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Fentanyl: Drug information

Fentanyl: Drug information
(For additional information see "Fentanyl: Patient drug information" and see "Fentanyl: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression has occurred with use of fentanyl, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of fentanyl or following a dose increase. The substitution of fentanyl buccal, intranasal, lozenge, or sublingual for any other fentanyl product may result in fatal overdose. Due to the risk of respiratory depression, fentanyl buccal, intranasal, lozenge, and sublingual are contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients; fentanyl transdermal is contraindicated for use as an as-needed analgesic, in nonopioid tolerant patients, in acute pain, and in postoperative pain. Only the patient should activate Ionsys dosing.

Addiction, abuse, and misuse:

Fentanyl exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing fentanyl, and monitor all patients regularly for the development of these behaviors and conditions.

Accidental exposure:

Accidental exposure of even one dose of fentanyl, especially by children, can result in a fatal overdose of fentanyl. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. Deaths due to a fatal overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal patch. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure. Fentanyl must be kept out of reach of children.

Cytochrome P450 3A4 Interaction:

The concomitant use of fentanyl with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl and any CYP3A4 inhibitor or inducer.

Neonatal opioid withdrawal syndrome:

Prolonged use of fentanyl during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of fentanyl and benzodiazepine or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Risk of medication errors (buccal, intranasal, lozenge, sublingual):

Substantial differences exist in the pharmacokinetic profile of fentanyl buccal, intranasal, lozenge, and sublingual compared with other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose. When prescribing, do not convert patients on a mcg-per-mcg basis from any other fentanyl products to fentanyl buccal, intranasal, lozenge, or sublingual. When dispensing, do not substitute a fentanyl buccal, intranasal, lozenge, or sublingual prescription for other fentanyl products.

REMS program:

Buccal, intranasal, lozenge, sublingual: Because of the risk for misuse, abuse, addiction, and overdose, fentanyl buccal, intranasal, lozenge, and sublingual are available only through a restricted program required by the FDA, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program, outpatients, health care providers who prescribe to outpatients, pharmacies, and distributors must enroll in the program. Further information is available at http://www.TIRFREMSaccess.com or by calling 1-866-822-1483.

Transdermal iontophoretic system (Ionsys): For use only in patients in the hospital. Discontinue treatment with before patients leave the hospital. Because of the risk of respiratory depression from accidental exposure, Ionsys is available through a restricted program called the Ionsys REMS Program. Healthcare facilities that dispense Ionsys must be certified in this program and comply with the REMS requirements.

Transdermal (Duragesic): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

Exposure to heat (Duragesic only):

Exposure of the fentanyl application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources.

Brand Names: US
  • Abstral [DSC];
  • Actiq;
  • Duragesic-100 [DSC];
  • Duragesic-12 [DSC];
  • Duragesic-25 [DSC];
  • Duragesic-50 [DSC];
  • Duragesic-75 [DSC];
  • Fentora;
  • Ionsys [DSC];
  • Lazanda;
  • Subsys
Brand Names: Canada
  • FentaNYL Citrate SDZ;
  • Fentora;
  • MYLAN-FentaNYL Matrix [DSC];
  • PMS-FentaNYL MTX;
  • RAN-FentaNYL Matrix [DSC];
  • SANDOZ FentaNYL;
  • TEVA-FentaNYL
Pharmacologic Category
  • Analgesic, Opioid;
  • Anilidopiperidine Opioid;
  • General Anesthetic
Dosing: Adult

Note: Ionsys (transdermal device) and Abstral (sublingual tablets) have been discontinued in the United States for >1 year.

Note: When used for managing severe pain, opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for pain. Maximize nonopioid analgesia, if appropriate, prior to initiation of opioid analgesia (Ref). Dosing provided is based on typical doses and some patients may require higher or lower doses. Individualize dosing and dosing intervals based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, cachexia, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time. For acute non–cancer-related pain severe enough to require an opioid, do not prescribe fentanyl for use on an outpatient basis; consider the use of other oral opioids. Before starting opioid therapy for chronic pain, establish realistic treatment goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh risks (Ref).

Acute pain, patient-controlled analgesia

Acute pain, patient-controlled analgesia (alternative agent): Note: Generally, fentanyl is the preferred opioid for patients with severe kidney or hepatic dysfunction and/or for patients who are unable to tolerate morphine or hydromorphone (Ref). For use in ICU, postoperative, or other closely monitored settings.

IV:

Example IV Patient-Controlled Analgesia Initial Dose Ranges for Opioid-Naive Patientsa

a For use to maintain pain control after initial pain control achieved. May adjust dosing and provide rescue bolus doses (eg, 5 to 20 mcg) if analgesia is inadequate (Mariano 2019).

b The use of a continuous background infusion for patient-controlled analgesia is generally not recommended for most patients because of the risk of respiratory depression, and use should be limited to carefully selected patients who are opioid tolerant and/or receiving care in a critical care unit, or if required to maintain baseline opioid dosing during intervals when oral or transdermal opioid administration is not possible (Arnold 2019; Mariano 2019).

Usual concentration

10 mcg/mL

Demand dose

Usual range: 5 to 20 mcg

Basal dose

In general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)b

Lockout interval

4 to 10 minutes

Maximum cumulative dose

75 mcg within 1 hour (or 300 mcg within a 4-hour period)

Acute postoperative pain

Acute postoperative pain:

Postoperative recovery/Postanesthesia care unit (ie, immediate postoperative period):

IV: 25 to 50 mcg every 5 minutes (moderate pain) or 50 to 100 mcg every 2 to 5 minutes (severe pain) until pain is relieved or unwanted side effects appear; after initial pain control, readdress postoperative analgesic regimen to optimize comfort (Ref).

IM: 50 to 100 mcg every 1 to 2 hours as needed. Note: IM route should only be used if IV administration is not available (eg, loss of IV access).

Transdermal device (Ionsys): Note: For hospital use only by patients under medical supervision for whom alternative treatments are inadequate and only after patients have been titrated to an acceptable level of analgesia using another opioid analgesic.

Apply 1 device to chest or upper outer arm only. Only the patient may activate the device (40 mcg dose of fentanyl per activation, delivered over 10 minutes; maximum: 6 doses per hour). Only 1 device may be applied at a time and operates for up to 24 hours or 80 doses, whichever comes first. Reapply every 24 hours, as necessary, with each subsequent device applied to a different skin site; maximum duration: 72 hours. If inadequate analgesia is achieved with 1 device, either provide additional supplemental analgesia or replace with an alternative analgesic. Refer to manufacturer's labeling for activation instructions and application sites.

Acute nonoperative severe pain

Acute nonoperative severe pain:

Note: For use in ICU or other closely monitored settings.

Intermittent dosing: IV, IM: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (Ref). Note: More frequent administration may be necessary when used by the IV route due to short duration of activity. IM route should only be used if IV administration is not available (eg, loss of IV access).

Chronic pain, including chronic cancer pain

Chronic pain, including chronic cancer pain:

Note: Opioids, including fentanyl, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred, with the exception of chronic pain from sickle cell disease and end-of-life care. Opioids, including fentanyl, should only be considered in patients with chronic, noncancer pain who are expected to experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref).

SUBQ continuous infusion: Note: For progressive illnesses (eg, cancer), a continuous SUBQ infusion, with or without a patient-controlled analgesia option, can be used as pain requirements increase. In general, SUBQ continuous infusion dose is equivalent to IV continuous infusion dose (Ref). Individualize dose based on previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain. Reported dosing varies greatly and is based on practice and patient needs; refer to institutional protocols (Ref).

Transdermal patch: Discontinue or taper all other around-the-clock or extended-release opioids when initiating therapy with fentanyl transdermal patch.

Initial: To convert patients from oral or parenteral opioids to fentanyl transdermal patch, a 24-hour analgesic requirement should be calculated (based on prior opioid use). Using the table below, the appropriate initial dose can be determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage equivalent and titrated to minimize adverse effects and provide analgesia. While there are useful tables of opioid equivalents available, substantial interpatient variability exists in relative potency of different opioids and products. Therefore, it is safer to underestimate the daily fentanyl requirement and provide breakthrough pain relief with rescue medication (eg, immediate-release opioid) than to overestimate requirements, which could result in adverse reactions. With the initial application, the absorption of transdermal fentanyl requires several hours to reach plateau; therefore, transdermal fentanyl is inappropriate for management of acute pain. Change patch every 72 hours. The majority of patients may be controlled on every-72-hour administration; however, some patients may require every-48-hour administration because of more breakthrough pain in the last 24 hours of each cycle.

Conversion from continuous IV infusion of fentanyl: In patients who have adequate pain relief with IV fentanyl infusion, may convert to transdermal dosing at a rate equivalent to the IV rate using a 2-step taper of the infusion to be completed over 12 hours after the patch is applied. Six hours after the application of the first patch, decrease the infusion to 50% of the original rate; discontinue infusion 12 hours after patch application (Ref).

Titration: Do not titrate more frequently than every 3 days after the initial application or every 6 days thereafter. Short-acting opioids may be required until analgesic efficacy is established and/or as supplements for breakthrough pain. The number and quantity of supplemental doses should be closely monitored. When increasing the dose, base the new dose on the daily requirement of supplemental opioids required by the patient during the second or third day of initial application. For example, if 24-hour oral morphine requirement for breakthrough pain is 50 mg, then may increase transdermal fentanyl dose by 25 mcg/hour (Ref).

Dose conversion guidelines for transdermal fentanyl (see table below):

Note: Using the manufacturer's recommended dose conversion guidelines, based upon the daily oral morphine dose, may underestimate the transdermal fentanyl strength required and result in the need for supplemental immediate-release opioid therapy for breakthrough pain or in the patient experiencing withdrawal syndrome (Ref). The manufacturers recommend a ratio of approximately 45 mg/24 hours of oral morphine to a 12 mcg/hour fentanyl dosage (US labeling) or the ratio of 45 to 59 mg/24 hours of oral morphine to a 12 mcg/hour fentanyl dosage (Canadian labeling). Below is a less conservative dosing conversion strategy based on a 2:1 ratio of oral morphine to transdermal fentanyl (Ref). For the more conservative dose conversion strategy, see the manufacturer's labeling. The table is only to be used for the conversion from current opioid therapy to transdermal fentanyl. Do not use this table to convert from transdermal fentanyl to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). This is not a table of equianalgesic doses.

Step 1: Determine the patient's 24-hour oral morphine requirement. If patient was not receiving oral morphine, must convert the 24-hour requirement to the oral morphine equivalent using a conversion chart or tool.

Step 2: Once the 24-hour oral morphine requirement is determined, use the Dose Conversion Guidelines to determine the appropriate fentanyl transdermal dose (mcg/hour).

Dose Conversion Guidelines: Recommended Initial Fentanyl Transdermal Dose Based Upon Daily Oral Morphine Dosea,b,c

Oral 24-Hour Morphine Dose (mg/day)

Fentanyl Transdermal Dose (mcg/hour)

a Portenoy 2019a.

b The table should not be used to convert from transdermal fentanyl to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

c Suggested doses for conversion to transdermal fentanyl from other opioids are less conservative than recommendations in the US product labeling. The recommendations in this table are based on guidance available at experienced centers.

25

12

50

25

100

50

150

75

200

100

250

125

300

150

350

175

400

200

450

225

500

250

550

275

600

300

Discontinuation or tapering of therapy :

When discontinuing or tapering long-term opioid therapy, the dose should be gradually tapered down. An optimal tapering schedule has not been established (Ref). Proposed schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). When discontinuing transdermal fentanyl and not converting to another opioid, particularly in patients who are physically opioid dependent, use a gradual downward titration (eg, decrease the dose by 25% every 2 to 4 weeks) (Ref). Upon system removal of transdermal fentanyl, ≥17 hours are required for a 50% decrease in fentanyl levels. Individualize discontinuation or taper based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns, as well as the opioid's pharmacokinetics. Slower tapers may be appropriate after long-term use (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (Ref). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Ref). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Ref). In patients who continue to take long-term opioid therapy but no longer require fentanyl for breakthrough pain, fentanyl can usually be discontinued without a taper.

Chronic cancer pain, management of breakthrough pain episodes

Chronic cancer pain, management of breakthrough pain episodes:

Transmucosal:

Note: For patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Dose titration should be done if patient requires more than 1 dose per breakthrough pain episode for several consecutive episodes. Patients experiencing >4 breakthrough pain episodes per day should have the dose of their long-term opioid reevaluated. Patients must remain on around-the-clock opioids during use (Ref).

Lozenge (Actiq): Note: Do not convert patients from any other fentanyl product to Actiq on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 200 mcg; individually titrate to provide adequate analgesia while minimizing adverse effects.

Initial dose: 200 mcg (consumed over 15 minutes) for all patients; if after 30 minutes from the start of the lozenge (ie, 15 minutes following the completion of the lozenge) pain is unrelieved, a second 200 mcg dose may be given over 15 minutes. A maximum of 1 additional dose can be given per pain episode; must wait at least 4 hours before treating another episode. To limit the number of units in the home during titration, only prescribe an initial titration supply of six 200 mcg lozenges.

