metered-dose spray pump.²⁴⁶

Carefully instruct patients in the proper use and disposal of the nasal spray pump.²⁴⁶ (See Storage under Stability and see Advice to Patients.)

Prior to initial use, prime the nasal spray pump by actuating the device 4 times into the carbon-lined disposal pouch provided by the manufacturer.²⁴⁶ If the inhaler has not been used for ≥5 days, prime the pump again by actuating it 1 time into the disposal pouch.²⁴⁶

To administer a dose, insert the nozzle of the bottle about ½ inch (1 cm) into the nostril, pointing the nozzle toward the bridge of the nose and tilting the bottle slightly.²⁴⁶ Depress the finger grips firmly until a click is audible and the number in the counting window advances by one.²⁴⁶ The patient may not feel the mist on the nasal mucous membranes.²⁴⁶

If the prescribed dose requires >1 spray into one nostril, alternate nostrils with each spray.²⁴⁶

Patients should remain seated for at least 1 minute after administering the drug.²⁴⁶

Consult the patient instructions in the medication guide for additional information about administration.²⁴⁶

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

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

Administer by direct IV injection, IV infusion, or IV via a controlled-delivery device for patient-controlled analgesia (PCA).^{b d f}

Dilution

May give undiluted as direct IV injection.^{b d}

May dilute in a compatible IV solution for infusion.^HID (See Solution Compatibility under Stability.)

Rate of Administration

Direct IV injection: Usually, slowly over several (e.g., 1–2) minutes.^d Occasionally, over <1 minute (e.g., for high-dose opiate anesthesia).^f

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.^f

IV infusion: Usually, slowly^d but occasionally rapidly (e.g., for high-dose opiate anesthesia).^f

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

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.^d

IM Injection

May administer by IM injection.^b However, IM administration of opiate analgesics is discouraged; IM injections can cause pain and are associated with unreliable absorption, resulting in inconsistent analgesia.⁴³⁰

Transdermal Administration

Carefully instruct patients in the proper use and disposal of fentanyl transdermal system (e.g., Duragesic).^{225 241} (See Storage under Stability and see Advice to Patients.)

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.²⁴²

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.^{225 242} 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.^{225 242}

Clip, not shave, hair at the application site prior to application.^{225 242}

Use only clear water if the site must be cleaned before transdermal application;^{225 242} do not use soaps, oils, lotions, alcohol, or any other agents that could irritate the skin or alter its characteristics.^{225 242}

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).^{225 242}

Avoid contact with unwashed or unclothed application sites; such contact can result in secondary exposure to the drug.²²⁵

Patients or caregivers who apply the transdermal system should wash their hands with soap and water immediately after application.²²⁵

Each transdermal system may be worn continuously for 72 hours; apply subsequent systems to a different site after removal of the previous system.^{225 242}

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.^{225 242} The edges of the system may be taped in place with first-aid tape if the patient experiences difficulty with system adhesion.^{225 242} If adhesion problems persist, a transparent adhesive film dressing (e.g., Bioclusive, Tegaderm) may be applied over the system.^{225 242}

Patients may bathe, shower, or swim while wearing transdermal systems,²⁴² 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.^{225 229 241} (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.^{225 242} Used systems may contain sufficient fentanyl to be fatal to children, pets, or other adults for whom the drug was not prescribed.²⁴²

Iontophoretic Transdermal Administration

Use fentanyl hydrochloride iontophoretic transdermal system (Ionsys) only in hospital settings for the management of acute postoperative pain.²⁴⁸ System must be removed before patient leaves the hospital.²⁴⁸

Carefully instruct patients in the proper use of the iontophoretic transdermal system.²⁴⁸ (See Advice to Patients.) Use only in patients who are alert enough and have adequate cognitive ability to understand the directions for use; only the patient should activate the device to administer a dose.²⁴⁸

A health care professional must observe the first dose to ensure that the device is functioning properly and that the patient understands how to operate the device.²⁴⁸

Each system is operational for 24 hours following assembly or until 80 doses have been delivered, whichever comes first.²⁴⁸

Apply only one system at a time.²⁴⁸ If continued therapy is desired following removal of one system, apply a new system at a different site.²⁴⁸

Gloves must be worn when handling the iontophoretic transdermal system; accidental contact with the hydrogels on the adhesive side of the system can result in fatal overdosage.²⁴⁸ If accidental contact with the skin occurs, rinse affected area thoroughly with water; do not use soap, alcohol, or other solvents since they may enhance percutaneous absorption of fentanyl.²⁴⁸

Assembly and Application

Remove the foil pouch and controller from the tray, then remove the drug unit from the pouch and place it on a hard flat surface.²⁴⁸ Align the matching shapes of the drug unit and controller and press both ends of the device to fully engage the snaps at each end.²⁴⁸ Following assembly, the digital display of the controller completes a self-test and then the system can be applied to the patient's skin.²⁴⁸

Do not use the system if the seal of the tray or drug unit pouch is broken or damaged.²⁴⁸

If necessary, clip (do not shave) hair at the intended application site.²⁴⁸ Cleanse the site with alcohol and allow to dry prior to application; do not use soaps, lotions, or other agents.²⁴⁸

Just prior to application, remove and discard the clear plastic liner covering the adhesive and hydrogels, taking care not to pull the red tab that is used when separating the device for disposal.²⁴⁸

Apply the system to healthy unbroken skin on the chest or upper outer aspect of either arm; with the adhesive side of the system touching the skin and the fingers placed along the edge of the system (taking care not to press the dosing button), press system firmly in place for ≥15 seconds, ensuring that the system adheres to the skin.²⁴⁸

If an iontophoretic system loosens from the skin, secure it to the patient’s skin by pressing the edges with the fingers or securing with a nonallergenic tape to ensure that all edges make complete contact with the skin.²⁴⁸ Apply the tape along the long edges of the system; do not apply tape over the dosing button, light, or digital display.²⁴⁸ Do not apply tape to blistered or broken skin.²⁴⁸

Consult manufacturer's prescribing information for additional information about assembly and application of the device.²⁴⁸

Operation of Device

Each activation of the device provides a 40-mcg dose over a 10-minute period.²⁴⁸ To initiate administration, the patient must press and release the dosing button on the device twice within 3 seconds.²⁴⁸ During delivery of one dose, the system is locked and will not respond to additional attempts to activate the device.²⁴⁸

The iontophoretic transdermal system delivers a maximum of 6 doses per hour and 80 doses per 24 hours (40 mcg per dose).²⁴⁸

Visual displays and audible beeps indicate the number of doses delivered and the functional status of the device.²⁴⁸

Consult manufacturer's prescribing information for additional information about operation of the device and troubleshooting device malfunction.²⁴⁸

Removal of Iontophoretic Transdermal System

Iontophoretic transdermal system may be removed at any time.²⁴⁸ Once a system has been removed, the same system must not be reapplied.²⁴⁸ Following 24 hours of use or delivery of 80 doses, the system is deactivated and should be removed.²⁴⁸

Handle the used system by the sides and top to avoid contact with the hydrogels.²⁴⁸ If either hydrogel becomes separated from the system during removal, use gloves or tweezers to remove the hydrogel from the skin; dispose of the hydrogel in accordance with the institution's procedures for controlled substance disposal.²⁴⁸

Following removal of the device from the skin, pull the red tab to separate the 2 housing units.²⁴⁸ The used bottom housing unit contains sufficient fentanyl to cause fatal overdosage.²⁴⁸ Fold the bottom housing unit in half with the adhesive side facing inward and dispose of in accordance with the institution's procedures for disposal of controlled substances.²⁴⁸ Depress the dosing button until the display goes blank and discard the remaining part of the system containing electronics in waste designed for batteries.²⁴⁸

Precautions Involving Medical Procedures and Equipment

The iontophoretic transdermal system is considered unsafe during magnetic resonance imaging (MRI) procedures and may be damaged by strong electromagnetic fields; remove the system prior to MRI or other radiographic imaging procedures, cardioversion, defibrillation, or diathermy.²⁴⁸

To prevent damage of the iontophoretic transdermal system, avoid contact with synthetic materials (e.g., carpeted flooring) during assembly and avoid exposure to electronic security systems.²⁴⁸

The recommended separation distance between the iontophoretic transdermal system and communications equipment or radio frequency identification (RFID) transmitters depends on the rated maximum output power and frequency of the transmitter.²⁴⁸ (See Incompatibility of Iontophoretic Transdermal Systems with Certain Medical Procedures and Equipment under Cautions.)

Epidural Administration

Preservative-free injections have been injected or infused epidurally†; 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.^b

Dosage

Available as fentanyl, fentanyl citrate, and fentanyl hydrochloride; dosage expressed in terms of fentanyl.^{225 227 230 245 246 247 248 b}

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.^{411 413 431 432 435}

Reduced dosage is indicated initially in poor-risk patients and geriatric patients.^b (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.^{700 703} (See Specific Drugs under Interactions.)

