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FentaNYL

Pronunciation

Pronunciation

(FEN ta nil)

Index Terms

  • Fentanyl Citrate
  • Fentanyl HCl
  • Fentanyl Hydrochloride
  • Fentanyl Patch
  • OTFC (Oral Transmucosal Fentanyl Citrate)

Dosage Forms

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

Film, for buccal application, as citrate [strength expressed as base]:

Onsolis: 200 mcg (30s); 400 mcg (30s); 600 mcg (30s); 800 mcg (30s); 1200 mcg (30s) [DSC]

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

Sublimaze: 100 mcg/2 mL (2 mL); 250 mcg/5 mL (5 mL); 1000 mcg/ 20 mL (20 mL [DSC])

Generic: 100 mcg/2 mL (2 mL); 250 mcg/5 mL (5 mL); 500 mcg/10 mL (10 mL); 1000 mcg/ 20 mL (20 mL); 2500 mcg/50 mL (50 mL)

Liquid, sublingual, as base [spray]:

Subsys: 100 mcg (30s); 200 mcg (30s); 400 mcg (30s); 600 mcg (30s); 800 mcg (30s) [contains dehydrated ethanol 63.6%, propylene glycol]

Lozenge, oral, as citrate [strength expressed as base, transmucosal]:

Actiq: 200 mcg (30s); 400 mcg (30s); 600 mcg (30s); 800 mcg (30s); 1200 mcg (30s); 1600 mcg (30s) [contains sugar 2 g/lozenge; berry flavor]

Generic: 200 mcg (30s); 400 mcg (30s); 600 mcg (30s); 800 mcg (30s); 1200 mcg (30s); 1600 mcg (30s)

Patch, transdermal, as base:

Duragesic: 12 [delivers 12.5 mcg/hr] (5s) [contains ethanol 0.1 mL/10 cm2; 5 cm2]

Duragesic: 25 [delivers 25 mcg/hr] (5s) [contains ethanol 0.1 mL/10 cm2; 10 cm2]

Duragesic: 50 [delivers 50 mcg/hr] (5s) [contains ethanol 0.1 mL/10 cm2; 20 cm2]

Duragesic: 75 [delivers 75 mcg/hr] (5s) [contains ethanol 0.1 mL/10 cm2; 30 cm2]

Duragesic: 100 [delivers 100 mcg/hr] (5s) [contains ethanol 0.1 mL/10 cm2; 40 cm2]

Ionsys: 40 mcg/actuation (6s) [iontophoretic transdermal system]

Generic: 12 [delivers 12.5 mcg/hr] (5s); 25 [delivers 25 mcg/hr] (5s); 50 [delivers 50 mcg/hr] (5s); 75 [delivers 75 mcg/hr] (5s); 87.5 [delivers 87.5 mcg/hr] (5s); 100 [delivers 100 mcg/hr] (5s)

Powder, for prescription compounding, as citrate: USP: 100% (1 g)

Solution, intranasal, as citrate [strength expressed as base, spray]:

Lazanda: 100 mcg/spray (5 mL); 300 mcg/spray (5 mL); 400 mcg/spray (5 mL) [delivers 8 metered sprays]

Tablet, for buccal application, as citrate [strength expressed as base]:

Fentora: 100 mcg (28s); 200 mcg (28s); 400 mcg (28s); 600 mcg (28s); 800 mcg (28s)

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

Abstral: 100 mcg (12s, 32s); 200 mcg (12s, 32s); 300 mcg (12s, 32s); 400 mcg (12s, 32s); 600 mcg (32s); 800 mcg (32s)

Brand Names: U.S.

  • Abstral
  • Actiq
  • Duragesic
  • Fentora
  • Ionsys
  • Lazanda
  • Onsolis [DSC]
  • Sublimaze
  • Subsys

Pharmacologic Category

  • Analgesic, Opioid
  • Anilidopiperidine Opioid
  • General Anesthetic

Pharmacology

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

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 and buccal film: 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: Children: 0.05 to 14 years of age (after long-term continuous infusion): ~15 L/kg (range: 5 to 30 L/kg)

Vdss: Adults: 4 to 6 L/kg

Metabolism

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

Excretion

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

Clearance: Newborn infants: Clearance may be significantly correlated to gestational age and birth weight (Saarenmaa 2000)

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

Time to Peak

Buccal film: 0.75 to 4 hours (median: 1 hour)

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

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

Nasal spray: Median: 15 to 21 minutes

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

Duration of Action

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

Half-Life Elimination

IV:

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)

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)

Nasal spray: 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 film: ~14 hours

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

Protein Binding

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

Special Populations: Renal Function Impairment

May alter kinetics because of alterations in clearance and plasma proteins.

Special Populations: Hepatic Function Impairment

May alter kinetics because of alterations in clearance and plasma proteins.

Special Populations: Elderly

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

Special Populations: Children

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.

Special Populations: Gender

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

Special Populations: Race

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

Use: Labeled Indications

Injection:

Pain management: Relief of pain, preoperative medication.

Surgery: Adjunct to general or regional anesthesia.

Transdermal device (eg, Ionsys): Postoperative pain, acute: Short-term management of acute postoperative pain in adult patients requiring opioid analgesia in the hospital.

Limitations of use: 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: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve fentanyl transdermal patch 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.