Dose titration: From the initial dose, closely monitor patients and modify the dose until patient reaches a dose providing adequate analgesia using a single dosage unit per breakthrough cancer pain episode. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses. If adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given for that episode; must wait at least 4 hours before treating another episode.

Maintenance dose: Once titrated to an effective dose, patients should generally use a single dosage unit per breakthrough pain episode. During any pain episode, if adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given over 15 minutes for that episode; must wait at least 4 hours before treating another episode. Consumption should be limited to ≤4 units per day (once an effective breakthrough dose is found). If adequate analgesia is not provided after treating several episodes of breakthrough pain using the same dose, increase dose to next highest lozenge strength (initially dispense no more than 6 units of the new strength). Reevaluate the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses.

Buccal tablet (Fentora): Note: Do not convert patients from any other fentanyl product to Fentora on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to buccal tablet (Fentora).

Initial dose: 100 mcg for all patients unless patient is already using Actiq; see Conversion from lozenge (Actiq) to buccal tablet (Fentora). If after 30 minutes pain is unrelieved, a second 100 mcg dose may be administered (US labeling) or an alternative analgesic rescue medication (other than Fentora) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Must wait at least 4 hours before treating another episode with buccal tablet.

Dose titration: If titration required, the 100 mcg dose may be increased to 200 mcg using two 100 mcg tablets (one on each side of mouth) with the next breakthrough pain episode. If 200 mcg dose is not successful, patient can use four 100 mcg tablets (two on each side of mouth) with the next breakthrough pain episode. If titration requires >400 mcg per dose, titrate using 200 mcg tablets; do not use more than 4 tablets simultaneously (maximum single dose: 800 mcg). During any breakthrough pain episode, if adequate relief is not achieved 30 minutes after buccal tablet application, a second dose of same strength for that breakthrough pain episode may be used (US labeling) or an alternative analgesic rescue medication (other than Fentora) may be given (Canadian labeling). Must wait at least 4 hours before treating another episode with buccal tablet.

Maintenance dose: Following titration, the effective maintenance dose using 1 tablet of the appropriate strength should be administered once per episode; if after 30 minutes pain is unrelieved, may administer a second dose of the same strength (US labeling) or an alternative analgesic rescue medication (other than Fentora) may be given (Canadian labeling). Must wait at least 4 hours before treating another episode with buccal tablet. Limit to 4 applications per day. Reevaluate the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day. Once an effective maintenance dose has been established, the buccal tablet may be administered sublingually (alternative route). To prevent confusion, patient should only have one strength available at a time. Once maintenance dose is determined, all other unused tablets should be disposed of and that strength (using a single tablet) should be used. Using more than 4 buccal tablets at a time has not been studied.

Conversion from lozenge (Actiq) to buccal tablet (Fentora):

Lozenge dose 200 or 400 mcg: Initial buccal tablet dose is 100 mcg; may titrate using multiples of 100 mcg.

Lozenge dose 600 or 800 mcg: Initial buccal tablet dose is 200 mcg; may titrate using multiples of 200 mcg.

Lozenge dose 1,200 or 1,600 mcg: Initial buccal tablet dose is 400 mcg (using two 200 mcg tablets); may titrate using multiples of 200 mcg.

Intranasal (Lazanda): Note: Do not convert patients from any other fentanyl product to Lazanda on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects.

Initial dose: 100 mcg (one 100 mcg spray in one nostril) for all patients; if after 30 minutes pain is unrelieved, an alternative rescue medication may be used. Must wait at least 2 hours before treating another episode with fentanyl intranasal. However, for the next pain episode, increase to a higher dose using the recommended dose titration steps.

Dose titration: If titration required, increase to a higher dose for the next pain episode using the following titration steps (Note: Must wait at least 2 hours before treating another episode with fentanyl intranasal): If no relief with 100 mcg dose, increase to 200 mcg dose per episode (one 100 mcg spray in each nostril); if no relief with 200 mcg dose, increase to 300 mcg dose per episode (alternating one 100 mcg spray in right nostril, one 100 mcg spray in left nostril, and one 100 mcg spray in the right nostril); if no relief with 300 mcg dose, increase to 400 mcg dose per episode (one 400 mcg spray in one nostril or alternating two 100 mcg sprays in each nostril); if no relief with 400 mcg dose, increase to 600 mcg dose per episode (one 300 mcg spray in each nostril); if no relief with 600 mcg dose, increase to 800 mcg dose per episode (one 400 mcg spray in each nostril). Note: Single doses >800 mcg have not been evaluated. Avoid use of a combination of dose strengths to treat an episode, as this may cause confusion and dosing errors.

Maintenance dose: Once maintenance dose for breakthrough pain episode has been determined, use that dose for subsequent episodes. For pain that is not relieved 30 minutes after Lazanda administration or if a separate breakthrough pain episode occurs within the 2-hour window before the next Lazanda dose is permitted, a rescue medication may be used. Limit Lazanda use to ≤4 doses per day. If patient is experiencing >4 breakthrough pain episodes per day, consider increasing the around-the-clock, long-acting opioid therapy; if long-acting opioid therapy dose is altered, reevaluate and retitrate Lazanda dose as needed. If response to maintenance dose changes (increase in adverse reactions or alterations in pain relief), dose readjustment may be necessary.

Sublingual:

Sublingual spray (Subsys): Note: Do not convert patients from any other fentanyl product to Subsys on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to sublingual spray (Subsys).

Initial dose: 100 mcg for all patients unless patient is already using Actiq; see Conversion from lozenge (Actiq) to sublingual spray (Subsys). If after 30 minutes pain is unrelieved, 1 additional 100 mcg dose may be given. A maximum of 2 doses can be given per breakthrough pain episode. Must wait at least 4 hours before treating another episode with sublingual spray.

Dose titration: If titration required, titrate to a dose that provides adequate analgesia (with tolerable side effects) using the following titration steps: If no relief with 100 mcg dose, increase to 200 mcg dose (using one 200 mcg unit); if no relief with 200 mcg dose, increase to 400 mcg dose (using one 400 mcg unit); if no relief with 400 mcg dose, increase to 600 mcg dose (using one 600 mcg unit); if no relief with 600 mcg dose, increase to 800 mcg dose (using one 800 mcg unit); if no relief with 800 mcg dose, increase to 1,200 mcg dose (using two 600 mcg units); if no relief with 1,200 mcg dose, increase to 1,600 mcg dose (using two 800 mcg units). During dose titration, if breakthrough pain is unrelieved 30 minutes after Subsys administration, 1 additional dose using the same strength may be administered (maximum: 2 doses per breakthrough pain episode); patient must wait 4 hours before treating another breakthrough pain episode with sublingual spray.

Maintenance dose: Once maintenance dose for breakthrough pain episode has been determined, use that dose for subsequent episodes. If occasional episodes of unrelieved breakthrough pain occur 30 minutes after Subsys administration, 1 additional dose using the same strength may be administered (maximum: 2 doses per breakthrough pain episode); patient must wait 4 hours before treating another breakthrough pain episode with sublingual spray. Once maintenance dose is determined, limit Subsys use to ≤4 doses per day. If response to maintenance dose changes (increase in adverse reactions or alterations in pain relief), dose readjustment may be necessary. If patient is experiencing >4 breakthrough pain episodes per day, reevaluate the around-the-clock, long-acting opioid therapy.

Conversion from lozenge (Actiq) to sublingual spray (Subsys):

Lozenge dose 200 or 400 mcg: Initial sublingual spray dose is 100 mcg; may titrate using multiples of 100 mcg.

Lozenge dose 600 or 800 mcg: Initial sublingual spray dose is 200 mcg; may titrate using multiples of 200 mcg.

Lozenge dose 1,200 or 1,600 mcg: Initial sublingual spray dose is 400 mcg; may titrate using multiples of 400 mcg.

Sublingual tablet (Abstral): Note: Do not convert patients from any other fentanyl product to Abstral on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 100 mcg (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to sublingual tablet (Abstral).

Initial dose: 100 mcg for all patients unless patient is already using Actiq; see Conversion from lozenge (Actiq) to sublingual tablet (Abstral). If after 30 minutes pain is unrelieved, a second 100 mcg dose may be given (US labeling) or an alternative rescue medication (other than Abstral) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Must wait at least 2 hours before treating another episode with sublingual tablet.

Dose titration: If titration required, increase in 100 mcg increments (up to 400 mcg) over consecutive breakthrough episodes. If titration requires >400 mcg per dose, increase in increments of 200 mcg, starting with a 600 mcg dose and titrating up to 800 mcg. During titration, patients may use multiples of 100 mcg and/or 200 mcg tablets for any single dose; do not exceed 4 tablets at one time; safety and efficacy of doses >800 mcg have not been evaluated. During dose titration, if breakthrough pain is unrelieved 30 minutes after sublingual tablet administration, 1 additional dose using the same strength may be administered (US labeling) or an alternative rescue medication (other than Abstral) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Must wait 2 hours before treating another breakthrough pain episode with sublingual tablet.

Maintenance dose: Once maintenance dose for breakthrough pain episode has been determined, use only 1 tablet of the appropriate strength per episode; if pain is unrelieved with maintenance dose, a second dose may be given after 30 minutes (US labeling) or an alternative rescue medication (other than Abstral) may be given (Canadian labeling). A maximum of 2 doses (or 1 dose [Canadian labeling]) can be given per breakthrough pain episode. Separate treatment of subsequent episodes by ≥2 hours; limit Abstral use to ≤4 doses per day. Consider reevaluating the around-the-clock, long-acting opioid therapy in patients experiencing >4 breakthrough pain episodes per day; if long-acting opioid therapy dose altered, reevaluate and retitrate Abstral dose as needed.

Conversion from lozenge (Actiq) to sublingual tablet (Abstral):

Lozenge dose of 200 mcg: Initial sublingual tablet dose is 100 mcg; may titrate using multiples of 100 mcg.

Lozenge dose of 400, 600, 800, or 1,200 mcg: Initial sublingual tablet dose is 200 mcg; may titrate using multiples of 200 mcg.

Lozenge dose of 1,600 mcg: Initial sublingual tablet dose is 400 mcg; may titrate using multiples of 400 mcg.

Critically ill patients in the ICU, pain and sedation

Critically ill patients in the ICU, pain and sedation (off-label use):

Note: Multimodal approaches (eg, a combination of analgesics and techniques) should typically be employed for pain control in this setting. Pain should be monitored using validated scales (eg, behavioral pain scale, critical-care pain observation tool) in ICU patients who are unable to self-report (Ref).

Intermittent dosing:

Loading dose: IV: 25 to 100 mcg or 1 to 2 mcg/kg; may repeat dose if severe pain persists and adverse effects are minimal at the time of expected peak effect (eg, ~5 minutes after administration) (Ref). Follow with intermittent maintenance dose or a continuous infusion.

Maintenance dose: IV: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (Ref).

Continuous infusion:

IV: After initial loading dose (see Intermittent dosing: Loading dose), begin continuous infusion at an initial rate of 25 to 50 mcg/hour; titrate every 30 to 60 minutes to clinical effect (ie, pain control and/or sedation). Usual dosing range: 50 to 200 mcg/hour (some patients may require doses as high as 300 mcg/hour); weight-based dosing range: 0.7 to 10 mcg/kg/hour (Ref). Note: Fentanyl can accumulate in lipid stores when used for extended periods of time and may result in prolonged sedation and reduced ability to liberate from mechanical ventilator (Ref). May administer an additional small bolus dose (eg, 25 mcg) prior to increasing the infusion rate (Ref).

Procedural sedation and analgesia

Procedural sedation and analgesia:

Outside the operating room (alternative agent) (off-label use) :

IV: 0.5 to 1 mcg/kg every 2 minutes until desired level of sedation and analgesia achieved (Ref); generally, the maximum total dose is 250 mcg. If administered with other sedatives (eg, etomidate, propofol, midazolam), do not exceed single doses of 0.5 mcg/kg (Ref).

Intranasal (using parenteral solution [50 mcg/mL]) (off-label route): 1 to 2 mcg/kg as a single dose; administer half the dose in each nostril; maximum total dose: 100 mcg (50 mcg per nostril; based on volume) (Ref). Note: Recommend using a nasal atomizer for delivery (Ref).

Analgesia during monitored anesthesia care or regional anesthesia: IV: Usual initial dose range: 0.5 to 2 mcg/kg, administered in incremental boluses of 25 to 50 mcg, titrated to effect. When used in combination with a sedative (eg, midazolam), consider dosage reduction (Ref). Note: Since an IV should be in place with anesthesia, the IM route is rarely used but still maintained as an option in the manufacturer's labeling. If IM route is used, the dose is equivalent to the recommended IV dose.

Rapid sequence intubation, pretreatment

Rapid sequence intubation, pretreatment (off-label use): IV: Usual dose: 50 to 200 mcg (or 1 to 3 mcg/kg) over 30 to 60 seconds administered ~3 minutes prior to induction. In patients with tenuous hemodynamic status, use lower doses (eg, 1 mcg/kg [or 50 mcg]) or avoid use; in patients with elevated intracranial pressure, use higher doses (eg, 3 mcg/kg [or 200 mcg]) (Ref).