Individualize dosage of fentanyl according to the clinical status of the patient, desired therapeutic effect, and age and weight.^{225 227 228 230 d} The most important factor in determining the appropriate dose of transdermal fentanyl is the degree of existing opiate tolerance.²²⁵

Pediatric Patients

Anesthesia and Analgesia

IV or IM

Neonates and infants, anesthesia and analgesia: 1–4 mcg/kg per dose IV, repeated every 2–4 hours as needed, or continuous IV infusion of 0.5–5 mcg/kg per hour.^g

Children 2–12 years of age, anesthesia induction and maintenance phase: Usually, 1.7–3.3 mcg/kg IV or IM.^{b d}

Children 2–12 years of age, analgesia: Usually, 1–3 mcg/kg IV or IM, repeated every 30–60 minutes as needed, or continuous IV infusion of 1–5 mcg/kg per hour.^f

Children >12 years of age, analgesia: 0.5–1 mcg/kg IV or IM, repeated every 30–60 minutes as needed.^g

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.^f

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.^f

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 opiate tolerant.²²⁵ (See Uses.) Risk of fatal respiratory depression when administered to patients not already opiate tolerant.²²⁵ (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.²²⁵ Fatal overdosage possible with the first transdermal dose if the dosage is overestimated.²²⁵

Discontinue all other around-the-clock opiate analgesics when therapy with fentanyl transdermal system is initiated.²²⁵

The manufacturers provide specific dosage recommendations for switching opiate-tolerant children ≥2 years of age from certain oral or parenteral opiates to fentanyl transdermal system (see Table 8 and Table 9).²²⁵

Alternatively, to switch children ≥2 years of age who currently are receiving other opiate therapy or dosages that are not listed in Table 8 or Table 9 to fentanyl transdermal system, calculate the opiate analgesic requirements during the previous 24 hours.²²⁵ Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using a reliable source.²²⁵ Finally, calculate the equivalent dosage of fentanyl transdermal system using Table 10.²²⁵

The manufacturers consider the initial dosages of transdermal fentanyl in Tables 8, 9, and 10 to be conservative estimates.²²⁵ Do not use the dosage conversion guidelines in these tables to switch patients from fentanyl transdermal system to oral or parenteral opiates, since dosage of oral or parenteral opiates may be overestimated.²²⁵

For transdermal dosages >100 mcg/hour, apply multiple systems at different sites simultaneously.²²⁵

Dosing intervals <72 hours have not been evaluated in children and adolescents and cannot be recommended in this population.²²⁵

Because of substantial interpatient variability in relative potency of opiate analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opiate requirements and provide “rescue” therapy with an immediate-release opiate analgesic than to overestimate the requirements and manage an adverse reaction.²²⁵

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).²²⁵

If analgesia is inadequate after initial application, dosage may be titrated upward after 3 days.²²⁵

Give supplemental doses of a short-acting opiate as needed during the initial application period and subsequently thereafter as necessary to relieve breakthrough pain.²²⁵

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 opiates during the second or third day after initial application.²²⁵

Because subsequent equilibrium with an increased dosage may require up to 6 days to achieve, make further increases in dosage based on supplemental opiate requirements no more frequently than every 6 days (i.e., after two 72-hour application periods with a given dosage).²²⁵

To convert supplemental opiate 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.²²⁵

If unacceptable adverse effects are observed, decrease subsequent dosage.²²⁵

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.²²⁵

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.²²⁵

During long-term therapy, continually reevaluate need for continued opiate therapy.²²⁵

Discontinuance of Transdermal Fentanyl Therapy

Transdermal (e.g., Duragesic)

To switch to another opiate, remove the fentanyl transdermal system and titrate the dosage of the other opiate according to patient response.²²⁵

Substantial amounts of fentanyl continue to be absorbed from the skin for ≥24 hours after removal of the transdermal system.²²⁵ It generally takes 20–27 hours for serum fentanyl concentrations to decline by 50% following removal of the system.²²⁵

Symptoms of withdrawal (e.g., nausea, vomiting, diarrhea, anxiety, shivering) may occur in some patients after switching to another opiate agonist or following discontinuance of the fentanyl transdermal system.^{225 229}

When transdermal fentanyl is discontinued and another opiate analgesic is not initiated, withdraw fentanyl gradually (e.g., reduce dosage by 50% every 6 days) to avoid precipitation of withdrawal symptoms.²²⁵ Dosage level at which transdermal fentanyl may be discontinued without producing withdrawal symptoms is not known.²²⁵

Adults

Analgesia

IM or IV

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

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

Alternatively for analgesia: 0.5–1 mcg/kg IM or IV, repeated every 30–60 minutes as needed.^g

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.^f

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.^f

Anesthesia

Adjunct to General Anesthesia

IV or IM

May be given in low-dose, moderate-dose, or high-dose regimens.^{b d}

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

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.^{b d}

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.^{b d}

IV Infusion

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

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

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

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

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.^b

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.^b

Postoperative Pain, Restlessness, Tachypnea, and Emergence Delirium

IM

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

Postoperative Pain

Transdermal (Iontophoretic transdermal system [Ionsys])

Iontophoretic transdermal system provides a 40-mcg dose over a 10-minute period following each activation of the device.²⁴⁸ During delivery of one dose, the system is locked and will not respond to additional attempts to activate the device.²⁴⁸

Initiate iontophoretic transdermal therapy only after the patient has achieved acceptable analgesia for postoperative pain with other opiate analgesics.²⁴⁸

Use only one system at a time; if analgesia is inadequate, initiate supplemental or alternative analgesic therapy.²⁴⁸

Iontophoretic transdermal system delivers a maximum of 6 doses per hour and 80 doses per 24 hours.²⁴⁸ Each system is operational for 24 hours following assembly or until 80 doses have been delivered, whichever comes first.²⁴⁸ Maximum recommended duration of iontophoretic transdermal therapy is 72 hours.²⁴⁸

If continued analgesic therapy is required following discontinuance of iontophoretic transdermal therapy, titrate dosage of the new analgesic until adequate analgesia is obtained, keeping in mind that serum fentanyl concentrations will decline slowly following removal of the iontophoretic transdermal system.²⁴⁸ During the analgesic conversion period, monitor for respiratory and CNS depression.²⁴⁸

Breakthrough Malignant (Cancer) Pain in Opiate-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.²²⁷ (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opiate tolerant.²²⁷ (See Malignant [Cancer] Pain under Uses.) Patients must continue receiving around-the-clock opiate analgesic therapy while receiving the buccal lozenges for breakthrough pain.²²⁷

Initially, 200 mcg for breakthrough episode in all patients.²²⁷

Prescribe 6 lozenges initially; use all 6 lozenges for various breakthrough episodes before increasing the dose.²²⁷ To reduce risk of overdosage, patient should have only one strength of lozenges available for use at any one time.²²⁷

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.²²⁷

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).²²⁷

Maximum of 2 lozenges per breakthrough pain episode may be given, if necessary, during dosage titration phase.²²⁷

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.²²⁷

During titration phase, evaluate each new dose over several breakthrough pain episodes to determine efficacy and tolerability.²²⁷

After treating one episode of breakthrough pain, patient must wait ≥4 hours before treating a subsequent episode of breakthrough pain with the buccal lozenges.²²⁷

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.²²⁷

Once an appropriate dose has been achieved, patients generally should use only 1 lozenge of the appropriate strength per episode of breakthrough pain.²²⁷ 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.²²⁷

During maintenance therapy, generally increase dosage only if several consecutive episodes require >1 lozenge of the current dose for pain relief.²²⁷

If patient experiences >4 breakthrough pain episodes daily, reevaluate dosage of opiates used around the clock for chronic cancer pain.²²⁷

When opiate therapy is discontinued, gradually taper the opiate dosage to avoid manifestations associated with abrupt withdrawal.²²⁷ Dosage level at which the buccal lozenges may be discontinued without producing manifestations of opiate withdrawal is not known.²²⁷

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.²³⁰ (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opiate tolerant.²³⁰ (See Malignant [Cancer] Pain under Uses.) Patients must continue receiving around-the-clock opiate analgesic therapy while receiving the buccal tablets for breakthrough pain.²³⁰

Initially, 100 mcg for breakthrough episode in all patients except those being switched from fentanyl citrate buccal lozenges.^{230 232 234}

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 2).²⁴⁵ Instruct patients to discontinue use of the buccal lozenges and to dispose of any remaining lozenges.²³⁰

Manufacturer states that these doses should be considered starting doses for the buccal tablets and are not intended to represent equianalgesic doses.^{230 232}

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.^{230 232} 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.²³⁰

Titrate dosage with close monitoring to a level that provides adequate analgesia with acceptable adverse effects.^{230 232}

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.²³⁰

During dosage titration, 1 dose may include administration of 1–4 tablets of the same strength.²³⁰ Administer no more than 4 tablets simultaneously.²³⁰ 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.²³⁰

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.²³⁰ 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).²³⁰ If doses >400 mcg (i.e., doses of 600 or 800 mcg) are required, titrate dosage using multiples of 200-mcg tablets.²³⁰

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 2]), titrate buccal tablet dosage using multiples of 200-mcg tablets.²³⁰

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.^{230 232 234} 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.^{230 232}

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.^{230 232}

During titration phase, evaluate each new dose over several breakthrough pain episodes to determine efficacy and tolerability.²³⁰

Once titrated to an adequate dose, breakthrough pain episodes generally should be treated effectively with 1 buccal tablet.^{230 232} 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.²³⁰

Some patients may require adjustment of the intrabuccal fentanyl dosage to maintain effective analgesia for breakthrough pain episodes;²³⁰ however, dosage generally should be increased only if several consecutive episodes require administration of >1 intrabuccal dose for pain relief.^{230 232}

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.^{230 232 234}

If patient experiences >4 breakthrough pain episodes daily, reevaluate dosage of opiates used around the clock for chronic cancer pain.^{230 232}

Presence of grade 1 mucositis does not appear to substantially alter absorption or adverse effects of the buccal tablets.^{230 253}