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

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

Equianalgesic dose of another opioid for at least 1 week

Contraindications

Hypersensitivity to fentanyl or any component of the formulation

Additional contraindications for transdermal device (eg, Ionsys): Significant respiratory depression; acute or severe bronchial asthma; known or suspected paralytic ileus and GI obstruction; hypersensitivity to cetylpyridinium chloride (eg, Cepacol)

Additional contraindications for transdermal patches (eg, Duragesic): Severe respiratory disease or depression including acute asthma (unless patient is mechanically ventilated); paralytic ileus; patients requiring short-term therapy, management of acute or intermittent pain, postoperative or mild pain, and in patients who are not opioid tolerant

Additional contraindications for transmucosal buccal tablets (Fentora), buccal films (Onsolis), lozenges (eg, Actiq), sublingual tablets (Abstral), sublingual spray (Subsys), nasal spray (Lazanda): Contraindicated in the management of acute or postoperative pain (including headache, migraine, or dental pain), and in patients who are not opioid tolerant. Abstral and Onsolis also are contraindicated for acute pain management in the emergency room.

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

Injection: 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 respiratory depression or severe obstructive lung disease.

Transdermal patch: Hypersensitivity to other opioids; suspected surgical abdomen (eg, acute appendicitis, pancreatitis); known or suspected mechanical GI obstruction (eg, bowel obstruction, strictures); acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure and head injury; concurrent use of monoamine oxidase (MAO) inhibitors or within 14 days of therapy; women who are nursing, pregnant, or during labor and delivery

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

Dosing: Adult

Note: Ranges listed may not represent the maximum doses that may be required in some patients. Doses and dosage intervals should be titrated to pain relief/prevention. Monitor vital signs routinely. Single IM doses have duration of 1-2 hours, single IV doses last 0.5 to 1 hour.

Surgery:

Premedication: IM, slow IV: 50 to 100 mcg administered 30 to 60 minutes prior to surgery or slow IV: 25 to 50 mcg given shortly before induction (Barash, 2009)

Adjunct to general anesthesia: Slow IV:

Low dose: 1 to 2 mcg/kg depending on the indication (Miller, 2010); additional maintenance doses are generally not needed.

Moderate dose (fentanyl plus a sedative/hypnotic): Initial: 2 to 4 mcg/kg; Maintenance (bolus or infusion): 25 to 50 mcg every 15 to 30 minutes or 0.5 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.

High dose (opioid anesthesia): 4 to 20 mcg/kg bolus then 2 to 10 mcg/kg/hour (Miller, 2010); Note: High-dose fentanyl (ie, 20 to 50 mcg/kg) is rarely used, but is still described in the manufacturer’s label. The concept of fast-tracking and early extubation following cardiac surgery has essentially replaced high-dose fentanyl anesthesia.

Adjunct to regional anesthesia: 50 to 100 mcg IM or slow IV over 1 to 2 minutes. 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.

Postoperative recovery: IM, slow IV: 50 to 100 mcg every 1 to 2 hours as needed.

Postoperative pain: Epidural (Canadian labeling; not in US labeling): Initial: 100 mcg (diluted in 8 mL of preservative free NS to final concentration of 10 mcg/mL); may repeat with additional 100 mcg boluses on demand or alternatively may administer by continuous infusion at a rate of 1 mcg/kg/hour.

Pain management:

Postoperative pain, acute: Transdermal device (Ionsys): Apply one device to chest or upper outer arm only. Only the patient may activate the device (40 mcg dose of fentanyl per activation; maximum 6 doses per hour). Only one device may be applied at a time for up to 24 hours or 80 doses, whichever comes first. May be used for a maximum of 72 hours, with each subsequent device applied to a different skin site. If inadequate analgesia is achieved with one device, either provide additional supplemental analgesic medication or replace with an alternate analgesic medication. Refer to manufacturer’s labeling for activation instructions.

Note: For hospital use only by patients under medical supervision and direction and only after patients have been titrated to an acceptable level of analgesia using another opioid analgesic.

Severe pain:

Intermittent dosing: IM, IV (off-label dose): Slow IV: 25 to 35 mcg (based on ~70 kg patient) or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (SCCM [Barr, 2013]). Note: After the first dose, if severe pain persists and adverse effects are minimal at the time of expected peak effect (eg, ~5 minutes after IV administration), may repeat dose (APS, 2008). In addition, since the duration of activity with IV administration is 30 to 60 minutes, more frequent administration may be necessary when administered by this route.

Patient-controlled analgesia (PCA) (off-label use; American Pain Society, 2008; Miller, 2010): Opioid-naive: IV:

Usual concentration: 10 mcg/mL

Demand dose: Usual: 10 to 20 mcg

Lockout interval: 4 to 10 minutes

Usual basal rate: ≤50 mcg/hour. Note: Continuous basal infusions are not recommended for initial programming and should rarely be used; consider limiting infusion rate to 10 mcg/hour if used (Grass, 2005).

Critically-ill patients (off-label dose): Slow IV: 25 to 35 mcg (based on ~70 kg patient) or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (SCCM [Barr, 2013]). Note: More frequent dosing may be needed (eg, mechanically-ventilated patients).