General anesthesia

General anesthesia:

Preinduction: IV: 25 mcg; may repeat in increments of 25 mcg (typical total dose is ≤100 mcg) to provide pain relief or if patient requires a regional anesthesia procedure prior to surgery (Ref).

Induction: IV: 25 to 100 mcg (or 0.5 to 1 mcg/kg) (Ref). Some use a high-dose opioid induction technique (eg, 10 to 25 mcg/kg) for select patients (eg, those with poor myocardial function) who will remain intubated for several hours postoperatively (Ref).

Maintenance:

Intermittent: IV: 25 to 50 mcg bolus as needed; may be used to provide supplemental analgesia during maintenance of general anesthesia with inhaled agents (Ref).

Continuous infusion: IV: 1 to 2 mcg/kg/hour as supplement to total IV anesthesia (TIVA) when controlled postoperative ventilation is planned (Ref).

Neuraxial analgesia

Neuraxial analgesia:

Epidural: Note: Reserve use for patients with severe acute pain (eg, after major abdominal surgery, cancer pain, during labor and delivery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (Ref). Use a preservative-free formulation intended for neuraxial use (Ref).

Single dose: 25 to 100 mcg; may provide adequate relief for up to 8 hours. May repeat with additional 100 mcg boluses on demand (Ref) or alternatively may administer by a continuous infusion (Ref).

Continuous infusion: 25 to 100 mcg/hour (fentanyl alone). When combined with a local anesthetic (eg, bupivacaine), fentanyl requirement is less (Ref).

Intrathecal: Note: Reserve use for patients with severe acute pain (eg, after major abdominal surgery, cancer pain, during labor and delivery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (Ref). Use a preservative-free formulation intended for neuraxial use (Ref).

Single dose: 15 to 25 mcg; may provide adequate relief for up to 6 hours. When combined with a local anesthetic (eg, bupivacaine), fentanyl dose requirement is less (eg, 10 to 15 mcg instead of 15 to 25 mcg) (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Although limited pharmacokinetic data exist in patients with renal insufficiency, <7% to 10% of fentanyl is excreted as unchanged drug and its metabolites are inactive. Fentanyl may be used and is generally considered safe for use in patients with kidney impairment with low initial doses and careful monitoring for accumulation and adverse effects (Ref).

Altered Kidney Function:

Injection: CrCl <50 mL/minute:

No dosage adjustment necessary when single or infrequent bolus doses are used for short interventional procedures (Ref). For more frequent dosing, use small, incremental doses to titrate based on analgesic response and adverse effects (Ref). May need to decrease dose to avoid accumulation (Ref), especially with continuous infusions (Ref).

Transdermal (patch):

Note: Although the manufacturer recommends to avoid use of transdermal fentanyl in severe impairment, fentanyl can be used safely in these patients with caution and close monitoring with initial and long-term use (Ref). The following dose adjustments have been proposed when initiating transdermal fentanyl:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 10 to 50 mL/minute: Initial: 75% of normal dose (Ref).

CrCl <10 mL/minute: Initial: 50% of normal dose (Ref).

Transdermal (device): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); fentanyl pharmacokinetics may be altered in kidney disease.

Transmucosal (buccal tablet, sublingual spray/tablet, lozenge) and intranasal: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Although fentanyl pharmacokinetics may be altered in kidney disease, transmucosal fentanyl can be used successfully in the management of breakthrough cancer pain. Doses should be titrated to reach clinical effect with careful monitoring of patients with severe kidney disease.

Dialysis, Intermittent (thrice weekly): Not dialyzable (Ref):

Transdermal patch: Initial: 50% of normal dose (Ref).

All other formulations/routes: Use lowest effective dose with gradual titration and close monitoring of response and adverse effects (Ref).

Peritoneal dialysis:

Transdermal patch: Initial: 50% of normal dose (Ref).

All other formulations/routes: Use lowest effective dose with gradual titration and close monitoring of response and adverse effects (Ref).

CRRT:

All formulations/routes: Use lowest effective dose with gradual titration and close monitoring of response and adverse effects (Ref).

Dosing: Hepatic Impairment: Adult

Injection: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Transdermal (device): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); fentanyl pharmacokinetics may be altered in hepatic disease.

Transdermal (patch):

Mild to moderate impairment: Initial: Reduce dose by 50%.

Severe impairment: Use not recommended.

Transmucosal (buccal tablet, sublingual spray/tablet, lozenge) and intranasal: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Although fentanyl pharmacokinetics may be altered in hepatic disease, fentanyl can be used successfully in the management of breakthrough cancer pain. Doses should be titrated to reach clinical effect with careful monitoring of patients with severe hepatic disease.

Dosing: Pediatric

(For additional information see "Fentanyl: Pediatric drug information")

Note: Ionsys (transdermal device) and Abstral (sublingual tablets) have been discontinued in the United States for >1 year. Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance.

Acute pain

Acute pain:

Parenteral:

Infants: Limited data available: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 2- to 4-hour intervals; in opioid-tolerant or younger infants, titration to higher doses may be required (up to 4 mcg/kg/dose) (Ref).

Children: Limited data available in <2 years of age: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 30- to 60-minute intervals; in opioid-tolerant children, titration to higher doses may be required. Note: Usual adolescent starting dose is 25 to 50 mcg (Ref).

Adolescents: Note: After the first dose, if severe pain persists and adverse effects are minimal at the time of expected peak effect, may repeat dose (Ref).

<50 kg: Initial: IV: 0.5 to 1 mcg/kg/dose may repeat every 1 to 2 hours although some patients may require more frequent dosing (eg, 30-minute intervals) (Ref).

≥50 kg: Initial: IV: 25 to 50 mcg every 1 to 2 hours although some patients may require more frequent dosing (eg, 30-minute intervals) (Ref).

Intranasal (using parenteral preparation): Limited data available: Children ≥10 kg and Adolescents: Intranasal: Usual dose: 1.5 to 2 mcg/kg once; maximum dose: 100 mcg/dose (Ref); some studies that used an initial dose of 1.5 mcg/kg allowed for second dose of 0.5 to 0.75 mcg/kg, at the discretion of the physician, 10 to 20 minutes after the first dose (Ref).

Procedural sedation and analgesia

Procedural sedation and analgesia:

Parenteral:

Infants and Children: Limited data available in <2 years of age: IM, IV: 1 to 2 mcg/kg/dose; administer 3 minutes before the procedure; maximum dose: 50 mcg/dose; may repeat 1/2 original dose every 3 to 5 minutes if necessary; titrate to effect (Ref).

Adolescents: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg, repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5-minute intervals if needed. Note: Higher doses are used for major procedures.

Intranasal (using parenteral preparation): Limited data available: Infants and Children weighing ≥10 kg and Adolescents: Intranasal: 1.5 to 2 mcg/kg administered 15 minutes prior to procedure; maximum dose: 100 mcg/dose (Ref).

Anesthesia, general; adjunct

Anesthesia, general; adjunct:

Children 2 to 12 years: IM, IV: 2 to 3 mcg/kg/dose; Note: An IV should be in place with general anesthesia so the IM route is rarely used but still maintained as an option in the manufacturer's labeling.

Adolescents:

Low dose: IV: 0.5 to 2 mcg/kg/dose depending on the indication.

Moderate dose: IV: Initial: 2 to 20 mcg/kg/dose; Maintenance (bolus or infusion): 1 to 2 mcg/kg/hour. Discontinuing fentanyl infusion 30 to 60 minutes prior to the end of surgery will usually allow adequate ventilation upon emergence from anesthesia. For "fast-tracking" and early extubation following major surgery, total fentanyl doses are limited to 10 to 15 mcg/kg.

High dose: IV: 20 to 50 mcg/kg/dose; Note: High-dose fentanyl as an adjunct to general anesthesia is rarely used, but is still described in the manufacturer's label.

Anesthesia, general without additional anesthetic agents

Anesthesia, general without additional anesthetic agents: Adolescents: IV: 50 to 100 mcg/kg/dose with O2 and skeletal muscle relaxant.

Anesthesia, regional; adjunct

Anesthesia, regional; adjunct: Adolescents: IM, IV: 50 to 100 mcg; Note: An IV should be in place with regional anesthesia so the IM route is rarely used but still maintained as an option in the manufacturer's labeling.

Cancer pain; breakthrough

Cancer pain; breakthrough: Note: For use in patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Patients must remain on around-the-clock opioids during use.

Transmucosal lozenge (eg, Actiq):

Adolescents ≥16 years:

Initial: 200 mcg (consumed over 15 minutes) for all patients; if after 30 minutes from the start of the lozenge (ie, 15 minutes following the completion of the lozenge), the pain is unrelieved, a second 200 mcg dose may be given over 15 minutes. A maximum of 1 additional dose can be given per pain episode; must wait at least 4 hours before treating another episode. To limit the number of units in the home during titration, only prescribe an initial titration supply of six 200 mcg lozenges. Note: Do not convert patients from any other fentanyl product to Actiq on a mcg-per-mcg basis. Patients previously using another fentanyl product should be initiated at a dose of 200 mcg; individually titrate to provide adequate analgesia while minimizing adverse effects.

Dose titration: Dose titration should be done if patient requires more than 1 dose/breakthrough pain episode for several consecutive episodes. From the initial dose, closely follow patients and modify the dose until patient reaches a dose providing adequate analgesia using a single dosage unit per breakthrough cancer pain episode. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses. If adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given for that episode; must wait at least 4 hours before treating another episode.

Maintenance dose: Once titrated to an effective dose, patients should generally use a single dosage unit per breakthrough pain episode. During any pain episode, if adequate relief is not achieved 15 minutes after completion of the first dose (ie, 30 minutes after the start of the lozenge), only 1 additional lozenge of the same strength may be given over 15 minutes for that episode; must wait at least 4 hours before treating another episode. Consumption should be limited to ≤4 units per day (once an effective breakthrough dose is found). If adequate analgesia is not provided after treating several episodes of breakthrough pain using the same dose, increase dose to next highest lozenge strength (initially dispense no more than 6 units of the new strength). Consider increasing the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day and have their long-term opioid re-evaluated. If signs/symptoms of excessive opioid effects (eg, respiratory depression) occur, immediately remove the dosage unit from the patient's mouth, dispose of properly, and reduce subsequent doses.

Chronic pain, moderate to severe

Chronic pain, moderate to severe (opioid-tolerant):

Transdermal patch (eg, Duragesic): Note: For use in patients who are opioid-tolerant receiving at least 60 mg oral morphine equivalents per day. Discontinue or taper all other around-the-clock or extended-release opioids when initiating therapy with fentanyl transdermal patch:

Children ≥2 years and Adolescents:

Initial: 25 mcg/hour system or higher based on previous opioid dosing. To convert patients from oral or parenteral opioids to transdermal patch, a 24-hour analgesic requirement should be calculated (based on prior opioid use). Using the following tables, the appropriate initial dose can be determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage equivalent and titrated to minimize adverse effects and provide analgesia. Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily fentanyl requirement and provide breakthrough pain relief with rescue medication (eg, immediate release opioid) than to overestimate requirements. With the initial application, the absorption of transdermal fentanyl requires several hours to reach plateau; therefore, transdermal fentanyl is inappropriate for management of acute pain. Change patch every 72 hours.

Conversion from continuous infusion of fentanyl: In patients who have adequate pain relief with a fentanyl infusion, fentanyl may be converted to transdermal dosing at a rate equivalent to the intravenous rate. Based on experience in adults, a two-step taper of the infusion to be completed over 12 hours may be considered (Ref) after the patch is applied. The infusion is decreased to 50% of the original rate 6 hours after the application of the first patch, and subsequently discontinued twelve hours after application.

Titration: Short-acting agents may be required until analgesic efficacy is established and/or as supplements for “breakthrough” pain. The amount of supplemental doses should be closely monitored. Appropriate dosage increases may be based on daily supplemental dosage using the ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage.

Frequency of adjustment: The dosage should not be titrated more frequently than every 3 days after the initial dose or every 6 days thereafter. Titrate dose based on the daily dose of supplemental opioids required by the patient on the second or third day of the initial application. Note: Upon discontinuation, ~17 hours are required for a 50% decrease in fentanyl levels.

Frequency of application: The majority of patients may be controlled on every 72-hour administration; however, a small number of adult patients have required every 48-hour administration.

Discontinuation: When discontinuing transdermal fentanyl and not converting to another opioid, use a gradual downward titration, such as decreasing the dose by 50% every 6 days, to reduce the possibility of withdrawal symptoms.

Dose conversion guidelines for transdermal fentanyl from other opioids (see tables).

Note: The conversion factors in these tables are only to be used for the conversion from current opioid therapy to Duragesic patch. Conversion factors in this table cannot be used to convert from Duragesic to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). US and Canadian dose conversion guidelines differ; consult table for US recommendations. The Canadian product is not approved in pediatric patients. These are not tables of equianalgesic doses.