When opiate therapy is discontinued, gradually taper the opiate dosage to avoid manifestations associated with abrupt withdrawal.^{225 227 230} Dosage level at which the buccal tablets may be discontinued without producing manifestations of opiate withdrawal is not known.²³⁰

Sublingual (Sublingual tablets [Abstral])

Because of differences in pharmacokinetic properties, do not switch patients on a mcg-per-mcg basis from any other fentanyl preparation to the sublingual tablets; sublingual tablets are not equivalent to other fentanyl preparations and are not a generic version of any other fentanyl preparation.²⁴⁵ (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opiate tolerant.²⁴⁵ (See Malignant [Cancer] Pain under Uses.) Patients must continue receiving around-the-clock opiate analgesic therapy while receiving the sublingual tablets for breakthrough pain.²⁴⁵

Initially, 100 mcg for breakthrough episode in all patients except those being switched from fentanyl citrate buccal lozenges.²⁴⁵ If adequate analgesia is not achieved with the first 100-mcg dose, titrate dosage in a stepwise manner (see Table 3) with close monitoring to a level that provides adequate analgesia and acceptable adverse effects.²⁴⁵

In patients being switched from the buccal lozenges to the sublingual tablets, base the initial sublingual tablet dose on the current buccal lozenge dose (see Table 4).²⁴⁵ Instruct patient to discontinue use of the buccal lozenges and dispose of any remaining lozenges.²⁴⁵ If adequate analgesia is not achieved with the initial dose of sublingual tablets, initiate dosage titration with close monitoring using a sublingual tablet strength of 100 mcg in patients receiving a buccal lozenge dose of 200 mcg, a sublingual tablet strength of 200 mcg in those receiving a buccal lozenge dose of 400, 600, 800, or 1200 mcg, or a sublingual tablet strength of 400 mcg in those receiving a buccal lozenge dose of 1600 mcg; then proceed with titration in multiples of the initial sublingual tablet strength.²⁴⁵

During dosage titration, patients can use multiples of 100- and/or 200-mcg tablets for any single dose; however, no more than 4 tablets should be administered at one time.²⁴⁵

During dosage titration, if breakthrough pain is not relieved within 30 minutes following the initial sublingual tablet dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.²⁴⁵ No more than 2 doses of the sublingual tablets may be given during a single episode of breakthrough pain.²⁴⁵ Patients must wait ≥2 hours before treating a subsequent episode of breakthrough pain with the sublingual tablets.²⁴⁵ Patients may use a rescue analgesic as directed by their clinician if the sublingual tablets do not provide adequate pain relief.²⁴⁵

Safety and efficacy of sublingual tablet doses >800 mcg not established in clinical trials.²⁴⁵

Once an appropriate dose has been achieved, patients should use only 1 sublingual tablet of the appropriate strength per episode of breakthrough pain.²⁴⁵ On occasion during maintenance therapy, when a breakthrough pain episode is not relieved within 30 minutes after the first sublingual dose, patient may take only 1 additional dose during that episode of breakthrough pain.²⁴⁵ After treating one episode of breakthrough pain with the sublingual tablets, patient must wait ≥2 hours before treating a subsequent episode of breakthrough pain with the sublingual tablets.²⁴⁵

If response (analgesia or adverse reactions) to the titrated sublingual tablet dosage changes markedly, dosage adjustment may be necessary.²⁴⁵ If the patient experiences >4 breakthrough pain episodes daily, reevaluate the dosage of opiates used around the clock for chronic cancer pain.²⁴⁵ If the long-acting opiate or the dosage of the long-acting opiate is changed, reevaluate the sublingual tablet dosage and re-titrate as necessary.²⁴⁵ Limit use of the sublingual tablets to no more than 4 episodes of breakthrough pain daily.²⁴⁵

In patients no longer requiring opiate analgesia, consider discontinuing the sublingual tablets along with the gradual tapering of other opiate analgesics to avoid manifestations of abrupt opiate withdrawal.²⁴⁵

In patients who continue to take around-the-clock opiate analgesics for persistent pain but no longer require treatment for breakthrough pain, the sublingual tablets generally can be discontinued immediately.²⁴⁵

Sublingual (Sublingual spray [Subsys])

Because of differences in pharmacokinetic properties, do not switch patients on a mcg-per-mcg basis from any other fentanyl preparation to the sublingual spray; sublingual spray is not equivalent to other fentanyl preparations.²⁴⁷ (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opiate tolerant.²⁴⁷ (See Malignant [Cancer] Pain under Uses.) Patients must continue receiving around-the-clock opiate analgesic therapy while receiving the sublingual spray for breakthrough pain.²⁴⁷

Initially, 100 mcg for breakthrough episode in all patients except those being switched from fentanyl citrate buccal lozenges.²⁴⁷ If adequate analgesia is not achieved with the first 100-mcg dose, titrate dosage in a stepwise manner (see Table 5) with close monitoring to a level that provides adequate analgesia and acceptable adverse effects with a single dose per episode of breakthrough pain.²⁴⁷

In patients being switched from fentanyl citrate buccal lozenges to the sublingual spray, base the initial sublingual spray dose on the current buccal lozenge dose (see Table 6).²⁴⁷ Instruct patient to stop using the buccal lozenges and dispose of any remaining lozenges.²⁴⁷ If adequate analgesia is not achieved with the initial dose of the sublingual spray, initiate dosage titration using a sublingual spray strength of 100 mcg in patients receiving a buccal lozenge dose of ≤400 mcg, a sublingual spray strength of 200 mcg in those receiving a buccal lozenge dose of 600 or 800 mcg, or a sublingual spray strength of 400 mcg in those receiving a buccal lozenge dose of 1200 or 1600 mcg; then proceed to titrate dosage in multiples of the initial spray unit strength.²⁴⁷

Instruct patient to record sublingual spray use over several episodes of breakthrough pain and to discuss their experience with their clinician to decide whether dosage adjustment is warranted.²⁴⁷

During dosage titration, patients should have only one strength of sublingual spray available at any time.²⁴⁷

During dosage titration period, if breakthrough pain is not relieved within 30 minutes following the initial sublingual dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.²⁴⁷ No more than 2 doses of the sublingual spray may be given during a single episode of breakthrough pain.²⁴⁷ Patients must wait ≥4 hours before treating a subsequent episode of breakthrough pain with fentanyl sublingual spray.²⁴⁷

Once an appropriate dose has been achieved, patients generally should use only 1 dose of the appropriate strength per episode of breakthrough pain.²⁴⁷ On occasion during maintenance therapy, when a breakthrough pain episode is not relieved within 30 minutes after the first sublingual dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.²⁴⁷ After treating one episode of breakthrough pain with the sublingual spray, patients must wait ≥4 hours before treating a subsequent episode of breakthrough pain with the sublingual spray.²⁴⁷ Once an appropriate dose has been achieved, patients should administer no more than 4 doses of fentanyl sublingual spray daily.²⁴⁷

Some patients may require adjustment of sublingual spray dosage to maintain effective analgesia; generally increase dosage only if several consecutive episodes require administration of >1 sublingual dose for pain relief.²⁴⁷ If a single sublingual spray dose produces excessive opiate effects, decrease subsequent doses.²⁴⁷ If the patient experiences >4 breakthrough pain episodes daily, reevaluate the dosage of opiates used around the clock for persistent cancer pain.²⁴⁷ If pain worsens, reevaluate the patient's condition.²⁴⁷

Patients with grade 2 mucositis should not receive fentanyl sublingual spray unless the benefits outweigh the potential risk of respiratory depression from increased drug exposure.²⁴⁷ Closely monitor those with grade 1 mucositis, especially during treatment initiation.²⁴⁷ (See Special Populations under Pharmacokinetics: Absorption.)

Intranasal (Nasal spray [Lazanda])

Because of differences in pharmacokinetic properties and individual variability, do not switch patients on a mcg-per-mcg basis from any other fentanyl preparation to the nasal spray; nasal spray is not equivalent to other fentanyl preparations and is not a generic version of other fentanyl preparations.²⁴⁶ (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Use only in patients who are opiate tolerant.²⁴⁶ (See Malignant [Cancer] Pain under Uses.) Patients must continue receiving around-the-clock opiate analgesic therapy while receiving the nasal spray for breakthrough pain.²⁴⁶

After initial priming (4 sprays), each nasal inhaler delivers eight 100-µL sprays, each containing 100, 300, or 400 mcg of fentanyl per metered spray.²⁴⁶

Initially, 100 mcg (1 spray) in one nostril for breakthrough episode in all patients, including those switching from therapy with another fentanyl preparation.²⁴⁶

If adequate analgesia is obtained within 30 minutes following the initial 100-mcg dose, confirm efficacy of the 100-mcg dose in the next episode of breakthrough pain.²⁴⁶ If adequate, use this dose for subsequent episodes of breakthrough pain.²⁴⁶

If adequate analgesia is not achieved with the initial 100-mcg dose, increase dosage in stepwise manner (see Table 7) with careful monitoring over consecutive episodes of breakthrough pain to achieve adequate analgesia with acceptable adverse effects.²⁴⁶ Once an appropriate dose has been established, use that dose for each subsequent episode of breakthrough pain.²⁴⁶

Safety and efficacy of doses >800 mcg not established in clinical trials.²⁴⁶

Do not combine different dosage strengths to treat a single episode of breakthrough pain; this could result in dosage errors.²⁴⁶

Patient must wait ≥2 hours after treating one episode of breakthrough pain with the nasal spray before treating a subsequent episode of breakthrough pain with the nasal spray.²⁴⁶