Continuous infusion: 50 to 700 mcg/hour (based on ~70 kg patient) or 0.7 to 10 mcg/kg/hour (SCCM [Barr, 2013]).

Alternative continuous infusion dosing: 1 to 2 mcg/kg bolus followed by an initial rate of 1 to 2 mcg/kg/hour (Peng, 1999) or 25 to 100 mcg bolus followed by an initial rate of 25 to 200 mcg/hour (Liu, 2003). Note: When pain is not controlled, may administer an additional small bolus dose (eg, 25 to 50 mcg) prior to increasing the infusion rate (Loper 1990; Peng, 1999; Salomaki, 1991).

Intrathecal (off-label use; American Pain Society, 2008): Must be preservative-free. Doses must be adjusted for age, injection site, and patient’s medical condition and degree of opioid tolerance.

Single dose: 5 to 25 mcg; may provide adequate relief for up to 6 hours

Continuous infusion: Not recommended in acute pain management due to risk of excessive accumulation. For chronic cancer pain, infusion of very small doses may be practical (American Pain Society, 2008).

Epidural (off-label use; American Pain Society, 2008): Must be preservative-free. Doses must be adjusted for age, injection site, and patient’s medical condition and degree of opioid tolerance

Single dose: 25 to 100 mcg; may provide adequate relief for up to 8 hours

Continuous infusion: 25 to 100 mcg/hour (fentanyl alone). When combined with a local anesthetic (eg, bupivacaine or ropivacaine), fentanyl requirement are less (Manion, 2011).

Breakthrough cancer pain: Transmucosal: 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/breakthrough pain episode for several consecutive episodes. Patients experiencing >4 breakthrough pain episodes per day should have the dose of their long-term opioid re-evaluated. Patients must remain on around-the-clock opioids during use.

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), 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.

Dose titration: 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. 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 film (Onsolis): Note: Do not convert patients from any other fentanyl product to Onsolis 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 for all patients; if after 30 minutes pain is unrelieved, the patient may use an alternative rescue medication as directed by their health care provider. Do not redose with Onsolis within an episode; buccal film should only be used once per breakthrough cancer pain episode. Must wait at least 2 hours before treating another episode with buccal film.

Dose titration: If titration required, increase dose in 200 mcg increments once per episode using multiples of the 200 mcg film (for doses up to 800 mcg); do not redose within a single episode of breakthrough pain and separate single doses by ≥2 hours. During titration, do not exceed 4 simultaneous applications of the 200 mcg films (800 mcg) (when using multiple films, do not place on top of each other; film may be placed on both sides of mouth); if >800 mcg required, treat next episode with one 1200 mcg film (maximum dose: 1200 mcg). Once maintenance dose is determined, all other unused films should be disposed of and that strength (using a single film) should be used. During any pain episode, if adequate relief is not achieved after 30 minutes following buccal film application, a rescue medication (as determined by health care provider) may be used.

Maintenance dose: Determined dose applied as a single film once per episode and separated by ≥2 hours (dose range: 200 to 1200 mcg); limit to 4 applications per day. Consider increasing the around-the-clock opioid therapy in patients experiencing >4 breakthrough pain episodes per day.

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; 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 already using Actiq; see Conversion from lozenge (Actiq) to buccal tablet (Fentora); if after 30 minutes pain is unrelieved, the US labeling suggests that a second 100 mcg dose may be administered (maximum of 2 doses per breakthrough pain episode). The Canadian labeling recommends only a single dose per breakthrough pain episode; patients experiencing breakthrough pain after administration may take an alternative analgesic as rescue medication after 30 minutes. Must wait at least 4 hours before treating another episode with Fentora buccal tablet.

Dose titration: If titration required, 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 pain episode, if adequate relief is not achieved after 30 minutes following buccal tablet application, a second dose of same strength per breakthrough pain episode may be used. The Canadian labeling recommends only a single dose per breakthrough pain episode; patients experiencing breakthrough pain after administration may take an alternative analgesic as rescue medication after 30 minutes. Must wait at least 4 hours before treating another episode with Fentora 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; The Canadian labeling recommends only a single dose per breakthrough pain episode; patients experiencing breakthrough pain after administration may take an alternative analgesic as rescue medication after 30 minutes. Must wait ≥4 hours before treating another episode with Fentora buccal tablet. Limit to 4 applications per day. Consider increasing 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 (alternate 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 four buccal tablets at a time has not been studied.

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

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

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

Lozenge dose 1200 to 1600 mcg: Initial buccal tablet dose is 400 mcg (using two 200 mcg tablets); may titrate using multiples of 200 mcg

Nasal spray (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; 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 as directed by their health care provider. Must wait at least 2 hours before treating another episode with Lazanda nasal spray. 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 these titration steps (Note: Must wait at least 2 hours before treating another episode with Lazanda nasal spray): 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 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. There are no data supporting the use of a combination of dose strengths. 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 after 30 minutes of 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 episodes of breakthrough pain 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, re-evaluate 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 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; 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 already using Actiq; see Conversion from lozenge (Actiq) to sublingual spray (Subsys). If pain is unrelieved, 1 additional 100 mcg dose may be given 30 minutes after administration of the first dose. 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 1200 mcg dose (using two 600 mcg units); if no relief with 1200 mcg dose, increase to 1600 mcg dose (using two 800 mcg units). During dose titration, if breakthrough pain 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 following 30 minutes of 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 Subsys. Once maintenance dose is determined, limit Subsys use to ≤4 episodes of breakthrough pain 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, consider increasing the around-the-clock, long-acting opioid therapy.