US Labeling: Dose Conversion Guidelines: Recommended Initial Duragesic Dose Based Upon Daily Oral Morphine Dosea

Oral 24-Hour Morphine

(mg/day)

Duragesic Doseb,c

(mcg/hour)

aThe table should NOT be used to convert from transdermal fentanyl (Duragesic) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

bPediatric patients initiating therapy on a 25 mcg/hour Duragesic system should be opioid-tolerant and receiving at least 60 mg oral morphine equivalents per day.

cA fentanyl 37.5 mcg/hour transdermal system is also available and may be considered during conversion from prior opioids or dose titration.

60 to 134

25

135 to 224

50

225 to 314

75

315 to 404

100

405 to 494

125

495 to 584

150

585 to 674

175

675 to 764

200

765 to 854

225

855 to 944

250

945 to 1,034

275

1,035 to 1,124

300

US Labeling: Dose Conversion Guidelinesa

Current Analgesic

Daily Dosage

(mg/day)

aThe table should NOT be used to convert from transdermal fentanyl (Duragesic) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

Morphine (IM/IV)

10 to 22

23 to 37

38 to 52

53 to 67

Oxycodone (oral)

30 to 67

67.5 to 112

112.5 to 157

157.5 to 202

Codeine (oral)

150 to 447

-

-

-

Hydromorphone (oral)

8 to 17

17.1 to 28

28.1 to 39

39.1 to 51

Hydromorphone (IV)

1.5 to 3.4

3.5 to 5.6

5.7 to 7.9

8 to 10

Meperidine (IM)

75 to 165

166 to 278

279 to 390

391 to 503

Methadone (oral)

20 to 44

45 to 74

75 to 104

105 to 134

Duragesic (fentanyl transdermal) recommended dose (mcg/hour)

25 mcg/hour

50 mcg/hour

75 mcg/hour

100 mcg/hour

Continuous analgesia/sedation

Continuous analgesia/sedation:

Infants and Children: Limited data available in <2 years of age: Initial IV bolus: 1 to 2 mcg/kg followed by continuous IV infusion at initial rate: 1 mcg/kg/hour; titrate to effect; usual range: 1 to 3 mcg/kg/hour; some patients may require higher rates (5 mcg/kg/hour) (Ref).

Adolescents:

≤50 kg: Initial IV bolus: 0.5 to 2 mcg/kg followed by continuous IV infusion at initial rate: 0.5 to 2 mcg/kg/hour based on expert recommendations for children and pediatric patients ≤50 kg (Ref).

>50 kg: Initial IV bolus: 25 to 100 mcg/dose followed by continuous IV infusion at initial rate: 25 to 200 mcg/hour based on expert recommendations for pediatric patients and experience in adult patients (Ref).

Endotracheal intubation, emergent

Endotracheal intubation, emergent: Limited data available: Infants and Children: IV: 1 to 5 mcg/kg/dose (Ref).

Patient-controlled analgesia

Patient-controlled analgesia (PCA): Limited data available:

Note: PCA has been used in children as young as 5 years; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed (Ref):

Children ≥5 years and Adolescents; opioid-naive: IV:

Patient weight ≤50 kg:

Usual concentration: Determined by weight; some centers use the following:

Children <12 kg: 10 mcg/mL.

Children 12 to 30 kg: 25 mcg/mL.

Children >30 kg: 50 mcg/mL.

Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose; usual range: 0.5 to 1 mcg/kg/dose.

Lockout: Usual initial: 5 doses/hour.

Lockout interval: Range: 6 to 8 minutes.

Usual basal rate: 0 to 0.5 mcg/kg/hour.

Patient weight >50 kg:

Usual concentration: 50 mcg/mL.

Demand dose: Usual initial: 20 mcg; usual range: 10 to 50 mcg.

Lockout interval: Usual initial: 6 minutes; usual range: 5 to 8 minutes.

Usual basal rate: ≤50 mcg/hour.

Preoperative sedation

Preoperative sedation: Adolescents <18 years: IM, IV: 50 to 100 mcg administered 30 to 60 minutes prior to surgery or slow IV: 25 to 50 mcg given shortly before induction (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Injection: There are no dosage adjustments provided in the manufacturer's labeling; however, the following guidelines have been used by some clinicians (Ref):

Infants, Children, and Adolescents: The following assumes dosages of 0.5 to 2 mcg/kg/dose or 1 to 5 mcg/kg/hour in normal renal function: IV:

GFR >50 mL/minute/1.73 m2: No adjustment required.

GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of usual dose.

GFR <10 mL/minute/1.73 m2: Administer 50% of usual dose.

Intermittent hemodialysis: Administer 50% of usual dose.

Peritoneal dialysis (PD): Administer 50% of usual dose.

Continuous renal replacement therapy (CRRT): Administer 75% of usual dose.

Transdermal (patch): Pediatric patients ≥2 years: Degree of impairment (ie, CrCl) not defined in manufacturer's labeling.

Mild to moderate impairment: Initial: Reduce dose by 50%.

Severe impairment: Use not recommended.

Transmucosal (lozenge [eg, Actiq]) and nasal spray: Adolescents ≥16 years: Although fentanyl pharmacokinetics may be altered in renal disease, fentanyl can be used successfully in the management of breakthrough cancer pain. Use with caution; reduce initial dose and titrate to reach clinical effect with careful monitoring of patients, especially those with severe renal disease.

Dosing: Hepatic Impairment: Pediatric

Injection: There are no dosage adjustments provided in the manufacturer's labeling.

Transdermal (patch): Pediatric patients ≥2 years:

Mild to moderate impairment: Initial: Reduce dose by 50%.

Severe impairment: Use not recommended.

Transmucosal (lozenge [eg, Actiq]): Adolescents ≥16 years: Although fentanyl pharmacokinetics may be altered in hepatic disease, fentanyl can be used successfully in the management of breakthrough cancer pain. Use with caution; reduce initial dose and titrate to reach clinical effect with careful monitoring of patients, especially those with severe hepatic disease.

Dosing: Older Adult

Elderly patients have been found to be twice as sensitive as younger patients to the effects of fentanyl. A wide range of doses may be used. When choosing a dose, take into consideration the following patient factors: age, weight, physical status, underlying disease states, other drugs used, type of anesthesia used, and the surgical procedure to be performed.

Transmucosal lozenge (eg, Actiq): In clinical trials, patients who were >65 years of age were titrated to a mean dose that was 200 mcg less than that of younger patients.

Dosing: Obesity: Adult

The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):

IV: Use a standard, non–weight-based dose (based on indication) in the majority of patients (eg, pain, ICU analgesia/sedation), then titrate to clinical effect (Ref). If weight-based doses are utilized, use adjusted body weight for initial weight-based dose calculations (based on indication), then titrate to clinical effect (Ref). Clinicians should not change dosing weight from one weight metric to another during therapy (ie, adjusted body weight to/from actual body weight) (Ref). Refer to adult dosing for indication-specific doses.

Non-IV route (eg, transdermal, IM, intranasal): Use a standard non–weight-based dose (based on indication), then titrate to clinical effect (Ref). Refer to adult dosing for indication-specific doses.

Rationale for recommendations: Studies evaluating other opioids in patients with obesity have shown large variations in opioid requirements with no relationship to actual body weight (Ref). Pharmacokinetic studies evaluating fentanyl, a highly lipophilic compound, have shown that if actual body weight is used for calculating dosing in patients with obesity, this may lead to excessive fentanyl concentrations and accumulation with continued use due to reduced clearance as actual body weight increases (Ref). Therefore, use of an alternative size descriptor is recommended for dosing fentanyl in patients with obesity.

Guidelines have suggested using lean body weight (LBW) for initial weight-based dosing of opioids, titrated to effect (Ref); however, there are concerns with calculation errors when using the complex LBW formula, especially in critical situations (Ref). There are also concerns with underdosing in clinical situations where there is a need to optimize drug concentrations (eg, procedural sedation). Use of an alternative size descriptor (ie, adjusted body weight) is recommended for weight-based dosing in patients with class 1, 2, or 3 obesity (BMI ≥30 kg/m2) (Ref).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Liquid, Sublingual, as base:

Subsys: 100 mcg (1 ea [DSC], 10 ea); 200 mcg (1 ea [DSC], 30 ea); 400 mcg (1 ea [DSC], 30 ea); 600 mcg (1 ea [DSC], 30 ea); 800 mcg (1 ea, 30 ea); 1200 mcg (2 ea); 1600 mcg (2 ea) [contains alcohol, usp, levomenthol, propylene glycol]

Lozenge on a Handle, Buccal, as citrate [strength expressed as base]:

Actiq: 200 mcg (1 ea, 30 ea); 400 mcg (1 ea, 30 ea); 600 mcg (1 ea, 30 ea); 800 mcg (1 ea, 30 ea); 1200 mcg (1 ea, 30 ea); 1600 mcg (1 ea, 30 ea) [berry flavor]

Generic: 200 mcg (1 ea, 30 ea); 400 mcg (1 ea, 30 ea); 600 mcg (1 ea, 30 ea); 800 mcg (1 ea, 30 ea); 1200 mcg (1 ea, 30 ea); 1600 mcg (1 ea, 30 ea)

Patch, Transdermal, as hydrochloride [strength expressed as base]:

Ionsys: 40 mcg/actuation (1 ea [DSC], 6 ea [DSC])

Patch 72 Hour, Transdermal, as base:

Duragesic-12: 12 [delivers 12.5 mcg/hr] (5 ea [DSC])

Duragesic-25: 25 [delivers 25 mcg/hr] (5 ea [DSC])

Duragesic-50: 50 [delivers 50 mcg/hr] (5 ea [DSC])

Duragesic-75: 75 [delivers 75 mcg/hr] (5 ea [DSC])

Duragesic-100: 100 [delivers 100 mcg/hr] (5 ea [DSC])

Generic: 100 [delivers 100 mcg/hr] (1 ea, 5 ea); 12 [delivers 12.5 mcg/hr] (1 ea, 5 ea); 25 [delivers 25 mcg/hr] (1 ea, 5 ea); 37.5 [delivers 37.5 mcg/hr] (1 ea, 5 ea); 50 [delivers 50 mcg/hr] (1 ea, 5 ea); 62.5 [delivers 62.5 mcg/hr] (1 ea, 5 ea); 75 [delivers 75 mcg/hr] (1 ea, 5 ea); 87.5 [delivers 87.5 mcg/hr] (1 ea, 5 ea)

Solution, Injection [preservative free]:

Generic: 2500 mcg/50 mL (50 mL)

Solution, Injection, as citrate [preservative free]:

Generic: 50 mcg/mL (1 mL); 2500 mcg/50 mL (50 mL)

Solution, Injection, as citrate [strength expressed as base, preservative free]:

Generic: 100 mcg/2 mL (2 mL); 1000 mcg/20 mL (20 mL); 250 mcg/5 mL (5 mL); 500 mcg/10 mL (10 mL)

Solution, Intravenous, as citrate [strength expressed as base]:

Generic: 2500 mcg/50 mL (50 mL)

Solution, Nasal, as citrate [strength expressed as base]:

Lazanda: 100 mcg/actuation (1 ea); 400 mcg/actuation (1 ea); 300 mcg/spray (1 ea [DSC]) [contains propylparaben]

Solution Cartridge, Injection, as citrate [strength expressed as base, preservative free]:

Generic: 100 mcg/2 mL (2 mL)

Solution Prefilled Syringe, Injection, as citrate:

Generic: 100 mcg/2 mL (2 mL)

Solution Prefilled Syringe, Injection, as citrate [preservative free]:

Generic: 50 mcg/mL (1 mL)

Solution Prefilled Syringe, Intravenous, as citrate:

Generic: 100 mcg/10 mL (10 mL); 500 mcg/50 mL (50 mL); 1000 mcg/20 mL (20 mL); 2500 mcg/50 mL (50 mL)

Solution Prefilled Syringe, Intravenous, as citrate [strength expressed as base]:

Generic: 100 mcg/2 mL (2 mL)

Tablet, Buccal, as citrate [strength expressed as base]:

Fentora: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg

Generic: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg

Tablet Sublingual, Sublingual, as citrate [strength expressed as base]:

Abstral: 100 mcg [DSC], 200 mcg [DSC], 300 mcg [DSC], 400 mcg [DSC], 600 mcg [DSC], 800 mcg [DSC]

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Patch 72 Hour, Transdermal:

Generic: 37 mcg/hr (5 ea)

Patch 72 Hour, Transdermal, as base:

Generic: 100 [delivers 100 mcg/hr] (5 ea); 12 [delivers 12.5 mcg/hr] (5 ea); 25 [delivers 25 mcg/hr] (5 ea); 50 [delivers 50 mcg/hr] (5 ea); 75 [delivers 75 mcg/hr] (5 ea)

Solution, Injection, as citrate:

Generic: 50 mcg/mL (1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 50 mL)

Solution, Injection, as citrate [strength expressed as base]:

Generic: 100 mcg/2 mL (2 mL)

Tablet, Buccal, as citrate [strength expressed as base]:

Fentora: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg

Product Availability

Ionsys (transdermal device) and Abstral (sublingual tablets) have been discontinued in the United States for >1 year.

Controlled Substance

C-II

Prescribing and Access Restrictions

As a requirement of the REMS program, access is restricted.