Do not use the nasal spray to treat >4 episodes of breakthrough pain daily.²⁴⁶

Patient may use a rescue analgesic (as directed by clinician) if breakthrough pain is not relieved within 30 minutes following a nasal spray dose or if a separate episode of breakthrough pain occurs before the next nasal spray dose is permitted.²⁴⁶

If response (analgesia or adverse reactions) to the titrated nasal spray dosage changes markedly, dosage adjustment may be necessary.²⁴⁶ If the patient experiences >4 breakthrough pain episodes daily, reevaluate the dosage of opiates used around the clock for chronic cancer pain.²⁴⁶ If the long-acting opiate or the dosage of the long-acting opiate is changed, reevaluate the nasal spray dosage and re-titrate as necessary.²⁴⁶

In patients no longer requiring opiate analgesia, consider discontinuing the nasal spray along with gradual tapering of other opiate analgesics to avoid manifestations of abrupt opiate withdrawal.²⁴⁶

In patients who continue to take around-the-clock opiates for persistent pain but no longer require treatment for breakthrough pain, nasal spray generally can be discontinued immediately.²⁴⁶

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 opiate tolerant.²²⁵ (See Uses.) Risk of fatal respiratory depression when administered to patients not already opiate tolerant.²²⁵ (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.²²⁵ Fatal overdose possible with the first transdermal dose if the dosage is overestimated.²²⁵

Discontinue all other around-the-clock opiate analgesics when therapy with fentanyl transdermal system is initiated.²²⁵

The manufacturers provide specific dosage recommendations for switching opiate-tolerant patients from certain oral or parenteral opiates to fentanyl transdermal system (see Table 8 and Table 9).²²⁵

Alternatively, to switch patients who currently are receiving other opiate therapy or dosages that are not listed in Table 8 or Table 9 to fentanyl transdermal system, calculate the opiate analgesic requirements during the previous 24 hours.²²⁵ Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using a reliable source.²²⁵ Finally, calculate the equivalent dosage of fentanyl transdermal system using Table 10.²²⁵

The manufacturers consider the initial dosages of transdermal fentanyl in Tables 8, 9, and 10 to be conservative estimates.²²⁵ Do not use the dosage conversion guidelines in these tables to switch patients from fentanyl transdermal system to oral or parenteral opiates, since dosage of oral or parenteral opiates may be overestimated.²²⁵

For transdermal dosages >100 mcg/hour, apply multiple systems at different sites simultaneously.²²⁵

Because of substantial interpatient variability in relative potency of opiate analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opiate requirements and provide “rescue” therapy with an immediate-release opiate analgesic than to overestimate the requirements and manage an adverse reaction.²²⁵

If overdosage occurs, monitor patient for at least 72–96 hours because of long elimination half-life of this formulation (20–27 hours).²²⁵

If analgesia is inadequate after initial application, dosage may be titrated upward after 3 days.²²⁵

Give supplemental doses of a short-acting opiate as needed during the initial application period and subsequently thereafter as necessary to relieve breakthrough pain.²²⁵

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 opiates during the second or third day after initial application.²²⁵

Because subsequent equilibrium with an increased dosage may require up to 6 days to achieve, make further increases in dosage based on supplemental opiate requirements no more frequently than every 6 days (i.e., after two 72-hour application periods with a given dosage).²²⁵

To convert supplemental opiate 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.²²⁵

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.²²⁵ 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.²²⁵

If unacceptable adverse effects are observed, decrease subsequent dosage.²²⁵

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.²²⁵

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.²²⁵

During long-term therapy, continually reevaluate need for continued opiate therapy.²²⁵

Discontinuance of Transdermal Fentanyl Therapy

Transdermal (e.g., Duragesic)

To switch to another opiate, remove the fentanyl transdermal system and titrate the dosage of the other opiate according to patient response.²²⁵

Substantial amounts of fentanyl continue to be absorbed from the skin for ≥24 hours after removal of the transdermal system.²²⁵ It generally takes 20–27 hours or serum fentanyl concentrations to decline by 50% following removal of the system.²²⁵

Symptoms of withdrawal (e.g., nausea, vomiting, diarrhea, anxiety, shivering) may occur in some patients after switching to another opiate agonist or following discontinuance of the fentanyl transdermal system.^{225 229}

When transdermal fentanyl is discontinued and another opiate analgesic is not initiated, withdraw fentanyl gradually (e.g., reduce dosage by 50% every 6 days) to avoid precipitation of withdrawal symptoms.²²⁵ Dosage level at which transdermal fentanyl may be discontinued without producing withdrawal symptoms is not known.²²⁵

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 opiate analgesia (generally ≤3 days and rarely >7 days).^{411 433 434 435}

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.⁴¹¹ Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.^{423 431}

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).^{411 420 421 423}

Special Populations

Hepatic Impairment

Parenteral fentanyl: Reduce initial dosage.^c

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.²²⁵ Because of long half-life of this formulation, avoid use in patients with severe hepatic impairment.²²⁵

Transmucosal immediate-release preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray): Insufficient information available to support recommendations regarding use; if used, caution advised.^{227 230 245 246 247}

Fentanyl hydrochloride iontophoretic transdermal system: Insufficient information available to support recommendations regarding use; monitor closely for CNS and respiratory depression, especially when initiating therapy.²⁴⁸

Renal Impairment

Parenteral fentanyl: Reduce initial dosage.^{c d}

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.²²⁵ Because of long half-life of this formulation, avoid use in patients with severe renal impairment.²²⁵

Transmucosal immediate-release preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray): Insufficient information available to support recommendations regarding use; if used, caution advised.^{227 230 245 246 247}

Fentanyl hydrochloride iontophoretic transdermal system: Insufficient information available to support recommendations regarding use; monitor closely for CNS and respiratory depression, especially when initiating therapy.²⁴⁸

Geriatric Patients

Titrate fentanyl dosage carefully.^{225 227 230 245 246}

Parenteral fentanyl: Reduce initial doses; response to initial dosing should be considered in determining subsequent incremental doses.^{b d}

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.²²⁵

Buccal lozenges: Doses in patients >65 years of age generally are about 200 mcg lower than those required in younger adults.²²⁷

Buccal tablets: Doses in patients >65 years of age are slightly lower than those required in younger adults.²³⁰

Sublingual tablets: Median dose is similar in patients ≥65 years of age and younger adults.²⁴⁵

Cautions for Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride

Contraindications

• Known hypersensitivity to fentanyl or any ingredient or component of the respective formulation (e.g., cetylpyridinium chloride in the iontophoretic transdermal system).^{225 227 230 245 246 247 248 d}

• Transmucosal immediate-release preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) contraindicated in the management of acute pain (e.g., migraine or other headaches, dental pain, emergency department use) or postoperative pain and in non-opiate-tolerant patients because of the risk of life-threatening respiratory depression.^{227 230 245 246 247}

• Fentanyl transdermal system contraindicated in the management of acute, mild, intermittent, or postoperative pain (e.g., following outpatient or day surgery [e.g., tonsillectomy]); in patients who require opiate analgesia for a short period of time; and in patients who are not opiate tolerant because of the prolonged duration of effects and risk of serious or life-threatening respiratory depression.^{225 241}

• Fentanyl transdermal system also contraindicated in 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.²²⁵

• Iontophoretic transdermal system contraindicated in patients with substantial respiratory depression, acute or severe bronchial asthma, or known or suspected paralytic ileus and GI obstruction.²⁴⁸

Warnings/Precautions

Warnings

Fentanyl shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.^b

Respiratory Depression

The major toxicity associated with fentanyl.^{227 230 247} Serious, life-threatening, or fatal respiratory depression can occur even when used as recommended.^{225 245 246 248}

Occurs most frequently in patients with respiratory disease and in geriatric, cachectic, and debilitated patients, usually following large initial doses in nontolerant patients, or when given concomitantly with drugs that depress respiration.^{225 227 230 245 246 247}

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.^{225 227 230 245 246 247 248 c d} Monitor closely, particularly when initiating therapy or titrating dosage.^{225 227 230 245 246 247 248} During anesthesia, this can be managed with assisted or controlled respiration.^d Use nonopiate analgesics if possible.^{225 248}

Carbon dioxide retention from opiate-induced respiratory depression can exacerbate the drug's sedative effects.^{225 227 230 245 246 247 248}

The respiratory depressant effect may persist longer than the analgesic effect.^d

Use fentanyl only under the supervision of qualified clinicians.^{225 227 230 245 246 247 248 d} (See Supervised Administration under Cautions.)