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

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

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

Lozenge dose 1,200 to 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.

Initial dose:

US labeling: 100 mcg for all patients; if pain is unrelieved, a second 100 mcg dose may be given 30 minutes after administration of the first dose. A maximum of 2 doses can be given per breakthrough pain episode. Must wait at least 2 hours before treating another episode with sublingual tablet.

Canadian labeling: 100 mcg for all patients; if pain is unrelieved 30 minutes after administration of Abstral, an alternative rescue medication (other than Abstral) may be given. Administer only 1 dose of Abstral 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 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 unrelieved 30 minutes after sublingual tablet administration, the US labeling suggests that 1 additional dose using the same strength may be administered (maximum: 2 doses per breakthrough pain episode); the Canadian labeling recommends use of an alternative rescue medication and limits use of Abstral to 1 dose per breakthrough pain episode. Patient 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 in the appropriate strength per episode; if pain is unrelieved with maintenance dose:

US labeling: A second dose may be given after 30 minutes; maximum of 2 doses/episode of breakthrough pain; separate treatment of subsequent episodes by ≥2 hours; limit treatment to ≤4 breakthrough episodes per day.

Canadian labeling: Administer alternative rescue medication after 30 minutes; maximum of 1 Abstral dose/episode of breakthrough pain; separate treatment of subsequent episodes by ≥2 hours; limit treatment to ≤4 breakthrough episodes per day.

Consider increasing the around-the-clock long-acting opioid therapy in patients experiencing >4 breakthrough pain episodes per day; if long-acting opioid therapy dose altered, re-evaluate and retitrate Abstral dose as needed.

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

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

Lozenge dose 400 to 1,200 mcg: Initial sublingual tablet dose is 200 mcg; may titrate using multiples of 200 mcg

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

Chronic pain management (opioid-tolerant patients only): 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 transdermal patch, a 24-hour analgesic requirement should be calculated (based on prior opioid use). Using the 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. A two-step taper of the infusion to be completed over 12 hours has been recommended (Kornick, 2001) after the patch is applied. The infusion is decreased to 50% of the original rate six 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 (US labeling) or using the ratio of 45 to 59 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl dosage (Canadian labeling).

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 require 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 (see tables).

Note: US and Canadian dose conversion guidelines differ; consult appropriate table. The conversion factors in these tables are only to be used for the conversion from current opioid therapy to Duragesic. 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). These are not tables of equianalgesic doses.

U.S. Labeling: Dose Conversion Guidelines: Recommended Initial Duragesic® Dose Based Upon Daily Oral Morphine Dose1,2

Oral 24-Hour Morphine

(mg/day)

Duragesic Dose3

(mcg/h)

1The 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.

2Recommendations are based on U.S. product labeling for Duragesic.

3Pediatric 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.

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 1034

275

1035 to 1124

300

Table has been converted to the following text.

U.S. Labeling: Dose Conversion Guidelines: Recommended Initial Duragesic® Dose Based Upon Daily Oral Morphine Dose1,2,3

• 60 to 134 mg morphine oral/day = 25 mcg/hour Duragesic

• 135 to 224 mg morphine oral/day = 50 mcg/hour Duragesic

• 225 to 314 mg morphine oral/day = 75 mcg/hour Duragesic

• 315 to 404 mg morphine oral/day = 100 mcg/hour Duragesic

• 405 to 494 mg morphine oral/day = 125 mcg/hour Duragesic

• 495 to 584 mg morphine oral/day = 150 mcg/hour Duragesic

• 585 to 674 mg morphine oral/day = 175 mcg/hour Duragesic

• 675 to 764 mg morphine oral/day = 200 mcg/hour Duragesic

• 765 to 854 mg morphine oral/day = 225 mcg/hour Duragesic

• 855 to 944 mg morphine oral/day = 250 mcg/hour Duragesic

• 945 to 1034 mg morphine oral/day = 275 mcg/hour Duragesic

• 1035 to 1124 mg morphine oral/day = 300 mcg/hour Duragesic

1The 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.

2Recommendations are based on U.S. product labeling for Duragesic.

3 Pediatric 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.

U.S. Labeling: Dose Conversion Guidelines1,2

Current Analgesic

Daily Dosage

(mg/day)

1The 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.

2Recommendations are based on U.S. product labeling for Duragesic.

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

Fentanyl transdermal recommended dose (mcg/h)

25 mcg/h

50 mcg/h

75 mcg/h

100 mcg/h

Table has been converted to the following text.