Transmucosal immediate-release fentanyl products (eg, sublingual tablets and spray, oral lozenges, buccal tablets, intranasal) are only available through the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS program. Enrollment in the program is required for outpatients, prescribers for outpatient use, pharmacies (inpatient and outpatient), and distributors. Enrollment is not required for inpatient administration (eg, hospitals, hospices, long-term care facilities), inpatients, and prescribers who prescribe to inpatients. Further information is available at 1-866-822-1483 or at www.TIRFREMSaccess.com

Note: Effective December, 2011, individual REMs programs for TIRF products were combined into a single access program (TIRF REMS Access). Prescribers and pharmacies that were enrolled in at least one individual REMS program for these products will automatically be transitioned to the single access program.

Administration: Adult

Epidural (Canadian labeling; not in US labeling): For postoperative pain management may administer as bolus dose (diluted in preservative free NS to a final concentration of 10 mcg/mL) or by continuous infusion at a rate of 1 mcg/kg/hour. Use within 24 hours.

Parenteral: Administer IM or IV slowly over 1 to 2 minutes; rapid IV infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest. May also administer SubQ, by continuous infusion, or PCA (off-label).

Transdermal device (eg, Ionsys): Always wear gloves when handling the device. Avoid contact with synthetic materials (such as carpeted flooring) while assembling and avoid exposing the device to electronic security systems. Prior to administration, clip excessive hair from application site if necessary (do not shave); clean the site with alcohol and let dry; do not use soaps, lotions, or other agents. Apply one device to healthy, unbroken/intact, non-irritated, and non-irradiated skin on the chest or upper outer arm only. Allow only the patient to self-administer doses; each on-demand dose is delivered over a 10-minute period. Each device operates up to 24 hours or 80 doses, whichever comes first. After 24 hours have elapsed, or 80 doses have been delivered, the device will not deliver any additional doses; if the patient tries to initiate a dose, the device will ignore the dose request. Ionsys may be used for a maximum of 72 hours, with each subsequent device applied to a different skin site. Refer to manufacturer's labeling for complete activation, administration, and removal instructions.

Transdermal patch (eg, Duragesic): Apply to nonirritated and nonirradiated skin on a flat surface, such as chest, back, flank, or upper arm; apply to the upper back in patients with cognitive impairment. Hair at application site may be clipped (do not shave). If application site must be cleaned prior to application, clean site with clear water and allow to dry completely. Do not use damaged, cut or leaking patches; patch may be less effective. Do not use soaps, oils, lotions, alcohol, or any other agents to cleanse skin before application because they may irritate the skin or alter its characteristics. Immediately after removal from sealed package, firmly press patch in place and hold for 30 seconds. Wash hands immediately with soap and water after applying patch. Change patch every 72 hours; apply new patch to a different skin site. Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl and should be avoided. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, tanning lamps, hot tub, sunbathing, saunas, heated water beds). If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape. If there is continued difficulty with adhesion, an adhesive film dressing (eg, Bioclusive, Tegaderm) may be applied over the system. Dispose of any used or unused patches by removing patch from protective pouch and liner, fold adhesive ends together and flush patch down toilet immediately. Do not flush pouch or protective liner as such items can be discarded in the trash. For used and unused patches, the Canadian labeling recommends folding adhesive ends together and returning to a pharmacy for proper disposal; temporary storage in a biohazard container may be used before returning to pharmacy.

Lozenge: Foil overwrap should be removed just prior to administration. Place the unit in mouth between the cheek and gum and allow it to dissolve. Do not chew. Lozenge may be moved from one side of the mouth to the other using the handle. The unit should be consumed over a period of 15 minutes. After consumption of a complete unit, the handle may be disposed of in a trash container that is out of the reach of children. For a unit that still has any drug matrix remaining on the handle, the handle should be placed under hot running tap water until the entire drug matrix has dissolved. Special child-resistant containers are available to temporarily store partially consumed units that cannot be disposed of immediately. Refer to manufacturer's labeling for additional disposal instructions.

Buccal tablet: Patient should not open blister until ready to administer. The blister backing should be peeled back to expose the tablet; tablet should not be pushed out through the blister. Immediately use tablet once removed from blister. Place entire tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or under the tongue (US labeling recommends for maintenance dosing only; Canadian labeling does not restrict sublingual use to maintenance dosing only); should dissolve in about 14 to 25 minutes. If remnants remain after 30 minutes, they may be swallowed with water. Tablet should not be split, crushed, sucked, chewed, or swallowed whole. When possible, alternate sides of mouth with each dose.

Intranasal:

Lazanda: Prior to initial use, prime device by spraying 4 sprays into the provided pouch (the counting window will show a green bar when the bottle is ready for use). Insert nozzle a short distance into the nose (~1/2 inch or 1 cm) and point towards the bridge of the nose (while closing off the other nostril using 1 finger). Press on finger grips until a “click” sound is heard and the number in the counting window advances by one. The “click” sound and dose counter are the only reliable methods for ensuring a dose has been administered (spray is not always felt on the nasal mucosa). Patient should remain seated for at least 1 minute following administration. Do not blow nose for ≥30 minutes after administration. Wash hands before and after use. If not used within 5 days, re-prime by spraying once. There are 8 full therapeutic sprays in each bottle; do not continue to use bottle after “8” sprays have been used. Dispose of bottle and contents if it has been ≥60 days since first use. Before disposal, all unopened or partially used bottles must be completely emptied by spraying the contents into the provided pouch. After “8” therapeutic sprays has been reached on the counter, patients should continue to spray an additional four sprays into the pouch to ensure that any residual fentanyl has been expelled (an audible click will no longer be heard and the counter will not advance beyond “8”). The empty bottle and the sealed pouch must be put into the child-resistant container before placing in the trash. Wash hands with soap and water immediately after handling the pouch. If the pouch is lost, another one can be ordered by the patient or caregiver by calling 1-866-458-6389.

Parenteral solution (off-label route): Using 50 mcg/mL parenteral solution, administer half the dose in each nostril using a mucosal atomizer device (preferred) or drip into nostril with a needleless syringe; maximum volume per nostril: 1 mL (Ref).

SubQ continuous infusions: Change site every 3 to 7 days or when erythema occurs (Ref). To maintain comfort, the SubQ infusion rate should generally not exceed 5 mL/hour (Ref).

Sublingual spray: Open sealed blister unit with scissors immediately prior to administration. Contents of unit should be sprayed into mouth under the tongue. Dispose of each unit dose immediately after use; place used unit into one of the provided white disposal bags. After sealing appropriately, discard in the trash. Dispose of any unused units as soon as no longer needed. Prior to disposal, empty all the medicine into the provided charcoal-lined disposal pouch. The disposal pouch should then be placed into the white disposal bag, sealed appropriately, and discarded in the trash.

Sublingual tablet: Remove from the blister unit immediately prior to administration. Place tablet directly under the tongue on the floor of the mouth and allow to completely dissolve; do not chew, suck, or swallow. Do not eat or drink anything until tablet is completely dissolved. In patients with a dry mouth, water may be used to moisten the buccal mucosa just before administration. To dispose of sublingual tablets; remove any unused tablets from the blister cards and dispose by flushing down the toilet. In Canada, it is recommended that unused tablets be disposed of via a pharmacy take back program.

Administration: Pediatric

Parenteral: IV:

Neonates: Administer as a continuous infusion via an infusion pump or by slow IV push over 3 to 5 minutes. Larger bolus doses (>5 mcg/kg) should be administered over 5 to 10 minutes; may also administer intermittent doses via syringe pump over 15 to 30 minutes (Ref). Risk of chest wall rigidity is minimized when doses are administered over at least 1 to 2 minutes (Ref).

Infants, Children, and Adolescents: Administer by slow IV push over 3 to 5 minutes or by continuous infusion. Larger bolus doses (>5 mcg/kg) should be given by slow IV push over 5 to 10 minutes.

Transdermal patch: Children ≥2 years and Adolescents: Apply to nonhairy, clean, dry, nonirritated, intact skin of the flat area of front or back of upper torso, flank area, or upper arm; apply to upper back in young children or in people with cognitive impairment to decrease the potential of the patient removing the patch. Monitor the adhesion of the system closely in children. Clip hair prior to application, do not shave area; prior to application, skin may be cleaned with clear water (do not use soaps, lotions, alcohol, oils, or other substances which may irritate the skin); allow skin to dry thoroughly prior to application. Apply patch immediately after removing from package; firmly press in place and hold for at least 30 seconds; change patch every 72 hours; remove old patch before applying new patch; do not apply new patch to same place as old patch; wash hands after applying patch. If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape; if difficulty with adhesion persists, an adhesive film dressing (eg, Bioclusive, Tegaderm) may be applied over the system. If patch falls off before 72 hours, a new patch may be applied to a different skin site. Dispose of any used or unused patches by removing patch from protective pouch and liner, fold adhesive ends together and flush patch down toilet immediately. Do not flush pouch or protective liner as such items can be discarded in the trash.

Note: Transdermal patch is a membrane-controlled system; do not cut the patch to deliver partial doses; do not use patches that are cut, damaged, or leaking; do not use if seal of package is broken; rate of drug delivery may be significantly increased if patch is cut, damaged, or leaking and result in absorption of a potentially fatal dose; reservoir contents and adhesion may be affected if cut; if partial dose is needed, surface area of patch can be blocked proportionally using adhesive bandage (Ref). Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin as they may increase transdermal absorption; use copious amounts of water. Avoid exposing application site to external heat sources (eg, electric blanket, heating pad, heat lamp, tanning lamp, sauna, heated water bed, hot tub, hot baths, sunbathing). Dispose of properly.

Transmucosal products:

Intranasal (using parenteral preparation):

Solution (parenteral preparation): If congested, suction nostrils prior to administration. Using a 50 mcg/mL solution, administer half of the dose to each nostril using an atomizer such as the MAD Nasal Drug delivery device or drip into the nostril slowly with a syringe; higher concentrations (150 mcg/mL and 300 mcg/mL) have been studied to prevent excess volume administration, but comparative trials have not been performed (Ref).

Oral lozenge (eg, Actiq): Adolescents ≥16 years: Oral: Foil overwrap should be removed just prior to administration, patient should place the unit in mouth between cheek and lower gum; occasionally move lozenge from one side of the mouth to the other and allow it to dissolve. Do not bite or chew lozenge; consume lozenge over 15 minutes. Remove handle after lozenge is consumed. Early removal should be considered if the patient has achieved an adequate response and/or shows signs of respiratory depression. After consumption of a complete unit, the handle may be disposed of in a trash container that is out of the reach of children. For a partially consumed unit, or a unit that still has any drug matrix remaining on the handle, the handle should be placed under hot running tap water until the drug matrix has dissolved. Special child-resistant containers are available to temporarily store partially consumed units that cannot be disposed of immediately.

Usual Infusion Concentrations: Adult

IV infusion: 10 mcg/mL

Usual Infusion Concentrations: Pediatric

IV infusion: 10 mcg/mL, 50 mcg/mL

Use: Labeled Indications

Pain management, acute and chronic pain:

Injection: Surgery: Adjunct to general or regional anesthesia; preoperative medication; analgesic during anesthesia and in the immediate postoperative period.

Transdermal device (eg, Ionsys): Postoperative pain, acute: Short-term management of acute postoperative pain severe enough to require an opioid analgesic in the hospital and for which alternative treatments are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. Not for home use. Transdermal device is for use only in patients in the hospital. Discontinue treatment with the device before patients leave the hospital. The device is for use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

Transdermal patch (eg, Duragesic): Chronic pain: Management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Not indicated as an as-needed analgesic.

Transmucosal lozenge (eg, Actiq), buccal tablet (Fentora), intranasal (Lazanda), sublingual tablet (Abstral), sublingual spray (Subsys): Cancer pain, breakthrough: Management of breakthrough cancer pain in opioid-tolerant patients ≥18 years (Abstral, Fentora, Lazanda, Subsys) and ≥16 years (Actiq) of age who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Limitations of use: Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency department. As a part of the TIRF REMS Access program, these products may be dispensed only to outpatients enrolled in the program. For inpatient administration (eg, hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

Note: "Opioid-tolerant" patients are defined as patients who are taking at least:

Oral morphine 60 mg/day, or

Transdermal fentanyl 25 mcg/hour, or

Oral oxycodone 30 mg/day, or

Oral hydromorphone 8 mg/day, or

Oral oxymorphone 25 mg/day, or

Oral hydrocodone 60 mg/day, or

Equianalgesic dose of another opioid for at least 1 week

Use: Off-Label: Adult

Critically ill patients in the ICU (analgesia and sedation); Procedural sedation and analgesia, outside the operating room; Rapid sequence intubation (pretreatment)

Medication Safety Issues
Sound-alike/look-alike issues:

FentaNYL may be confused with alfentanil, SUFentanil

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Administration issues:

Fentanyl transdermal system patches: Leakage of fentanyl gel from the patch has been reported; patch may be less effective; do not use. Thoroughly wash any skin surfaces coming into direct contact with gel with water (do not use soap). May contain conducting metal (eg, aluminum); remove patch prior to MRI.