Serious, life-threatening, or fatal respiratory depression can occur at any time during therapy with fentanyl transdermal system, but risk is greatest during initiation of therapy and following dosage increases.²²⁵ Monitor closely for respiratory depression, especially during first 24–72 hours of therapy and following any dosage increase.²²⁵ Observe patients who receive an overdose of transdermal fentanyl for at least 72–96 hours, since serum concentrations decline gradually (approximate 50% reduction in 20–27 hours) after system removal.²²⁵

Use fentanyl hydrochloride iontophoretic transdermal system only in the hospital setting; only the patient should activate the device.²⁴⁸

Use of fentanyl transdermal system or transmucosal immediate-release preparations in non-opiate-tolerant patients may result in fatal respiratory depression and is contraindicated.^{225 227 230 245 246 247}

Use of cut, damaged, or altered transdermal systems may expose the patient or caregiver to the contents of the system and result in rapid release of fentanyl and absorption of a potentially lethal dose of the drug.^{225 229 242}

Death and life-threatening adverse effects reported in patients receiving fentanyl transdermal system; attributed to inappropriate prescribing (e.g., use for postoperative pain, occasional or mild pain, or headaches) and incorrect use by patients (application of too many systems, application of heat to the system, replacement of systems too frequently).^{221 223 225 241} Use only in opiate-tolerant patients with pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic and in whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.²²⁵

Death and life-threatening adverse effects reported in patients receiving transmucosal immediate-release fentanyl preparations; attributed to improper patient selection (e.g., use of these formulations in patients who were not opiate tolerant) and/or improper dosage.^{227 230 232 233 245 246 247} Use these formulations only for treatment of breakthrough pain in patients who are already receiving opiates for persistent cancer pain and are opiate tolerant.^{227 230 232 245 246 247}

Do not switch patients from one transmucosal immediate-release fentanyl preparation (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) 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.^{227 230 245 246 247} Such substitution may result in fatal overdosage.^{227 230 245 246 247} (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Avoid use of fentanyl sublingual spray in patients with grade 2 or worse mucositis unless benefits are expected to outweigh risks of respiratory depression; the increase in fentanyl exposure in these patients may be large and variable.²⁴⁷ (See Absorption: Special Populations, under Pharmacokinetics.) Carefully monitor those with grade 1 mucositis for respiratory and CNS depression, particularly during initiation of therapy.²⁴⁷

Consider offering naloxone when opiate agonists are prescribed for patients at increased risk of opiate overdosage (e.g., those with history of overdose or substance use disorder, those receiving ≥50 mg of morphine sulfate [or equivalent] daily, those receiving benzodiazepines concomitantly, those with medical conditions that could increase sensitivity to opiates).^{411 431}

Dependence, Abuse, and Addiction

Physical dependence and tolerance may develop with repeated administration.^{225 227 230 245 246 247 c} Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.^{225 227 230 245 246 247} After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.^{225 227 230}

High potential for abuse; subject to misuse, addiction, and criminal diversion.^{225 227 230 245 246 247 248} Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse.^{225 227 230 246 247 248} Abuse can result in overdosage and death.^{225 230 248}

Proper patient assessment and prescribing practices, proper storage and disposal, and periodic reevaluation of therapy may help limit potential for abuse.^{225 227 230 245 246 247 248}

Assess each patient’s risk for addiction, abuse, and misuse prior to prescribing;^{225 248} monitor all patients for development of these behaviors or conditions.^{225 227 230 245 246 248} Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.^{225 227 230 245 246 247 248}

The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for these behaviors and conditions.^{225 227 245 246 248}

Modified-release (e.g., extended-release) opiates (e.g., fentanyl transdermal system) are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit.²²⁵ Abuse or misuse of fentanyl transdermal systems by intentionally compromising the delivery system may result in uncontrolled delivery of fentanyl and can result in a fatal overdose.²²⁵

Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations

Substantial pharmacokinetic differences exist among transmucosal immediate-release formulations of fentanyl (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray), and between these formulations and other preparations of the drug; the differences in rate and extent of absorption may be clinically important; potential for fatal overdosage.^{227 230 245 246 247} (See Bioavailability under Pharmacokinetics.)

Transmucosal immediate-release fentanyl formulations must not be prescribed or dispensed interchangeably (e.g., on a mcg-per-mcg basis) with each other or with any other fentanyl preparation.^{227 230 232 245 246 247}

Only limited information is available for safely switching from one transmucosal immediate-release formulation to another.^{230 245 246 247} (See Dosage under Dosage and Administration.)

Accidental 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).²²⁵ If accidental exposure occurs, remove system and wash area of contact with water.^{225 229}

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.²²⁵

Risk of fatal overdosage if transmucosal immediate-release preparations are ingested by non-opiate-tolerant individuals or individuals for whom drug was not prescribed.^{225 227 230 245 246 247} If accidental exposure to solid transmucosal dosage forms occurs, attempt to remove dosage form from mouth.^{227 230 245}

Risk of fatal overdosage following accidental exposure to an intact fentanyl hydrochloride iontophoretic transdermal system or the fentanyl-containing hydrogel component, especially by a child, through contact with skin or mucous membranes.²⁴⁸ If system is not handled correctly using gloves, health care professionals are at risk.²⁴⁸ If accidental exposure to intact system or its components occurs, rinse affected area thoroughly and immediately with water.²⁴⁸ System must be removed from patient's skin prior to hospital discharge.²⁴⁸

Accidentally exposed individuals should seek medical attention immediately.^{225 229 230 245 246 247 248}

Proper storage, handling, and disposal are essential to prevent accidental exposure.^{225 227 230 245 246 247 248} (See Advice to Patients, see Administration under Dosage and Administration, and see Storage under Stability.)

Interactions with CYP3A4 Inhibitors

Concomitant use of fentanyl with CYP3A4 inhibitors may increase plasma fentanyl concentrations, increasing or prolonging opiate effects and potentially resulting in fatal respiratory depression.^{225 227 230 245 246 247 248} (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 opiate toxicity and adjust dosage accordingly; drug release from the system and percutaneous permeability of the drug are temperature dependent.^{225 241} Serum fentanyl concentrations theoretically could increase by approximately one-third when body temperature increases to 40°C.²²⁵

Patients should avoid strenuous exertion that leads to increased core body temperature while wearing the transdermal system.²²⁵

Application of heat over the fentanyl transdermal system increases mean exposure and peak plasma concentrations by 120 and 61%, respectively; fatal overdosage reported.²²⁵ 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.^{225 229 241}

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates, including fentanyl, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.^{416 417 418 700 701 702 703} Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.^{416 417 418 435 700 701}

Reserve concomitant use of fentanyl and other CNS depressants for patients in whom alternative treatment options are inadequate.^{700 703} (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 opiates for anesthesia or the management of pain (depending on use) and in the management of respiratory effects of potent opiates.^{225 227 230 245 246 247 248 d}

Opiate antagonist and facilities for administration of oxygen and controlled respiration should be available during and immediately following IV administration.^{b d}

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) opiates for the management of cancer pain.^{227 230 245 246 247}

Use fentanyl transdermal system only under the supervision of clinicians who are experienced in continuous administration of potent opiates for the management of chronic pain.²²⁵

Serotonin Syndrome

Serotonin syndrome reported during concurrent use of opiate agonists, including fentanyl, and serotonergic drugs or drugs that impair serotonin metabolism (e.g., MAO inhibitors).⁴⁰⁰ (See Interactions.)

Serotonin syndrome may occur at usual dosages.⁴⁰⁰ 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).⁴⁰⁰

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.⁴⁰⁰ Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.⁴⁰⁰

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.⁴⁰⁰ If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.⁴⁰⁰ In some patients, switching to a different opiate improved symptoms.⁴⁰⁰

Incompatibility of Iontophoretic Transdermal Systems with Certain Medical Procedures and Equipment

Fentanyl hydrochloride iontophoretic transdermal system is considered unsafe for use with MRI.²⁴⁸ System contains metal components and must be removed prior to MRI procedure to avoid patient injury and system damage.²⁴⁸ Not known whether exposure to MRI procedure increases fentanyl release from the system.²⁴⁸ If patient is inadvertently exposed to MRI while wearing an iontophoretic transdermal system, monitor for CNS and respiratory depression.²⁴⁸

Strong electromagnetic fields set up by cardioversion, defibrillation, radiographic imaging, computed-tomography (CT) scanning, or diathermy can damage the iontophoretic transdermal system, and radiopaque components of the iontophoretic transdermal system may interfere with radiographic imaging or CT scanning.²⁴⁸ Remove the iontophoretic transdermal system prior to these medical procedures.²⁴⁸ If the system is exposed to such procedures and does not appear to function normally, remove the exposed system and apply a new system.²⁴⁸

Avoid contact with synthetic materials (e.g., carpeted flooring) to reduce the possibility of electrostatic discharge and damage to the iontophoretic transdermal system; also avoid exposure to electronic security systems to avoid possible damage to the iontophoretic transdermal system.²⁴⁸

Use of the iontophoretic transdermal system near communications equipment (e.g., base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast, TV broadcast, radio) and radio frequency identification (RFID) transmitters can damage the iontophoretic transdermal system; the recommended separation distance between the iontophoretic transdermal system and communications equipment or RFID transmitters ranges from 0.12–23 meters, depending on the rated maximum output power and frequency of the transmitter.²⁴⁸

If exposure to electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs and the iontophoretic transdermal system does not appear to function normally, remove the exposed system and apply a new system.²⁴⁸

The low-level electrical current provided by the iontophoretic transdermal system does not result in electromagnetic interference with electromechanical devices such as pacemakers or electrical monitoring equipment.²⁴⁸

Consult manufacturer's prescribing information for additional information on electromagnetic compatibility and troubleshooting for device malfunction.²⁴⁸

Head Injury and Increased Intracranial Pressure

May reduce respiratory drive; the resultant carbon dioxide retention can further increase intracranial pressure.^{225 248}

May obscure the clinical course in patients with head injuries;^{225 227 230 245 246 247 248} use only if clinically warranted.^{227 230 245 246 247}

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.^{227 230 245 246 247 248}

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.²²⁵

Musculoskeletal Effects

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

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 opiate agonists.^{225 227 230 245 246 247 b}

Hypotension

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.^{225 248}

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).^{225 248} (See Specific Drugs and Foods under Interactions.) Monitor these patients for hypotension after initiation of therapy or dosage titration.^{225 248}

Cardiac Arrhythmia

Because of cholinergic effects, may cause bradycardia.^{225 227 230 245 246 247 248 c d} Caution in patients with cardiac bradyarrhythmias;^{227 230 245 246 247 c d} monitor closely for changes in heart rate, particularly during initiation of therapy.^{225 248}

Interactions with MAO Inhibitors

Severe and unpredictable potentiation by MAO inhibitors may occur.^{225 227 230 245 246 247 248} Avoid use in patients who are receiving or have received MAO inhibitors within 14 days.^{225 227 230 245 246 247 248}

Seizure Disorders

May aggravate preexisting seizure disorder.²⁴⁸ Monitor for worsened seizure control.²⁴⁸

May induce or aggravate seizures in some clinical settings.²⁴⁸

Debilitated and Special Risk Patients

Increased risk of life-threatening respiratory depression in geriatric, cachectic, or debilitated patients because of altered pharmacokinetics.^{225 248} Monitor closely, especially when initiating therapy, titrating dosage, or using other respiratory depressants concomitantly.^{225 248}

Use with caution in patients with pulmonary disease.^{225 227 230 245 246 247 248} (See Respiratory Depression under Cautions.)