U.S. Labeling: Dose Conversion Guidelines1,2

• Morphine (IM/IV):

10 to 22 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

23 to 37 mg/day: recommended Duragesic transdermal dose: 50 mcg/hour

38 to 52 mg/day: recommended Duragesic transdermal dose: 75 mcg/hour

53 to 67 mg/day: recommended Duragesic transdermal dose: 100 mcg/hour

• Oxycodone (oral):

30 to 67 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

67.5 to 112 mg/day: recommended Duragesic transdermal dose: 50 mcg/hour

112.5 to 157 mg/day: recommended Duragesic transdermal dose: 75 mcg/hour

157.5 to 202 mg/day: recommended Duragesic transdermal dose: 100 mcg/hour

• Codeine (oral): 150 to 447 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

• Hydromorphone (oral):

8 to 17 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

17.1 to 28 mg/day: recommended Duragesic transdermal dose: 50 mcg/hour

28.1 to 39 mg/day: recommended Duragesic transdermal dose: 75 mcg/hour

39.1 to 51 mg/day: recommended Duragesic transdermal dose: 100 mcg/hour

• Hydromorphone (IV):

1.5 to 3.4 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

3.5 to 5.6 mg/day: recommended Duragesic transdermal dose: 50 mcg/hour

5.7 to 7.9 mg/day: recommended Duragesic transdermal dose: 75 mcg/hour

8 to 10 mg/day: recommended Duragesic transdermal dose: 100 mcg/hour

• Meperidine (IM):

75 to 165 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

166 to 278 mg/day: recommended Duragesic transdermal dose: 50 mcg/hour

279 to 390 mg/day: recommended Duragesic transdermal dose: 75 mcg/hour

391 to 503 mg/day: recommended Duragesic transdermal dose: 100 mcg/hour

• Methadone (oral):

20 to 44 mg/day: recommended Duragesic transdermal dose: 25 mcg/hour

45 to 74 mg/day: recommended Duragesic transdermal dose: 50 mcg/hour

75 to 104 mg/day: recommended Duragesic transdermal dose: 75 mcg/hour

105 to 134 mg/day: recommended Duragesic transdermal dose: 100 mcg/hour

1The 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.

2Recommendations are based on U.S. product labeling for Duragesic.

Transdermal patch (Duragesic MAT [Canadian product]): Adults:

Canadian Labeling: Dose Conversion Guidelines (Adults): Recommended Initial Duragesic MAT Dose Based Upon Daily Oral Morphine Dose1,2

Oral 24-Hour Morphine

(Current Dose in mg/day)

Duragesic MAT Dose

(Initial Dose in mcg/h)

1The table should NOT be used to convert from transdermal fentanyl (Duragesic MAT) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

2Recommendations are based on Canadian product labeling for Duragesic MAT.

Note: The 12 mcg/hour dose included in this table is to be used for incremental dose adjustment and is generally not recommended for initial dosing, except for patients in whom lower starting doses are deemed clinically appropriate.

45 to 59

12

60 to 134

25

135 to 179

37

180 to 224

50

225 to 269

62

270 to 314

75

315 to 359

87

360 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 1034

275

1035 to 1124

300

Table has been converted to the following text.

Canadian Labeling: Dose Conversion Guidelines (Adults): Recommended Initial Duragesic MAT Dose Based Upon Daily Oral Morphine Dose1,2

Current 24 hour oral morphine dose: 45 to 59 mg/day, then

Initial Duragesic MAT transdermal patch dose: 12 mcg/hour

Current 24 hour oral morphine dose: 60 to 134 mg/day, then

Initial Duragesic MAT transdermal patch dose: 25 mcg/hour

Current 24 hour oral morphine dose: 135 to 179 mg/day, then

Initial Duragesic MAT transdermal patch dose: 37 mcg/hour

Current 24 hour oral morphine dose: 180 to 224 mg/day, then

Initial Duragesic MAT transdermal patch dose: 50 mcg/hour

Current 24 hour oral morphine dose: 225 to 269 mg/day, then

Initial Duragesic MAT transdermal patch dose: 62 mcg/hour

Current 24 hour oral morphine dose: 270 to 314 mg/day, then

Initial Duragesic MAT transdermal patch dose: 75 mcg/hour

Current 24 hour oral morphine dose: 315 to 359 mg/day, then

Initial Duragesic MAT transdermal patch dose: 87 mcg/hour

Current 24 hour oral morphine dose: 360 to 404 mg/day, then

Initial Duragesic MAT transdermal patch dose: 100 mcg/hour

Current 24 hour oral morphine dose: 405 to 494 mg/day, then

Initial Duragesic MAT transdermal patch dose: 125 mcg/hour

Current 24 hour oral morphine dose: 495 to 584 mg/day, then

Initial Duragesic MAT transdermal patch dose: 150 mcg/hour

Current 24 hour oral morphine dose: 585 to 674 mg/day, then

Initial Duragesic MAT transdermal patch dose: 175 mcg/hour

Current 24 hour oral morphine dose: 675 to 764 mg/day, then

Initial Duragesic MAT transdermal patch dose: 200 mcg/hour

Current 24 hour oral morphine dose: 765 to 854 mg/day, then

Initial Duragesic MAT transdermal patch dose: 225 mcg/hour

Current 24 hour oral morphine dose: 855 to 944 mg/day, then

Initial Duragesic MAT transdermal patch dose: 250 mcg/hour

Current 24 hour oral morphine dose: 945 to 1034 mg/day, then

Initial Duragesic MAT transdermal patch dose: 275 mcg/hour

Current 24 hour oral morphine dose: 1035 to 1124 mg/day, then

Initial Duragesic MAT transdermal patch dose: 300 mcg/hour

1The table should NOT be used to convert from transdermal fentanyl (Duragesic MAT) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

2Recommendations are based on Canadian product labeling for Duragesic MAT.