Other safety concerns:

Fentanyl transdermal system patches:

Avoid use of patches in opioid-naive patients and/or acute pain. Patches are only intended for use in opioid-tolerant patients; steps should be taken to verify opioid status and type of pain being treated prior to prescribing to prevent inappropriate use. Serious harm, including fatalities, are associated with use of patches in opioid-naive patients. Dosing of transdermal fentanyl patches may be confusing. Transdermal fentanyl patches should always be prescribed in mcg/hour, not size. Patch dosage form of Duragesic-12 actually delivers 12.5 mcg/hour of fentanyl. Use caution, as orders may be written as “Duragesic 12.5” which can be erroneously interpreted as a 125 mcg dose.

Patches should be stored and disposed of with care to avoid accidental exposure to children. The FDA has issued numerous safety advisories to warn users of the possible consequences (including hospitalization and death) of inappropriate storage or disposal of patches. According to the 2020 to 2021 ISMP Targeted Medication Safety Best Practices for Hospitals, patches should not be stored in automated dispensing cabinets or as unit stock in clinical areas where acute pain is primarily treated (eg, emergency departments, operating rooms, postanesthesia care units, procedural areas).

Abstral, Actiq, Fentora, and Subsys are not interchangeable; do not substitute doses on a mcg-per-mcg basis.

Adverse Reactions (Significant): Considerations
Opioid-induced constipation

Opioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction (OIBD), which is a broader term that encompasses additional GI opioid-induced adverse reactions including nausea, vomiting, and gastroesophageal reflux. Tolerance does not develop to OIC (Ref). Constipation due to fentanyl may decrease quality of life, contribute to nonadherence, and result in treatment failure (Ref). Transdermal fentanyl may cause less constipation than oral opioids (eg, oxycodone, morphine) (Ref). Fentanyl may cause less constipation than morphine in critically ill children (Ref).

Mechanism: Time-related; activity in both the central and enteric nervous systems, predominantly via the mu-opioid receptor, delays gastric emptying, inhibits peristalsis, impairs enzyme release, and produces antisecretory effects (Ref).

Onset: Varied; changes in peristalsis may occur 5 to 25 minutes after administration of opioids (Ref). However, OIC is defined based on a 7-day period of change (Ref).

Risk factors:

• Chronic opioid administration (Ref)

Opioid-induced respiratory depression

Serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of fentanyl (Ref). Fentanyl may be particularly hazardous secondary to potency, faster onset of action, and lower cross tolerance (Ref).

Mechanism: Dose-related; mediated predominately via the mu-opioid receptor. Activates specific CNS sites (ie, pre-Bötzinger complex and Kölliker-Fuse nucleus) that control respiratory rhythms (Ref).

Onset: Rapid; OIRD reported from 5 minutes to 1.2 hours (Ref).

Risk factors:

• Overdose (but may also occur at therapeutic doses)

• Initiation or dose escalation

• Opioid naive (Ref)

• Opioid misuse/abuse (Ref)

• Respiratory disease (eg, obstructive sleep apnea) (Ref)

• Cardiac disease (Ref)

• Morbid obesity (Ref)

• Older adults

• Kidney and/or liver impairment

• Cachectic or debilitated

• Concurrent benzodiazepines or other CNS depressants

• Concurrent use with cytochrome P450 3A4 inhibitors

Opioid-induced withdrawal

Abrupt discontinuation or dose reduction in patients who are physically dependent (ie, have opioid dependence) to opioids has been associated with a serious opioid-induced withdrawal syndrome (OIW), uncontrolled pain, attempts to find other opioids (including illicit), and suicide in all ages. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Reversal of analgesia, irritability, nausea, and vomiting, abdominal cramping, tachycardia, restlessness, and sweating are common symptoms. Symptoms typically dissipate over 4 to 7 days and fully resolve within 14 days; may cause significant distress but are rarely life-threatening (Ref).

Mechanism: Withdrawal; abrupt discontinuation in patients who are physically dependent on opioids results in noradrenergic hyperactivity. This hyperactivity occurs due to abrupt reversal of adaptive mechanisms related to cAMP, locus coeruleus firing rate, and norepinephrine levels that occur with prolonged exposure to opioids (Ref).

Onset: Rapid; symptoms typically occur within 12 hours after discontinuation and peak at 36 to 72 hours; varies based on half-life of opioid (Ref).

Risk factors:

• Prolonged exposure to opioids (Ref)

- Pediatrics: Neonates >1 week, infants, and children <22 months: Duration of ≥9 days or a total dose ≥2.5 mg/kg has been associated with a 100% chance of developing opioid withdrawal; similarly, a duration of 5 days or a total dose of 1.5 mg/kg has a reported 50% chance of developing opioid withdrawal (Ref)

• Opioid use disorder (Ref)

• Abrupt discontinuation or dose reduction (Ref)

• Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics

• Discontinuation of concurrent cytochrome P450 3A4 inhibitors

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Peripheral edema (5% to 32%)

Dermatologic: Hyperhidrosis (1% to 14%)

Endocrine & metabolic: Dehydration (9% to 21%), hypokalemia (2% to 15%), weight loss (3% to 11%)

Gastrointestinal: Abdominal pain (3% to 15%), anorexia (5% to 11%), constipation (1% to 26%), diarrhea (6% to 16%), dysgeusia (1% to 14%), nausea (2% to 42%), vomiting (1% to 37%)

Hematologic & oncologic: Anemia (3% to 32%), cancer pain (2% to 16%)

Local: Application site erythema (transdermal device: 14%)

Nervous system: Confusion (1% to 16%), depression (1% to 11%), dizziness (1% to 32%), drowsiness (3% to 20%), fatigue (2% to 20%), headache (1% to 17%), insomnia (1% to 11%)

Neuromuscular & skeletal: Asthenia (2% to 30%), back pain (4% to 11%)

Respiratory: Dyspnea (2% to 19%), pneumonia (2% to 16%)

1% to 10%:

Cardiovascular: Bradycardia (≥1%), chest pain (≥1%), chest wall pain (≥1%), deep vein thrombosis (≥1%), edema (≥1%), hypertension (≥1%), hypotension (2%), palpitations (4%), pulmonary embolism (nasal spray: ≥1%), sinus tachycardia (≥1%), tachycardia (≥1%), vascular injury (≥1%), vasodilation (1% to 4%)

Dermatologic: Alopecia (≥1%), cellulitis (≥1%), dermal ulcer (≥1%), diaphoresis (1% to 3%), ecchymoses (≥1%), erythema of skin (1%), night sweats (≥1%), pallor (≥1%), pressure ulcer (≥1%), pruritus (1% to 6%), skin lesion (≥1%), skin rash (1% to 8%)

Endocrine & metabolic: Cachexia (≥1%), hypercalcemia (≥1%), hyperglycemia (≥1%), hypoalbuminemia (≥1%), hypocalcemia (≥1%), hypomagnesemia (≥1%), hyponatremia (≥1%), lactic acidosis (≥1%)

Gastrointestinal: Abdominal distention (≥1%), aphthous stomatitis (sublingual tablet: ≥1%), decreased appetite (≥1%), delayed gastric emptying (≥1%), dyspepsia (≥1%), dysphagia (lozenge, buccal tablet, sublingual spray: ≥1%), eructation (≥1%), flatulence (≥1%), gastritis (≥1%), gastroenteritis (≥1%), gastroesophageal reflux disease (≥1%), gastrointestinal hemorrhage (≥1%), gingival pain (buccal tablet: ≥1%), gingival ulceration (sublingual tablet: ≥1%), gingivitis (lozenge: ≥1%), glossalgia (≥1%), glossitis (lozenge: ≥1%), hematemesis (≥1%), intestinal obstruction (2% to 4%; subileus: <1%), mucosal swelling (buccal tablet: ≥1%), oral candidiasis (lozenge, buccal tablet, sublingual spray: ≥1%), oral herpes simplex infection (≥1%), oral mucosa ulcer (lozenge, buccal and sublingual tablets, nasal spray: ≥1%; including lip ulceration), periodontal abscess (lozenge: (≥1%), rectal disease (≥1%), rectal pain (≥1%), stomach discomfort (≥1%), stomatitis (lozenge, buccal and sublingual tablets, sublingual spray: 1% to 8%), tongue disease (sublingual tablet: ≥1%), upper abdominal pain (3%), xerostomia (1% to 6%)

Genitourinary: Difficulty in micturition (≥1%), dysuria (≥1%), erectile dysfunction (≥1%), hematuria (≥1%), mastalgia (≥1%), pelvic pain (≥1%), scrotal edema (≥1%), urinary incontinence (≥1%), urinary retention (1% to 3%), urinary tract infection (≥1%), urinary urgency (≥1%), vaginal hemorrhage (≥1%), vaginitis (≥1%)

Hematologic & oncologic: Breast neoplasm (≥1%), bruise (≥1%), leukopenia (≥1%), lymphadenopathy (≥1%), lymphedema (≥1%), neutropenia (2% to 8%), pancytopenia (≥1%), rectal hemorrhage (≥1%), thrombocytopenia (≥1%)

Hepatic: Ascites (≥1%), increased serum alkaline phosphatase (≥1%), increased serum aspartate aminotransferase (≥1%), jaundice (≥1%)

Hypersensitivity: Hypersensitivity reaction (≥1%)

Infection: Fungal infection (≥1%), infection (≥1%), influenza (≥1%), sepsis (≥1%), tooth abscess (≥1%), viral infection (≥1%)

Local: Application site irritation (buccal tablet, sublingual spray: ≤3%), application site pain (buccal tablet, transdermal device: ≤4%), application site reaction (buccal tablet, transdermal patch: ≤10%), application site vesicles (buccal tablet, nasal spray, transdermal patch and device: ≤3%)

Nervous system: Abnormal dreams (1%), abnormal gait (1% to 5%), abnormality in thinking (1% to 2%), agitation (≥1%), altered sense of smell (≥1%), amnesia (≥1%), anxiety (2% to 9%), balance impairment (≥1%), chills (≥1%), disorientation (≥1%), disturbance in attention (≥1%), dysphoria (≥1%), emotional lability (≥1%), euphoria (≥1%), falling (≥1%), hallucination (1% to 2%), hypertonia (2%), hypoesthesia (≥1%), irritability (≥1%), lethargy (≥1%), malaise (4%), mental status changes (≥1%), migraine (≥1%), myasthenia (≥1%), myoclonus (4%), nervousness (1% to 4%), neuropathy (≥1%), pain (≥1%), paranoid ideation (≥1%), paresthesia (2%), peripheral neuropathy (≥1%), restlessness (≥1%), sedated state (≥1%), seizure (1% to 2%), sensation of cold (6%), sleep disturbance (≥1%), speech disturbance (≥1%), stupor (1% to 4%), tightness in chest or throat (≥1%), vertigo (1% to 4%), withdrawal syndrome (≥1%)

Neuromuscular & skeletal: Arthralgia (3% to 8%), arthropathy (≥1%), bone disease (≥1%), hypokinesia (≥1%), limb pain (≥1%), lower limb cramp (≥1%), muscle spasm (4%), myalgia (≥1%), neck pain (≥1%), ostealgia (≥1%), pathological fracture (≥1%), shoulder pain (≥1%), tremor (1% to 3%)

Ophthalmic: Blepharoptosis (nasal spray: ≥1%), blurred vision (≥1%), conjunctivitis (≥1%), dry eye syndrome (nasal spray: ≥1%), strabismus (nasal spray: ≥1%), swelling of eye (nasal spray: ≥1%), visual disturbance (1% to 2%)

Otic: Ear disease (≥1%, including pain), tinnitus (≥1%)

Renal: Hydronephrosis (≥1%), renal failure syndrome (≥1%)

Respiratory: Asthma (≥1%), bradypnea (≥1%), bronchitis (≥1%), cough (3% to 9%; increased cough: ≥1%), dyspnea on exertion (≥1%), epistaxis (≥1%), flu-like symptoms (≥1%), hemoptysis (≥1%), hypoxia (≥1%), increased bronchial secretions (≥1%), laryngitis (sublingual spray: ≥1%), nasal congestion (nasal spray: ≥1%), nasal discomfort (nasal spray: ≥1%), nasopharyngitis (≥1%), oropharyngeal pain (≥1%), pharyngitis (≥1%), pharyngolaryngeal pain (≥1%), pleural effusion (≥1%), post nasal drip (nasal spray: ≥1%), rhinitis (≥1%), rhinorrhea (nasal spray: ≥1%), sinusitis (≥1%), upper respiratory tract infection (≥1%), wheezing (≥1%)

Miscellaneous: Fever (5% to 7%), reduced intake of food/fluids (buccal tablet: ≥1%)

<1%:

Cardiovascular: Angina pectoris, cerebral ischemia, facial edema, orthostatic hypotension, peripheral vascular disease, subdural hematoma

Dermatologic: Allergic dermatitis, cheilitis, contact dermatitis, contact hypersensitivity (transdermal patch, application site), eczema, exfoliative dermatitis, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash (application site: transdermal device, lozenge)

Endocrine & metabolic: Decreased libido, hypoglycemia, increased thirst

Gastrointestinal: Dental caries, esophagitis, fecal impaction, fecal incontinence, gastrointestinal disease, gingival hemorrhage (lozenge), hiccups, mucous membrane disease