Pancreatic and Biliary Disease

May cause spasm of the sphincter of Oddi and increase serum amylase concentrations.^{225 248 c} Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.^{225 248}

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;^{400 401 402 403 404} causality not established.⁴⁰⁰ Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.⁴⁰⁰ Perform appropriate laboratory testing in patients with manifestations of hypogonadism.⁴⁰⁰

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.²²⁷ (See Transmucosal Immediate-release Fentanyl Preparations under Advice to Patients.) Each fentanyl citrate buccal lozenge contains 2 g of sugar.²²⁷

Diabetes Mellitus

Each buccal lozenge contains 2 g of sugar.²²⁷

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.²³⁰

Dermatologic reactions (e.g., erythema, pruritus, sweating, vesicles, papules/pustules) reported in patients receiving therapy with fentanyl hydrochloride iontophoretic transdermal system; generally limited to the application site.²⁴⁸ If reaction is severe, remove the system and discontinue further use.²⁴⁸

Specific Populations

Pregnancy

Category C.^{225 227 230 245 246 247 d}

Analysis of data from the National Birth Defects Prevention Study (large population-based, case-control study) suggests therapeutic use of opiates in pregnant women during organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.^{250 251}

Transient neonatal muscular rigidity reported in infants whose mothers received IV fentanyl.^{225 227 230 245 246 247}

Use of opiates during late pregnancy can result in neonatal respiratory depression.²⁵¹

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome;^{225 227 230 245 246 247} in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts.²²⁵ Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.²²⁵ Onset, duration, and severity vary depending on the specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.²²⁵

Lactation

Distributed into milk.^{225 227 230} Limited data suggest breast-fed infants receive an estimated 0.38% of the maternal weight-adjusted dosage.²⁴⁸ Potential risk (sedation, respiratory depression) to nursing infants.^{225 227 230 245 246 247}

Manufacturers of fentanyl transdermal system and transmucosal immediate-release fentanyl preparations (used only in opiate-tolerant patients) state these preparations should not be used in nursing women because of the potential for serious adverse effects in nursing infants.^{225 227 230 245 246 247}

Manufacturer of the iontophoretic transdermal system (used for short-term management of acute postoperative pain) states to consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed infant from either the drug or underlying maternal condition.²⁴⁸

Symptoms of withdrawal can occur in opiate-dependent infants upon cessation of breast-feeding by women receiving fentanyl.^{227 230 245 246 247}

Pediatric Use

Safety and efficacy of parenteral fentanyl citrate and fentanyl transdermal systems not established in children <2 years of age.^{225 b d}

Safety and efficacy of buccal lozenges not established in pediatric patients <16 years of age.²²⁷

Safety and efficacy of buccal tablets, sublingual tablets, sublingual spray, nasal spray, and iontophoretic transdermal system not established in patients <18 years of age.^{230 245 246 247 248}

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.^{225 242}

Transdermal systems, iontophoretic 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.^{227 229 230 245 246 247 248}

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.²²⁵ High risk of respiratory depression if a child accidentally ingests a transmucosal immediate-release preparation.^{227 230 245 246 247} (See Advice to Patients and see Accidental Exposure under Cautions.)

Geriatric Use

Pharmacokinetics may be altered, increasing risk of life-threatening respiratory depression.^{225 248} Monitor closely for sedation and respiratory depression, particularly during initiation or titration of therapy and when other respiratory depressants are used concomitantly.^{225 247 248} Use caution when titrating dosage.^{227 230 245 246} (See Geriatric Patients under Dosage and Administration.)

Clearance of IV fentanyl may be reduced.^{225 248} Geriatric patients may be more sensitive to effects of IV fentanyl.^{225 227 245 247}

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.²²⁵

Age did not substantially affect extent of drug absorption following iontophoretic transdermal administration.²⁴⁸

Dosage of buccal lozenges (following titration) generally about 200 mcg lower in geriatric patients than in younger adults.²²⁷ Median dosage of sublingual tablets (following titration) similar to that in younger adults.²⁴⁵ Dosage of buccal tablets (following titration) slightly lower in geriatric patients than in younger adults.²³⁰

Increased frequency of certain adverse effects (e.g., vomiting, constipation, abdominal pain) reported in geriatric patients compared with younger adults receiving buccal tablets.²³⁰ Safety profiles of buccal lozenges, sublingual tablets, sublingual spray, and nasal spray in geriatric patients generally similar to those observed in younger adults.^{227 245 246 247}

Certain adverse effects (hypotension, confusion, hypokalemia, hypoxia, hypoventilation) slightly more common in geriatric patients compared with younger adults receiving fentanyl hydrochloride iontophoretic transdermal system; however, no overall differences in safety and efficacy.²⁴⁸

Hepatic Impairment

Exercise caution and reduce initial parenteral dosage.^{c d}

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.²²⁵ Because of the long half-life of this formulation, avoid use in patients with severe hepatic impairment.²²⁵ (See Hepatic Impairment under Dosage and Administration.)

Insufficient information available to support recommendations regarding use of transmucosal immediate-release preparations or iontophoretic transdermal system; if used, caution advised.^{227 230 245 246 247 248}

Renal Impairment

Exercise caution and reduce initial parenteral dosage.^{c d}

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.²²⁵ Because of the long half-life of this formulation, avoid use in patients with severe renal impairment.²²⁵ (See Renal Impairment under Dosage and Administration.)

Insufficient information available to support recommendations regarding use of transmucosal immediate-release preparations or iontophoretic transdermal system; if used, caution advised.^{227 230 245 246 247 248}

Common Adverse Effects

Headache,^{225 227 230} nausea,^{225 227 230 247 248} vomiting,^{225 227 230 246 247 248} constipation,^{225 227 230 247} diarrhea,²²⁵ somnolence,^{225 227} confusion,²²⁷ asthenia,^{227 230} fatigue,²³⁰ dizziness,^{225 227 230} insomnia,²²⁵ anxiety,²²⁷ dyspnea,^{227 247} peripheral edema,²³⁰ dehydration,²³⁰ anemia.²³⁰

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

Transdermal system: Erythema (may persist for ≥6 hours after removal of the system), papules, pruritus, and edema at application site also occur frequently.^{203 206 212 225}

Iontophoretic transdermal system: Erythema at application site also occurs frequently.²⁴⁸

Buccal tablets: Application site reactions (e.g., paresthesia, pain, bleeding, ulceration, irritation) also occur frequently.²³⁰

Interactions for Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride

Metabolized by CYP3A4.^{225 227 230 245 246 247 248}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Possible increased plasma fentanyl concentrations; may result in increased or prolonged opiate effects, including potentially fatal respiratory depression.^{225 227 230 234 245 246 247 248} If concomitant use is necessary, monitor frequently and consider dosage adjustments until drug effects are stable.^{225 248} Following initiation or increase in dosage of a CYP3A4 inhibitor, carefully monitor patient for increased opiate effects over an extended time.^{227 230 245 246 247} Any increases in dosage should be conservative.^{227 230 245 246 247}

CYP3A4 inducers: Possible decreased plasma fentanyl concentrations; may result in decreased analgesic efficacy^{225 227 230 234 245 246 247 248} and/or development of opiate withdrawal.^{225 248} If concomitant use is necessary, monitor for opiate withdrawal and consider dosage adjustments until drug effects are stable.^{225 248} If the CYP3A4 inducer is discontinued, fentanyl concentrations may increase, possibly resulting in increased or prolonged therapeutic or adverse effects, including potentially fatal respiratory depression.^{225 246 248} If CYP3A4 inducer is discontinued or dosage is reduced, monitor for increased opiate effects and adjust fentanyl dosage as necessary.^{230 245 246 247}

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs.⁴⁰⁰ May occur at usual dosages.⁴⁰⁰ Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.⁴⁰⁰ (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.⁴⁰⁰

If serotonin syndrome is suspected, discontinue fentanyl, other opiate therapy, and/or any concurrently administered serotonergic agents.⁴⁰⁰

Specific Drugs and Foods

Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Well absorbed percutaneously following topical application of fentanyl transdermal system^{201 202 203 225} or fentanyl hydrochloride iontophoretic transdermal system²⁴⁸ and transmucosally following administration as buccal lozenge, buccal tablet, sublingual tablet, sublingual spray, or nasal spray.^{227 230 245 246 247}

Substantial pharmacokinetic differences exist among the transmucosal immediate-release fentanyl preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray); these preparations must not be substituted on a mcg-for-mcg basis.^{227 230 245 246 247} (See Clinically Important Pharmacokinetic Differences Among Fentanyl Formulations under Cautions.)