Note: The 12 mcg/hour dose included in this table is to be used for incremental dose adjustment and is generally not recommended for initial dosing, except for patients in whom lower starting doses are deemed clinically appropriate.

Canadian Labeling: Dosing Conversion Guidelines (Adults)1,2

Current Analgesic

Daily Dosage

(mg/day)

1The table should NOT be used to convert from transdermal fentanyl (Duragesic MAT) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

2Recommendations are based on Canadian product labeling for Duragesic MAT.

3Morphine dose conversion based upon I.M to oral dose ratio of 1:3.

4Insufficient data available to provide specific dosing recommendations. Use caution; adjust dose conservatively.

Morphine3

(IM/IV)

20 to 44

45 to 60

61 to 75

76 to 90

n/a4

n/a4

n/a4

Oxycodone

(oral)

30 to 66

67 to 90

91 to 112

113 to 134

135 to 157

158 to 179

180 to 202

Codeine

(oral)

150 to 447

448 to 597

598 to 747

748 to 897

898 to 1047

1048 to 1197

1198 to 1347

Hydromorphone

(oral)

8 to 16

17 to 22

23 to 28

29 to 33

34 to 39

40 to 45

46 to 51

Hydromorphone

(IV)

4 to 8.4

8.5 to 11.4

11.5 to 14.4

14.5 to 16.5

16.6 to 19.5

19.6 to 22.5

22.6 to 25.5

Fentanyl transdermal recommended dose

(mcg/h)

25 mcg/h

37 mcg/h

50 mcg/h

62 mcg/h

75 mcg/h

87 mcg/h

100 mcg/h

Table has been converted to the following text.

Canadian Dosing Conversion Guidelines (Adults)1,2

• Morphine (IM/IV)3:

20 to 44 mg/day: recommended Duragesic MAT transdermal dose: 25 mcg/hour

45 to 60 mg/day: recommended Duragesic MAT transdermal dose: 37 mcg/hour

61 to 75 mg/day: recommended Duragesic MAT transdermal dose: 50 mcg/hour

76 to 90 mg/day: recommended Duragesic MAT transdermal dose: 62 mcg/hour

>90 mg/day: Insufficient data available to provide specific dosing recommendations. Use caution; adjust dose conservatively.

• Oxycodone (oral):

30 to 66 mg/day: recommended Duragesic MAT transdermal dose: 25 mcg/hour

67 to 90 mg/day: recommended Duragesic MAT transdermal dose: 37 mcg/hour

91 to 112 mg/day: recommended Duragesic MAT transdermal dose: 50 mcg/hour

113 to 134 mg/day: recommended Duragesic MAT transdermal dose: 62 mcg/hour

135 to 157 mg/day: recommended Duragesic MAT transdermal dose: 75 mcg/hour

158 to 179 mg/day: recommended Duragesic MAT transdermal dose: 87 mcg/hour

180 to 202 mg/day: recommended Duragesic MAT transdermal dose: 100 mcg/hour

• Codeine (oral):

150 to 447 mg/day: recommended Duragesic MAT transdermal dose: 25 mcg/hour

448 to 597 mg/day: recommended Duragesic MAT transdermal dose: 37 mcg/hour

598 to 747 mg/day: recommended Duragesic MAT transdermal dose: 50 mcg/hour

748 to 897 mg/day: recommended Duragesic MAT transdermal dose: 62 mcg/hour

898 to 1047 mg/day: recommended Duragesic MAT transdermal dose: 75 mcg/hour

1048 to 1197 mg/day: recommended Duragesic MAT transdermal dose: 87 mcg/hour

1198 to 1347 mg/day: recommended Duragesic MAT transdermal dose: 100 mcg/hour

• Hydromorphone (oral):

8 to 16 mg/day: recommended Duragesic MAT transdermal dose: 25 mcg/hour

17 to 22 mg/day: recommended Duragesic MAT transdermal dose: 37 mcg/hour

23 to 28 mg/day: recommended Duragesic MAT transdermal dose: 50 mcg/hour

29 to 33 mg/day: recommended Duragesic MAT transdermal dose: 62 mcg/hour

34 to 39 mg/day: recommended Duragesic MAT transdermal dose: 75 mcg/hour

40 to 45 mg/day: recommended Duragesic MAT transdermal dose: 87 mcg/hour

46 to 51 mg/day: recommended Duragesic MAT transdermal dose: 100 mcg/hour

• Hydromorphone (IV):

4 to 8.4 mg/day: recommended Duragesic MAT transdermal dose: 25 mcg/hour

8.5 to 11.4 mg/day: recommended Duragesic MAT transdermal dose: 37 mcg/hour

11.5 to 14.4 mg/day: recommended Duragesic MAT transdermal dose: 50 mcg/hour

14.5 to 16.5 mg/day: recommended Duragesic MAT transdermal dose: 62 mcg/hour

16.6 to 19.5 mg/day: recommended Duragesic MAT transdermal dose: 75 mcg/hour

19.6 to 22.5 mg/day: recommended Duragesic MAT transdermal dose: 87 mcg/hour

22.6 to 25.5 mg/day: recommended Duragesic MAT transdermal dose: 100 mcg/hour

1The table should NOT be used to convert from transdermal fentanyl (Duragesic MAT) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

2Recommendations are based on Canadian product labeling for Duragesic MAT.