Genitourinary: Nocturia, oliguria, sexual disorder

Hematologic & oncologic: Granuloma, hemorrhage, prolonged bleeding time

Hepatic: Hepatorenal syndrome, liver tenderness

Infection: Bacterial infection, herpes zoster infection

Local: Application-site dermatitis (transdermal patch), local skin hyperpigmentation (transdermal device, lasting 2 to 3 weeks)

Nervous system: Ataxia, delirium, facial nerve paralysis, flank pain, hemiplegia, voice disorder

Neuromuscular & skeletal: Amyotrophy, arthritis, foot-drop, muscle twitching, myopathy, neck stiffness, synovitis, tendinopathy

Ophthalmic: Disease of the lacrimal apparatus, injury to eye region (hemorrhage), miosis

Otic: Deafness, reversible hearing loss

Renal: Polyuria, pyelonephritis, renal pain

Respiratory: Cyanosis, hyperventilation, pneumothorax, pulmonary disease, respiratory depression, respiratory failure, respiratory insufficiency

Miscellaneous: Cyst

Frequency not defined:

Cardiovascular: Acute myocardial infarction, atrial fibrillation, bigeminy, cardiac arrhythmia, flushing, syncope

Dermatologic: Exfoliation of skin (application site, transdermal device), papule of skin (application site, transdermal device), pustules (application site, transdermal device), xeroderma (application site, transdermal device)

Infection: Abscess

Local: Application site burning (transdermal device), application site discharge (transdermal device), application site edema (transdermal device), application site itching (transdermal device), application site rash (transdermal device)

Nervous system: Drug abuse, hypothermia, neonatal withdrawal, opioid dependence

Respiratory: Atelectasis

Miscellaneous: Abnormal healing

Postmarketing:

Dermatologic: Crusted skin (application site scab, transdermal device), skin erosion (application site, transdermal patch)

Gastrointestinal: Gingival recession (lozenge), tooth loss (lozenge)

Genitourinary: Hypogonadism (Brennan 2013; Debono 2011)

Hematologic & oncologic: Local hemorrhage (application site, transdermal device)

Infection: Localized infection (application site, transdermal device)

Local: Local tissue necrosis (application site, transdermal device)

Nervous system: Hyperesthesia, impaired consciousness, loss of consciousness

Neuromuscular & skeletal: Laryngospasm, muscle rigidity (can be dose related)

Respiratory: Apnea, hypoventilation, respiratory distress

Contraindications

Hypersensitivity (eg, anaphylaxis, hypersensitivity) to fentanyl or any component of the formulation.

Additional contraindications for transdermal device (Ionsys): Significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; gastrointestinal obstruction, including paralytic ileus (known or suspected); hypersensitivity to cetylpyridinium chloride (eg, Cepacol).

Additional contraindications for transdermal patch (Duragesic): Significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; gastrointestinal obstruction, including paralytic ileus (known or suspected); patients requiring short-term therapy, management of acute or intermittent pain, postoperative or mild pain; patients who are not opioid tolerant.

Additional contraindications for transmucosal buccal tablets (Fentora), lozenges (Actiq), sublingual tablets (Abstral), sublingual spray (Subsys), intranasal (Lazanda): Significant respiratory depression (Actiq, Fentora only); acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; gastrointestinal obstruction, including paralytic ileus (known or suspected); acute or postoperative pain (including headache, migraine, or dental pain); patients who are not opioid tolerant; acute pain management in the emergency room.

Canadian labeling: Additional contraindication (not in US labeling):

Injection: Hypersensitivity to other opioids; known or suspected mechanical GI obstruction (eg, bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis, pancreatitis); mild pain that can be managed with other pain medications; acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of a monoamine oxidase inhibitor (MAOI); septicemia; severe hemorrhage or shock; local infection at proposed injection site; disturbances in blood morphology and/or anticoagulant therapy or other concomitant drug therapy or medical conditions which could contraindicate the technique of epidural administration

Sublingual tablets (Abstral): Severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild pain that can be managed with other pain medications; acute pain management other than breakthrough or postoperative pain (including headache or migraine, dental pain or emergency room use); acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of an MAOI; breastfeeding women; during labor and delivery; opioid-nontolerant patients (including patients on intermittent or as needed opioid dosing).

Transdermal patch: Hypersensitivity to other opioids; suspected surgical abdomen (eg, acute appendicitis, pancreatitis); known or suspected mechanical GI obstruction (eg, bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use of MAOIs or within 14 days of therapy; perioperative pain; women who are nursing, pregnant, or during labor and delivery

Transmucosal buccal tablets (Fentora): Hypersensitivity to other opioids; acute pain management in the emergency room; known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); acute or severe bronchial asthma, chronic obstructive airway, status asthmaticus; acute respiratory depression; hypercapnia; cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use or use within 14 days of an MAOI

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

Concerns related to adverse effects:

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Allergic rhinitis: Intranasal: Allergic rhinitis is not expected to alter fentanyl absorption following nasal administration; however, use of nasal decongestants (eg, oxymetazoline) during episodes of rhinitis may result in lower peak concentrations and delayed Tmax, therefore, titration of intranasal fentanyl is not recommended during use of nasal decongestants.

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

• Bradycardia: Use with caution in patients with bradycardia or bradyarrhythmias (may produce further bradycardia).

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment. Avoid transdermal (patch) in patients with severe hepatic impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

• Obesity: Use with caution in patients who are morbidly obese.

• Oral mucositis: Sublingual spray (Subsys): Cancer patients with oral mucositis experienced increased fentanyl exposure following sublingual spray administration; avoid use in patients with ≥ grade 2 mucositis; use with caution in patients with grade 1 mucositis, and closely monitor for respiratory and CNS depression.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Special populations:

• Older adult: Use with caution in elderly patients; may be more sensitive to adverse effects. Decrease initial dose. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

Dosage form specific issues:

• Transdermal iontophoretic system (Ionsys):

- Accidental exposure to an intact Ionsys device or to the hydrogel component, especially by children, can result in a fatal overdose of fentanyl. Following accidental contact with the device or its components, immediately rinse the affected area thoroughly with water. Do not use soap, alcohol, or other solvent because they may enhance the drug's ability to penetrate the skin; monitor for signs of respiratory or CNS depression. If the device is not handled correctly using gloves, healthcare professionals are at risk of accidental exposure to a fatal overdose of fentanyl.

- Ionsys device is considered magnetic resonance unsafe. The device contains metal parts and must be removed and properly disposed of before an MRI procedure to avoid injury to the patient and damage to device. It is unknown if exposure to an MRI procedure increases release of fentanyl from the device. Monitor any patients wearing the device with inadvertent exposure to an MRI for signs of CNS and respiratory depression.

- Use of Ionsys device during cardioversion, defibrillation, X-ray, CT, or diathermy can damage the device from the strong electromagnetic fields set up by these procedures. The device contains radio-opaque components and may interfere with an X-ray image or CT scan. Remove and properly dispose of the device prior to cardioversion, defibrillation, X-ray, CT, or diathermy. Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge and damage to the device. Avoid exposing the device to electronic security systems to reduce the possibility of damage. Use near communications equipment (eg, base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast Radio) and Radio Frequency Identification (RFID) transmitters can damage the device. Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between the device and communications equipment or the RFID transmitter ranges between 0.12 and 23 meters. The low-level electrical current provided by the device does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment. If exposure to the procedures listed above, electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs, and if the device does not appear to function normally, remove and replace with a new device.

- Topical skin reactions (erythema, sweating, vesicles, papules/pustules) may occur with use and are typically limited to the application site area. If a severe skin reaction is observed, remove device and discontinue further use.

• Transdermal patch:

- Serum fentanyl concentrations may increase by approximately one-third for patients with a body temperature of 40°C (104°F) secondary to a temperature-dependent increase in fentanyl release from the patch and increased skin permeability.

- Avoid unclothed/unwashed application site exposure, inadvertent person-to-person patch transfer (eg, while hugging), incidental exposure (eg, sharing same bed, sitting on patch), intentional exposure (eg, chewing), or accidental exposure by caregivers when applying/removing patch.

- May contain conducting metal (eg, aluminum); remove patch prior to MRI.

Other warnings/precautions:

• Abuse/misuse/diversion:Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age and psychotropic medication use.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain antiseizure medications and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of) or substance use disorder, have higher opioid dosages (≥50 MME/day orally) (CDC [Dowell 2016]), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Warnings: Additional Pediatric Considerations

Dosage form specific:

Use transdermal patch in pediatric patients only if they are opioid-tolerant, receiving at least 60 mg oral morphine equivalents per day, and ≥2 years of age.

Use of Actiq was evaluated in a clinical trial of 15 opioid-tolerant pediatric patients (age: 5 to 15 years) with breakthrough pain; 12 of the 15 patients received doses of 200 mcg to 600 mcg; no conclusions about safety and efficacy could be drawn due to the small sample size.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Antiplatelet Agents (P2Y12 Inhibitors): FentaNYL may diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). FentaNYL may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a moderate CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of FentaNYL. Management: Consider fentanyl dose reductions when combined with a strong CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modification

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Decongestants: May decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Linezolid: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Meperidine: May enhance the CNS depressant effect of FentaNYL. Meperidine may enhance the serotonergic effect of FentaNYL. This could result in serotonin syndrome. Management: Consider alternatives to this combination. If use is necessary, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

MiFEPRIStone: May increase the serum concentration of FentaNYL. Risk X: Avoid combination

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): FentaNYL may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination

Monoamine Oxidase Inhibitors (Type B): FentaNYL may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid combination

Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Nefazodone: FentaNYL may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of FentaNYL. Management: Consider reducing fentanyl dose. Monitor for signs and symptoms of respiratory depression, sedation, and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia) when these agents are combined. Risk D: Consider therapy modification

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

PHENobarbital: May enhance the CNS depressant effect of FentaNYL. PHENobarbital may decrease the serum concentration of FentaNYL. Management: Avoid use of fentanyl and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May enhance the CNS depressant effect of FentaNYL. Primidone may decrease the serum concentration of FentaNYL. Management: Avoid use of fentanyl and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased fentanyl efficacy and withdrawal if combined. Risk D: Consider therapy modification

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Propofol: May enhance the CNS depressant effect of FentaNYL. Management: Consider alternatives to this combination when possible. If the combination is used, monitor more closely for bradycardia, apnea, and excessive CNS depression. Propofol induction dose requirements may be reduced. Pediatric patients may be at greater risk. Risk D: Consider therapy modification

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy

Serotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy

Serotonergic Non-Opioid CNS Depressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: FentaNYL may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification

Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

St John's Wort: May enhance the serotonergic effect of FentaNYL. This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of FentaNYL. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and reduced fentanyl effects (including withdrawal symptoms) when combined. Monitor for increased fentanyl effects if St. John's wort is discontinued. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

TraMADol: Serotonergic Opioids (High Risk) may enhance the CNS depressant effect of TraMADol. Serotonergic Opioids (High Risk) may enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013).

Pregnancy Considerations

Fentanyl crosses the placenta (Leuschen 1990). Fentanyl can be detected in neonatal urine 24 hours after maternal epidural administration (Moore 2016).

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 209 2019). Transient muscular rigidity has been observed in the neonate following maternal administration of IV fentanyl; symptoms of respiratory or neurological depression were not different than those observed in infants of untreated mothers following IV or epidural use during labor.

[US Boxed Warning]: Prolonged use of fentanyl during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psychophysiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Fentanyl IM and IV injection are commonly used to treat maternal pain during labor and immediately postpartum; the intranasal route has also been studied (ACOG 209 2019; Jabalameli 2016). Not all formulations are recommended.

The ACOG recommends that pregnant women should not be denied medically necessary surgery, regardless of trimester. If the procedure is elective, it should be delayed until after delivery (ACOG 775 2019).

Breastfeeding Considerations

Fentanyl and norfentanyl are present in breast milk (Cohen 2009).

The actual amount received by a breastfeeding infant varies. Reports are available following IV or epidural use during labor (Goma 2008; Leuschen 1990; Nitsun 2006; Steer 1992) or chronic maternal use of the transdermal patch (Cohen 2009). Not all studies evaluated concentrations of the active metabolite.

Nonopioid analgesics are preferred for breastfeeding females who require pain control peripartum or for surgery outside of the postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]). Fentanyl may be used when an opioid is needed (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]).

When opioids are needed in breastfeeding women, the lowest effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant. In general, a single occasional dose of an opioid analgesic may be compatible with breastfeeding (WHO 2002). Breastfeeding women using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness, sedation, feeding difficulties, or limpness (ACOG 209 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.

The Academy of Breast Feeding Medicine recommends postponing elective surgery until milk supply and breastfeeding are established. Milk should be expressed ahead of surgery when possible. In general, when the child is healthy and full term, breastfeeding may resume, or milk may be expressed once the mother is awake and in recovery. For children who are at risk for apnea, hypotension, or hypotonia, milk may be saved for later use when the child is at lower risk (ABM [Reece-Stremtan 2017]).

Dietary Considerations

Transmucosal lozenge contains 2 g sugar per unit.