Buccal lozenge: Bioavailability averages about 50%.²²⁷ 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.²²⁷

Buccal tablet: Bioavailability averages about 65%.²³⁰ 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.²³⁰ The time required for the buccal tablet to fully disintegrate does not appear to affect early systemic drug exposure.²³⁰ Time to peak plasma concentration and AUC are similar following either sublingual or intrabuccal administration of the buccal tablet.²³⁰

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.^{230 235}

Sublingual tablet: Estimated bioavailability is 54%.²⁴⁵ When administered at equivalent doses, multiple lower-strength sublingual tablets are bioequivalent to a single higher-strength sublingual tablet.²⁴⁵ Absorbed mainly from oral mucosa.²⁴⁵ Median time to peak plasma concentration is 30–60 minutes.²⁴⁵

Sublingual spray: Mean absolute bioavailability is 76%.²⁴⁷ Pharmacokinetic profile and bioavailability depend on the relative fractions of the dose that are absorbed from the sublingual mucosa and the GI tract.²⁴⁷ Median time to peak plasma concentration is 0.7–1.3 hours.²⁴⁷ Under fasted conditions, peak plasma concentration and total exposure not appreciably affected by pretreatment of oral cavity with hot water or refrigerated iced water or by beverages with either low or high pH.²⁴⁷

Sublingual spray versus buccal lozenge: When administered as sublingual spray rather than buccal lozenge, peak plasma concentration was 34% higher, AUC was 38% greater, and peak plasma concentration occurred earlier (median of 1.5 versus 2 hours).²⁴⁷

Nasal spray: Absorbed from the nasal mucosa.²⁴⁶ Median time to peak plasma concentration is 15–21 minutes.²⁴⁶

Nasal spray versus buccal lozenge: Nasal spray is approximately 20% more bioavailable than buccal lozenges; peak concentration with nasal spray is higher and occurs earlier (median of 15 minutes versus 1.5 hours) after administration.²⁴⁶

When consecutive doses of nasal spray were administered in the same nostril at intervals of 1, 2, or 4 hours, the peak plasma concentration after the second dose exceeded the peak plasma concentration after the first dose by 30, 25, or 10%, respectively.²⁴⁶ An interval of 2 hours between doses is recommended based on these data, time to peak plasma concentration, and frequency of breakthrough cancer pain.²⁴⁶

Allergic rhinitis does not substantially alter rate or extent of exposure of nasally administered fentanyl, but use of nasal decongestants for allergic rhinitis may alter exposure.²⁴⁶ (See Specific Drugs and Foods under Interactions.)

Fentanyl transdermal systems: Amount of fentanyl released from the system is proportional to the surface area of the system;²²⁵ however, actual amount of drug delivered to the skin exhibits interindividual variation.^{201 225 237 238 239 240} Peak concentration attained within 20–72 hours after initial application.²²⁵ 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.²²⁵

Application of heat over the transdermal system increases mean exposure and peak plasma concentrations by 120 and 61%, respectively.²²⁵

Following use of fentanyl transdermal system in non-opiate-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.²²⁵

Fentanyl hydrochloride iontophoretic transdermal system: Activation of dosing button activates an electrical current for 10 minutes, which delivers a dose from the drug reservoir through the skin and into the systemic circulation.²⁴⁸ Compared with IV administration, blood concentrations increase slowly following activation of the device and continue to increase for about 5 minutes after the completion of each 10-minute dose.²⁴⁸

Systemic absorption following administration as iontophoretic transdermal system increases as a function of time, independent of frequency of dosing.²⁴⁸ Upon initiation of therapy, expected systemic absorption is approximately 16 mcg; beginning about 10 hours after initiation of therapy, 40 mcg per dose is absorbed.²⁴⁸

Intersubject variability in AUC with iontophoretic transdermal therapy is similar to that observed with IV administration.²⁴⁸

Rate of drug delivery is similar following application of the iontophoretic transdermal system to either the upper outer arm or chest (the recommended application sites), but approximately 20% lower following application to lower inner arm; rates of drug delivery following application at other sites not established.²⁴⁸

Onset

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

IM administration: About 7–15 minutes.^b

Intrabuccal administration (tablet): About 10 minutes.²³⁵

Duration

IV administration, analgesia: 0.5–1 hours.^b

IM administration, analgesia: 1–2 hours.^b

Respiratory depressant effects may persist longer than analgesia.^b

Special Populations

Buccal tablets in patients with mucositis: Presence of grade 1 mucositis does not appear to substantially alter absorption.²³⁰

Sublingual spray in patients with mucositis: In those with grade 1 mucositis, peak plasma concentration and AUC increased by 73 and 52%, respectively, compared with patients without mucositis.²⁴⁷ In 2 patients with grade 2 mucositis, peak plasma concentrations increased fourfold and sevenfold and AUC increased threefold or more.²⁴⁷

Pharmacokinetics of fentanyl transdermal system in healthy Caucasian adults ≥65 years of age generally similar to that in adults 18–45 years of age; mean peak plasma concentration about 8% lower, AUC about 7% greater, and interindividual variability in AUC greater (58 versus 37%) in geriatric individuals compared with younger adults.²²⁵

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.²²⁵

Race and age do not appear to affect absorption from the iontophoretic transdermal system.²⁴⁸

Distribution

Extent

Fentanyl is highly lipophilic.^{227 230 245 246 247}

Distributes rapidly from blood into the brain, heart, lungs, kidneys, and spleen in animals; then redistributes more slowly into skeletal muscle and fat compartments;^{227 245 247} then redistributes slowly from these tissues into systemic circulation.^{213 225 248}

Following IV administration, estimated initial and second distribution half-lives are about 6 minutes and 1 hour, respectively.²⁴⁸

Large single or repeated doses can result in substantial accumulation, potentially resulting in an extended duration of effect.^{213 224}

Fentanyl crosses the placenta and is distributed into breast milk.^{225 227 230 245 246 247}

Plasma Protein Binding

80–85% bound, principally to α₁-acid glycoprotein but also to albumin, lipoproteins, and RBCs.^{213 224 227 230 245 246 247 248}

Alterations in blood pH may alter ionization of fentanyl and therefore its distribution between plasma and the CNS.^{225 248} The free drug fraction in plasma increases with acidosis.^{213 224 227 245 247}

Elimination

Metabolism

Metabolized extensively in the liver and the intestinal mucosa via CYP3A4 to norfentanyl (inactive metabolite);^{230 b} also undergoes hydrolysis.^b

Transdermally administered fentanyl does not appear to be metabolized in the skin.^{201 225 248}

Elimination Route

Principally in the urine, as inactive metabolites and to a lesser extent (<10%) as unchanged drug.^{225 227 230 b}

Half-life

IV: Estimated initial distribution half-life is 6 minutes, second distribution half-life is about 1 hour, and terminal half-life is about 16 hours.²⁴⁸

Buccal lozenges: Mean half-life of about 3.2–6.4 hours; terminal half-life of about 7 hours also reported.²²⁷

Buccal tablets: Median half-life of about 2.6–11.7 hours.²³⁰

Sublingual tablets: Mean half-life of 5–13.5 hours.²⁴⁵

Sublingual spray: Mean half-life of 5.3–12 hours.²⁴⁷

Nasal spray: Mean half-life of 15–25 hours (versus 18.6 hours with buccal lozenge).²⁴⁶

Fentanyl transdermal system: About 20–27 hours.²²⁵

Fentanyl hydrochloride iontophoretic transdermal system: Terminal half-life is similar to that following IV administration.²⁴⁸

Special Populations

In geriatric patients, clearance may be decreased and half-life increased.²²⁵

Pharmacokinetics of fentanyl transdermal system in healthy Caucasian adults ≥65 years of age generally similar to that in adults 18–45 years of age, but mean half-life is longer in geriatric individuals (34.4 versus 23.5 hours).²²⁵

Stability

Storage

Store in a secure place to prevent access by children and pets.^{225 227 230 245 246 247} Properly dispose of used or partially used dosage forms immediately after use.^{225 227 230 247}

Properly dispose of any unused dosage forms as soon as they are no longer needed.^{225 227 230 245 246 247} Patients and/or caregivers may contact the respective manufacturer or local Drug Enforcement Administration (DEA) office if they need assistance with disposal.^{227 230 245 246 247}

Intrabuccal

Buccal Lozenges

20–25°C (may be exposed to 15–30°C).²²⁷ Protect from freezing and moisture.²²⁷ Administer immediately after removal from blister package.²²⁷

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.²²⁷ Do not flush handles down the toilet.²²⁷

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.²²⁷

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.²²⁷

Buccal Tablets

20–25°C (may be exposed to 15–30°C).²³⁰ Protect from freezing and moisture.²³⁰ 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.²³⁰

To dispose of tablets that are no longer needed, manufacturer recommends removing the tablets from their blister packages and flushing them down the toilet.²³⁰

Intranasal

Nasal Solution

Up to 25°C; protect from light; do not freeze.²⁴⁶ Store nasal spray bottle in child-resistant container between uses; store pouch used for disposal of priming sprays, unwanted doses, and residual nasal solution in the cardboard carton.²⁴⁶

To dispose of unused, fully used, or partially used bottles of nasal spray that are no longer needed, empty bottle completely of accessible drug by spraying the remaining contents into the disposal pouch provided by the manufacturer and placing the emptied bottle and sealed pouch in the child-resistant container (also provided by manufacturer) prior to disposal.²⁴⁶ Consult patient instructions in the medication guide for additional information about disposal.²⁴⁶