3Morphine dose conversion based on IM to oral dose ratio of 1:3.

Dosing: Geriatric

Elderly 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: Pediatric

Note: Ranges listed may not represent the maximum doses that may be required in some patients. Doses and dosage intervals should be titrated to pain relief/prevention. Monitor vital signs routinely. Single IM doses have duration of 1 to 2 hours, single IV doses last 0.5 to 1 hour.

Surgery adjunct to anesthesia (induction and maintenance): Children ≥2 years and Adolescents: IV: 2 to 3 mcg/kg/dose every 1 to 2 hours as needed

Breakthrough cancer pain: Adolescents ≥16 years: Transmucosal lozenge (Actiq): Refer to adult dosing.

Chronic pain management: Children ≥2 years and Adolescents (opioid-tolerant patients): Transdermal patch (US labeling): Refer to adult dosing. Note: Canadian labeling does not approve of use in patients <18 years.

Pain management (off-label use): Patient-controlled analgesia (PCA) (off-label use; American Pain Society, 2008): Children <50 kg: IV: Note: Opioid-naive:

Usual concentration: 10 to 50 mcg/mL (varies by patient weight and institution)

Demand dose: 0.5 to 1 mcg/kg/dose

Lockout interval: 6 to 8 minutes

Usual basal rate (optional): ≤0.5 mcg/kg/hour. Note: Due to safety concerns, continuous basal infusions are not recommended for initial programming and should rarely be used (Grass, 2005).

Dosing: Renal Impairment

Injection: No dosage adjustment provided in 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 renal disease.

Transdermal (patch): 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 (buccal film/tablet, sublingual spray/tablet, lozenge) and nasal spray: Although fentanyl pharmacokinetics may be altered in renal 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 renal disease.

Dosing: Hepatic Impairment

Injection: No dosage adjustment provided in 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 film/tablet, sublingual spray/tablet, lozenge) and nasal spray: 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.

Administration

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.

IV: Administer as slow IV infusion over 1 to 2 minutes. May also be administered as continuous infusion or PCA (off-label use) routes. Muscular rigidity may occur with rapid IV administration.

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, such as chest, back, flank, or upper arm. Do not shave skin; hair at application site should be clipped. 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. Skin exposure from fentanyl gel leaking from patch may lead to serious adverse effects; thoroughly wash affected skin surfaces with water (do not use soap). Firmly press in place and hold for 30 seconds. Change patch every 72 hours. Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin; use copious amounts of water. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub). 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. The unit should be consumed over a period of 15 minutes. Handle should be removed after the 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.

Buccal film: Foil overwrap should be removed just prior to administration. Prior to placing film, wet inside of cheek using tongue or by rinsing with water. Place film inside mouth with the pink side of the unit against the inside of the moistened cheek. With finger, press the film against cheek and hold for 5 seconds. The film should stick to the inside of cheek after 5 seconds. The film should be left in place until it dissolves (usually within 15-30 minutes after application). Liquids may be consumed after 5 minutes of application. Food can be eaten after film dissolves. If using more than 1 film simultaneously (during titration period), apply films on either side of mouth (do not apply on top of each other). Do not chew or swallow film. Do not cut or tear the film. All patients must initiate therapy using the 200 mcg film. To dispose of film; remove foil overwrap from any unused, unneeded films and dispose by flushing down the toilet.

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.

Nasal spray: 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.

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. All patients must initiate therapy using the 100 mcg tablet. 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.

Dietary Considerations

Transmucosal lozenge contains 2 g sugar per unit.

Compatibility

Stable in D5W, NS.

Y-site administration: Incompatible with azithromycin, phenytoin.

Compatibility in syringe: Incompatible with pentobarbital.

Storage

Injection: Store intact vials/ampules at 20°C to 25°C (68°F to 77°F). Protect from light.

Nasal spray: Do not store above 25°C (77°F); do not freeze. Protect from light. Bottle should be stored in the provided child-resistant container when not in use and kept out of the reach of children at all times.

Transdermal device: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86° F).

Transdermal patch: Do not store above 25°C (77°F). Keep out of the reach of children.

Transmucosal (buccal film, buccal tablet, lozenge, sublingual spray, sublingual tablet): Store at 20°C to 25°C (68°F to 77°F). Protect from freezing and moisture. Keep out of the reach of children.

Drug Interactions

Alpha-/Beta-Agonists (Indirect-Acting): May decrease the serum concentration of FentaNYL. Specifically, fentanyl nasal spray serum concentrations may decrease and onset of effect may be delayed. Monitor therapy

Alpha1-Agonists: May decrease the serum concentration of FentaNYL. Specifically, fentanyl nasal spray serum concentrations may decrease and onset of effect may be delayed. Exceptions: Midodrine; Naphazoline (Ophthalmic); Phenylephrine (Ophthalmic); Phenylephrine (Topical). Monitor therapy

Alvimopan: Analgesics (Opioid) 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. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics 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. Consider therapy modification

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

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Beta-Blockers: Anilidopiperidine Opioids may enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

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

Calcium Channel Blockers (Nondihydropyridine): Anilidopiperidine Opioids may enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Anilidopiperidine Opioids may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