Monitoring Parameters

Pain relief; respiratory and mental status/alertness (especially in patients on concomitant CNS depressants, including benzodiazepines), BP, heart rate; signs of misuse, abuse, or addiction; symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile BP, hyperthermia), neuromuscular changes (eg, hyperreflexia, incoordination), and/or GI symptoms (eg, nausea, vomiting, diarrhea); symptoms of neonatal withdrawal syndrome in babies born to mothers using opioids during pregnancy, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight; during discontinuation of therapy, monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).

Transdermal patch: Monitor for 24 hours after application of first dose. Patients who experience adverse reactions should be monitored for at least 24 hours after removal of the patch. Drug continues to be absorbed from the skin for 24 hours or more following removal of the patch.

Alternate recommendations:

Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).

Mechanism of Action

Binds with stereospecific receptors at many sites within the CNS, increases pain threshold, alters pain reception, inhibits ascending pain pathways

Pharmacokinetics

Onset of action:

Children 3 to 12 years: Intranasal: 5 to 10 minutes (Borland 2002).

Adults: Analgesic: IM: 7 to 8 minutes; IV: Almost immediate (maximal analgesic and respiratory depressant effects may not be seen for several minutes); Transdermal patch (initial placement): 6 hours; Transmucosal: 5 to 15 minutes.

Duration: IM: 1 to 2 hours; IV: 0.5 to 1 hour; Transdermal (removal of patch/no replacement): Related to blood level; some effects may last 72 to 96 hours due to extended half-life and absorption from the skin, fentanyl concentrations decrease by ~50% in 20 to 27 hours; Transmucosal: Related to blood level; respiratory depressant effect may last longer than analgesic effect.

Absorption:

Transdermal, patch: Initial application: Drug is released at a nearly constant rate from the transdermal matrix system into the skin, where it accumulates; this results in a depot of fentanyl in the outer layer of skin. Fentanyl is absorbed into systemic circulation from the depot. This results in a gradual increase in serum concentration over the first 12 to 24 hours, followed by fairly constant concentrations for the remainder of the dosing interval. Absorption is decreased in cachectic patients (compared to normal size patients). Exposure to external heat increases drug absorption from patch.

Transdermal, device: At the activation of each dose, an electrical current is activated for 10 minutes, which moves a dose of fentanyl from the drug-containing reservoir through the skin and into the systemic circulation. Fentanyl concentrations increase slowly with device activation and continue to increase for ~5 minutes after the completion of each 10 minute dose. Absorption of fentanyl from the device increases as a function of time and is independent of frequency of dosing.

Transmucosal, buccal tablet: Rapid, ~50% from the buccal mucosa; remaining 50% swallowed with saliva and slowly absorbed from GI tract.

Transmucosal, lozenge: Rapid, ~25% from the buccal mucosa; 75% swallowed with saliva and slowly absorbed from GI tract.

Distribution: Highly lipophilic, redistributes into muscle and fat; Note: IV fentanyl exhibits a 3-compartment distribution model. Changes in blood pH may alter ionization of fentanyl and affect its distribution between plasma and CNS.

Vdss:

Preterm and term neonates: Note: Volume of distribution is highly variable and significantly influenced by patient weight (Norman 2019; Wu 2022).

Bolus dose: 5.1 ± 1 L/kg (Koehntop 1986).

Infants, Children, and Adolescents ≤14 years of age (after long-term continuous infusion): ~15 L/kg (range: 5 to 30 L/kg) (Katz 1993).

Adults: 4 to 6 L/kg.

Protein binding: 79% to 87%, primarily to alpha-1 acid glycoprotein; also binds to albumin and erythrocytes; Note: Free fraction increases with acidosis.

Metabolism: Hepatic, primarily via CYP3A4 by N-dealkylation (to norfentanyl) and hydroxylation to other inactive metabolites.

Bioavailability: Note: Comparative studies have found the buccal tablet to have a 30% to 50% greater exposure than the transmucosal lozenge.

Buccal tablet: 65%.

Lozenge: ~50%.

Sublingual spray: 76%.

Sublingual tablet: 54%.

Half-life elimination:

IV:

Preterm and term neonate (PNA ≤14 days): Bolus dose: 5.28 ± 1.17 hours (Koehntop 1986); Note: Half-life may be prolonged (1.5 to 3 times the population mean) in patients with increased intra-abdominal pressure (Koehntop 1986).

Pediatric patients 5 months to 4.5 years: 2.4 hours.

Pediatric patients 6 months to 14 years (after long-term continuous infusion): ~21 hours (range: 11 to 36 hours).

Adults: 2 to 4 hours; when administered as a continuous infusion, the half-life prolongs with infusion duration due to the large volume of distribution (Sessler 2008).

SUBQ bolus injection: 10 hours (Capper 2010).

Transdermal device: Terminal: ~16 hours.

Transdermal patch: 20 to 27 hours (apparent half-life is influenced by continued fentanyl absorption from skin).

Transmucosal products: 3 to 14 hours (dose dependent).

Intranasal: 15 to 25 hours (based on a multiple-dose pharmacokinetic study when doses are administered in the same nostril and separated by a 1-, 2-, or 4-hour time lapse).

Buccal tablet: 100 to 200 mcg: 3 to 4 hours; 400 to 800 mcg: 11 to 12 hours.

Time to peak:

Buccal tablet: 20 to 240 minutes (median: 47 minutes).

Lozenge: 20 to 480 minutes (median: 20 to 40 minutes).

Intranasal: Median: 15 to 21 minutes.

SubQ bolus injection: 10 to 30 minutes (median: 15 minutes) (Capper 2010).

Sublingual spray: 10 to 120 minutes (median: 90 minutes).

Sublingual tablet: 15 to 240 minutes (median: 30 to 60 minutes).

Transdermal patch: 20 to 72 hours; steady state serum concentrations are reached after two sequential 72-hour applications.

Excretion: Urine 75% (primarily as metabolites, <7% to 10% as unchanged drug); feces ~9%.

Clearance: Neonates: Clearance rapidly increased based on birthweight and PNA (Wu 2022); one study identified PNA as the most relevant covariate with very low clearance in the first few days after birth and then rapidly increasing until about 10 to 15 days of life (Völler 2019).

Pharmacokinetics: Additional Considerations

Altered kidney function: May alter kinetics because of alterations in clearance and plasma proteins.

Hepatic function impairment: May alter kinetics because of alterations in clearance and plasma proteins.

Pediatric: Plasma concentrations with transdermal use were approximately twice as high in pediatric patients 1.5 to 5 years of age, who are not opioid-tolerant, compared with adults. Pharmacokinetic parameters in older pediatric patients were similar to those seen in adults.

Older adult: Reduced clearance and terminal half-life is prolonged (transdermal).

Sex: Systemic exposure was higher in women after administration of buccal fentanyl (Fentora); this difference was largely attributed to differences in weight.

Race/ethnicity: Systemic exposure was higher in Japanese subjects after administration of buccal fentanyl (Fentora); this difference was largely attributed to differences in weight.

Extracorporeal membrane oxygenation (ECMO): Neonates, Infants, Children, and Adolescents: Increases in circulating blood volume and extraction of drug by the ECMO circuit (tubing and/or oxygenator) result in an increased volume of distribution (Vd) of drugs in patients on ECMO (Raffaeli 2019; Zimmerman 2020). As a result, larger doses/infusion rates may be required to achieve adequate pain control and level of sedation.

Pricing: US

Liquid (Subsys Sublingual)

100 mcg (per each): $91.96

200 mcg (per each): $121.38

400 mcg (per each): $184.01

600 mcg (per each): $244.64

800 mcg (per each): $305.69

1200 (600 X 2) mcg (per each): $244.64

1600 (800 X 2) mcg (per each): $305.69

Lozenge (Actiq Buccal)

200 mcg (per each): $104.87

400 mcg (per each): $132.72

600 mcg (per each): $162.66

800 mcg (per each): $192.53

1200 mcg (per each): $250.26

1600 mcg (per each): $308.72

Lozenge (fentaNYL Citrate Buccal)

200 mcg (per each): $18.80 - $18.83

400 mcg (per each): $23.82 - $23.85

600 mcg (per each): $29.18 - $29.21

800 mcg (per each): $34.57 - $34.61

1200 mcg (per each): $44.95 - $45.00

1600 mcg (per each): $55.44 - $55.50

Patch, 72-hour (fentaNYL Transdermal)

12 mcg/hr (per each): $20.30

25 mcg/hr (per each): $14.42 - $21.27

37.5 mcg/hr (per each): $65.31

50 mcg/hr (per each): $26.36 - $38.88

62.5 mcg/hr (per each): $94.91

75 mcg/hr (per each): $40.21 - $59.31

87.5 mcg/hr (per each): $129.22

100 mcg/hr (per each): $53.36 - $78.71

Solution (fentaNYL Citrate (PF) Injection)

50 mcg/mL (per mL): $2.34 - $2.65

100 mcg/2 mL (per mL): $0.76 - $1.27

250 mcg/5 mL (per mL): $0.46 - $0.72

500MCG/10ML (per mL): $0.37

1000 mcg/20 mL (per mL): $0.38 - $0.66

2500 mcg/50 mL (per mL): $0.43 - $0.60

Solution (fentaNYL Citrate Intravenous)

2500 mcg/50 mL (per mL): $0.53

Solution (Lazanda Nasal)

100 mcg/ACT (per each): $1,222.58

400 mcg/ACT (per each): $1,949.58

Solution Cartridge (fentaNYL Citrate (PF) Injection)

100 mcg/2 mL (per mL): $1.26

Solution Prefilled Syringe (fentaNYL Citrate Injection)

100 mcg/2 mL (per mL): $1.95

Solution Prefilled Syringe (fentaNYL Citrate PF Injection)

50 mcg/mL (per mL): $2.65

Tablets (fentaNYL Citrate Buccal)

100 mcg (per each): $58.06

200 mcg (per each): $73.35

400 mcg (per each): $106.43

600 mcg (per each): $138.18

800 mcg (per each): $170.23

Tablets (Fentora Buccal)

100 mcg (per each): $82.24

200 mcg (per each): $103.91

400 mcg (per each): $150.77

600 mcg (per each): $195.73

800 mcg (per each): $241.13

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Abstral (BH, BM, EG, ES, GB, HR, IE, LB, NO, PH, QA, TR);
  • Actiq (AU, CH, DE, DK, ES, FR, GB, IE, IL, IT, KR, PT, SE);
  • Adolor (CZ);
  • Breakyl (CZ, GB, LV);
  • Denpax (AU);
  • Dolforin (BG, CZ, LV);
  • Durasic (BD);
  • Durogesic (AE, AU, BH, CN, CO, CY, EG, ES, ID, IN, JO, LB, LK, MX, MY, PH, PK, PY, QA, SA, SG, TH, VN, ZA);
  • Durogesic D Trans (HK, KR, TW);
  • Durogesic D-Trans (BR, CR, DO, GT, HN, NI, PA);
  • Durotep MT (JP);
  • Effentora (CH, EE, ES, FI, GB, HR, IE, MT);
  • Etanyl (ID);
  • Fantamax (SG);
  • Fencino (GB);
  • Fenodid (CR, DO, GT, HN, NI, PA);
  • Fent (LK);
  • Fentaderm Patch (KR);
  • Fentadur Patch (KR);
  • Fentalis (GB, IE);
  • Fentamax Mat Patch (KR);
  • Fentanest (BR, ES, IT, MX, PY, UY);
  • Fentanila (CL);
  • Fentanilo (CU);
  • Fentanyl (SV);
  • Fentanyl Citrate (EC);
  • Fentavera (EG);
  • Fentax (PY);
  • Fentora (HK);
  • Fenvel (IT);
  • Filtaten (MX);
  • Instanyl (AT, CZ, DE, DK, EE, ES, FR, HR, IS, LT, LU, MT, NL, NO, PL, SE, SI, SK);
  • Instanyl Nasal (GB);
  • Ionsys (AT, BE, BG, CH, CZ, DE, DK, EE, FI, FR, GB, GR, IE, MT, NL, PT, RU, SE, SK, TR);
  • Leptanal (NO, SE);
  • Lunaldin (LV);
  • Matrifen (BE, CH, DE, DK, EE, FR, GB);
  • Mezolar Matrix (GB);
  • Oncolis (BM);
  • One Duro (JP);
  • Opifen (BD);
  • Opiodur (GB);
  • Osmanil (GB);
  • PecFent (GB);
  • Pecfent (HK);
  • Pentyl (BD);
  • Recivit (GB);
  • Sublimaze (AR, AU, GB, IE, NZ, PH, ZA);
  • Trofentyl (IN, PH);
  • Vellofent (RO);
  • Verfen (LK);
  • Victanyl (GB)


For country code abbreviations (show table)
  1. Abstral (fentanyl) [prescribing information]. Solana Beach, CA: Sentynl Therapeutics Inc; October 2019.
  2. Abstral (fentanyl) [product monograph]. St-Laurent, Quebec, Canada: Paladin Labs Inc; March 2018.
  3. Actiq (fentanyl) [prescribing information]. Parsippany, NJ: Teva Pharmaceuticals USA Inc; March 2021.
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