Parenteral

Injection

15–30°C (may be exposed to up to 40°C); protect from light.^b

Sublingual

Sublingual Spray

20–25°C (may be exposed to 15–30°C).²⁴⁷ Administer immediately after removal from the individually sealed blister package; do not use if the blister package was previously opened or tampered with.²⁴⁷ Child safety kit containing a portable carrying case, a lock for the bag, and safety latches for securing storage spaces in the home can be requested from the manufacturer.²⁴⁷

To dispose of unused units of fentanyl sublingual spray that are no longer needed, empty the units by spraying the contents into a charcoal-lined disposal pouch provided by the manufacturer; seal the pouch and place it and the emptied spray units in disposal bags (also provided by manufacturer); seal bags prior to disposal.²⁴⁷

To dispose of used spray units, place unit in a disposal bag provided by the manufacturer and seal bag prior to disposal.²⁴⁷

Consult the patient instructions in the medication guide for additional information about disposal.²⁴⁷

Sublingual Tablets

20–25°C (may be exposed to 15–30°C); protect from moisture.²⁴⁵ Administer immediately after removal from individually sealed blister package; do not use if blister package was previously opened or tampered with.²⁴⁵

To dispose of tablets that are no longer needed, manufacturer recommends removing the tablets from their blister packages and flushing them down the toilet.²⁴⁵

Topical

Fentanyl Transdermal Systems

Room temperature.^{225 237 238 239 240 252} Apply the system to the skin immediately after removal from the individually sealed package; discard if the seal was previously broken or the system has been cut, damaged, or altered in any way.²²⁵

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.^{225 242}

To dispose of used system, fold the system so that the adhesive side adheres to itself and then flush system down the toilet.^{225 242}

Fentanyl Hydrochloride Iontophoretic Transdermal Systems

25°C (may be exposed to 15–30°C).²⁴⁸ Assemble system and apply to skin immediately after removal from the individually sealed package; discard if the seal on the tray or drug unit pouch was previously broken or damaged.²⁴⁸

Dispose of used systems according to manufacturer's instructions.²⁴⁸ (See Removal of Iontophoretic Transdermal System under Dosage and Administration.)

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Hydrolyzed in acidic solutions.^b

Solution Compatibility^HID

Drug Compatibility

Actions

• A potent analgesic; shares the actions of the opiate agonists.^b

• Opiate agonists alter perception of and emotional response to pain.^f

• Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.^f

• Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).^f

• Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.^f

• Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.^f

• Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.^f

• Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).^f

• Respiratory depression may be mediated by μ-receptors, possibly μ₂-receptors (which may be distinct from μ₁-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.^f

• In equivalent analgesic doses, fentanyl is similar to morphine and meperidine in its respiratory effects except that respiration of healthy individuals returns to normal more quickly after fentanyl than after either of the other drugs.^b

• Exhibits little hypnotic activity, and histamine release rarely occurs.^b

Advice to Patients

• Provide manufacturer’s patient information (e.g., medication guide) to the patient each time fentanyl transdermal system or transmucosal immediate-release preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) of the drug are dispensed.^{225 227 229 230 245 246 247} (See REMS.)

• Risk of respiratory depression; most likely to occur following initiation of therapy or an increase in dosage; may occur at recommended dosages.^{225 227 230 245 246 247 248} Importance of seeking immediate medical attention if signs or symptoms of respiratory depression (e.g., difficulty breathing; slow, shallow breathing; extreme drowsiness with slowed breathing; feelings of faintness, dizziness, or confusion) occur.^{225 227 230 245 246 247 248}

• Importance of informing patients that fentanyl is a drug of abuse.^{225 227 229 230 245 246 247 248} Instruct patients to keep fentanyl in a secure place to prevent theft or misuse in the home or workplace.^{225 227 229 230 245 246 247} Risk of severe or fatal respiratory depression if fentanyl preparations are misused or used in individuals for whom the drug was not prescribed.^{225 227 229 230 245 246 247 248}

• 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.^{225 227 230 245 246 247} (See Administration under Dosage and Administration and also see Storage under Stability.) Specifically question patients and/or caregivers about the presence of children in the patient’s home on a full-time or visiting basis.^{227 230 234 245 246 247}

• Importance of adhering to prescribed dosage and instructions for administration.^{225 227 230 245 246 247}

• Importance of informing clinician if pain control is inadequate or adverse effects (e.g., constipation) occur, so that therapy may be adjusted based on individual requirements.^{227 229 230 245 246 247 248}

• 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 opiates, either therapeutically or illicitly;^{700 703} 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.^{225 227 229 230 245 246 247 700 703}

• Potential risk of serotonin syndrome with concurrent use of fentanyl and other serotonergic agents.⁴⁰⁰ Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.⁴⁰⁰

• Potential risk of adrenal insufficiency.⁴⁰⁰ Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.⁴⁰⁰

• Potential for fentanyl to impair mental and/or physical ability required for performance of potentially hazardous tasks;^{225 227 229 230 245 246 247} avoid driving or operating heavy machinery until effects on individual are known.^{225 227 229 230 245 246 247}

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.⁴⁰⁰ Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.⁴⁰⁰

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{225 227 229 230 245 246 247 248}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{225 227 229 230 245 246 247 248} Importance of informing women that long-term use during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.²²⁵

• Potential for severe constipation to occur.^{225 227 229 230 245 246 247}

• Importance of not abruptly discontinuing fentanyl following prolonged opiate therapy.^{225 227 229 230 245 246 247}

• Importance of informing patients of other important precautionary information.^{225 227 230 245 246 247 248} (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.^{227 230 245 246 247} (See TIRF REMS Restricted Distribution Program under Dosage and Administration.)

• Importance of using transmucosal immediate-release preparations (buccal lozenges, buccal tablets, sublingual tablets, sublingual spray, nasal spray) exactly as prescribed and only if opiate tolerant.^{227 230 245 246 247} Importance of not using these preparations for acute, postoperative, or short-term pain.^{227 230 245 246 247} Advise patients that if around-the-clock therapy with opiate analgesics is discontinued, they must stop taking transmucosal immediate-release fentanyl preparations for management of breakthrough pain.^{227 230 245 246 247}

• One transmucosal immediate-release preparation must not be substituted for another such preparation or for any other fentanyl preparation without consulting a clinician.^{227 230 245 246 247}

• Importance of having only one dosage strength available at any given time to minimize risk of dosage errors.^{227 230 232 247}

• Provide a child safety kit (available from manufacturer) to patients receiving fentanyl sublingual spray or buccal lozenges.^{227 247}

• Instruct patients to inform their dentist that they are receiving fentanyl citrate buccal lozenges, so that appropriate dental care is provided.²²⁷

• Advise patients with diabetes mellitus that fentanyl citrate buccal lozenges contain approximately 2 g of sugar per lozenge.²²⁷

• Inform patients and/or caregivers that transmucosal immediate-release preparations contain sufficient amounts of fentanyl to be fatal to a child.^{227 230 245 246 247} High risk of respiratory depression if a child accidentally ingests these preparations.^{227 229 230 245 246 247}

• Importance of seeking immediate medical treatment if a child, non-opiate-tolerant adult, or anyone other than the patient ingests a transmucosal immediate-release formulation.^{227 229 230 245 246 247}

Fentanyl Transdermal Systems

• Importance of using transdermal systems exactly as prescribed and only if opiate tolerant.^{225 229}

• Inform patients and/or their caregivers that transdermal systems contain sufficient amounts of fentanyl to be fatal to a child.²²⁵ 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.²²⁵ Instruct patients to take special precautions to avoid accidental contact (e.g., system transfer) when holding or caring for children.²²⁵

• Importance of not using transdermal systems that have been altered in any way (e.g., cut, damaged, folded so that only part of the system is exposed).^{225 242}

• If accidental exposure occurs, remove the system (if system transfer has occurred) and wash the exposed area with water.^{225 229} Seek immediate medical attention.²²⁵

• 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.^{225 229} Importance of contacting clinician if a high fever occurs during transdermal fentanyl therapy.^{225 229}

Fentanyl Hydrochloride Iontophoretic Transdermal Systems

• Importance of reading and understanding the manufacturer's guide for patients.²⁴⁸

• Importance of not leaving the hospital while still wearing an iontophoretic transdermal system.²⁴⁸ (See Ionsys REMS Restricted Distribution Program under Dosage and Administration.)

• Importance of not letting anyone else activate the dosing button of the device; allowing others to activate the device may result in fatal overdosage.²⁴⁸

• Advise patient that accidental exposure to the fentanyl hydrogel in the system may result in fatal overdosage.²⁴⁸ Advise patient to avoid contact with the hydrogels and adhesive surface of the system, to contact a health care professional immediately if the system becomes dislodged, and to refrain from removing or repositioning the system.²⁴⁸ Medical personnel must remove the system.²⁴⁸ Other individuals should not be allowed to touch the system if it becomes dislodged.²⁴⁸

• Importance of informing a health care professional if accidental exposure occurs and of immediately rinsing the affected area with copious amounts of water; do not use soap, alcohol, or other solvents since percutaneous absorption of the drug may be enhanced.²⁴⁸

• Importance of informing clinician of any allergy to cetylpyridinium chloride.²⁴⁸

• Advise patients that the current generated by the device is generally imperceptible to the patient.²⁴⁸

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.^{225 227 230 245 246 247 248}

Distribution of transmucosal immediate-release fentanyl and fentanyl citrate preparations and of fentanyl hydrochloride iontophoretic transdermal system is restricted.^{227 230 245 246 247 248} (See General under Dosage and Administration.)

* 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