CNS Depressants: May enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics 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. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Crizotinib: May increase the serum concentration of FentaNYL. Avoid combination

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

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

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of FentaNYL. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ioflupane I 123: FentaNYL may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

MAO Inhibitors: FentaNYL may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Avoid combination

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

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

MiFEPRIStone: May increase the serum concentration of FentaNYL. Management: Avoid fentanyl during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). 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. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of FentaNYL. Management: Monitor for increased opioid effects/toxicities if these agents are combined. Consider using lower initial doses of fentanyl. Canadian labeling recommends avoidance of this combination. Consider therapy modification

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

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. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

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

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

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

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

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of FentaNYL. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Confusion, dizziness, drowsiness, fatigue, headache, sedation

Endocrine & metabolic: Dehydration

Gastrointestinal: Constipation, nausea, vomiting

Local: Application site erythema (transdermal device)

Neuromuscular & skeletal: Weakness

Respiratory: Dyspnea

1% to 10%:

Cardiovascular: Atrial fibrillation, bigeminy, cardiac arrhythmia, chest pain, deep vein thrombosis, edema, hypertension, hypotension, myocardial infarction, orthostatic hypotension, palpitations, peripheral edema, pulmonary embolism (nasal spray), sinus tachycardia, syncope, tachycardia, vasodilatation

Central nervous system: Abnormal dreams, abnormal gait, abnormality in thinking, agitation, altered sense of smell, amnesia, anxiety, ataxia, chills, depression, disorientation, dysphoria, euphoria, hallucination, hypertonia, hypoesthesia, hypothermia, insomnia, irritability, lack of concentration, lethargy, malaise, mental status changes, migraine, nervousness, neuropathy, paranoia, paresthesia, restlessness, speech disturbance, stupor, vertigo, withdrawal syndrome

Dermatologic: Alopecia, cellulitis, decubitus ulcer, diaphoresis, erythema, exfoliation of skin (application site, transdermal device), hyperhidrosis, local papules (application site, transdermal device), night sweats, pallor, papule, pruritus, pustules (application site, transdermal device), skin rash, vesicobullous rash (application site, transdermal device)

Endocrine & metabolic: Hot flash, hypercalcemia, hyperglycemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, weight loss

Gastrointestinal: Abdominal distention, abdominal pain, anorexia, decreased appetite, diarrhea, dysgeusia, dyspepsia, dysphagia (buccal tablet/film/sublingual spray), flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal ulcer (gingival, lip, mouth; transmucosal use/nasal spray), gingival pain (buccal tablet), gingivitis (lozenge), glossitis (lozenge), hematemesis, intestinal obstruction, periodontal abscess (lozenge/buccal tablet), rectal pain, stomatitis (lozenge/buccal tablet/sublingual tablet/sublingual spray), tongue disease (sublingual tablet), xerostomia

Genitourinary: Urinary retention (3%), difficulty in micturition, dysuria, erectile dysfunction, mastalgia, urinary incontinence, urinary tract infection, urinary urgency, vaginal hemorrhage, vaginitis

Hematologic & oncologic: Anemia (3%), bruise, leukopenia, lymphadenopathy, neutropenia, thrombocytopenia

Hepatic: Ascites, increased serum alkaline phosphatase, increased serum AST, jaundice

Hypersensitivity: Hypersensitivity reaction

Infection: Abscess

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

Neuromuscular & skeletal: Arthralgia, back pain, leg cramps, limb pain, myalgia, tremor

Ophthalmic: Blepharoptosis, blurred vision, diplopia, dry eye syndrome, strabismus, swelling of eye, visual disturbance

Renal: Renal failure

Respiratory: Apnea, asthma, atelectasis, bronchitis, cough, dyspnea (exertional), epistaxis, flu-like symptoms, hemoptysis, hyperventilation, hypoventilation, hypoxia, laryngitis, nasal congestion (nasal spray), nasal discomfort (nasal spray), nasopharyngitis, pharyngitis, pharyngolaryngeal pain, pneumonia, postnasal drip (nasal spray), rhinitis, rhinorrhea (nasal spray), sinusitis, upper respiratory tract infection, wheezing

Miscellaneous: Fever, wound healing impairment

<1% (Limited to important or life-threatening): Allergic dermatitis, anaphylactoid reaction, angina pectoris, bradycardia, bronchoconstriction, chest wall rigidity, clonus, cyanosis, drug dependence (physical and psychological; with prolonged use), eczema, esophageal stenosis, exfoliative dermatitis, fecal impaction, flushing, genitourinary tract spasm, gingival hemorrhage, gum line erosion, hematuria, hostility, hypoglycemia, hypogonadism (Brennan 2013; Debono 2011), impaired consciousness, local hemorrhage, local hypersensitivity reaction, localized infection, local tissue necrosis, loss of consciousness, muscle spasm, muscle twitching, nocturia, oliguria, pancytopenia, pleural effusion, polyuria, respiratory distress, seizure, sexual disorder, skin erosion, Stevens-Johnson syndrome, subileus, swelling, swollen tongue, tonic-clonic seizures, tooth loss, upper abdominal pain

ALERT: U.S. Boxed Warning

Buccal:

Respiratory depression: Fatal respiratory depression has occurred in patients treated with fentanyl, including following use in opioid-nontolerant patients and improper dosing. The substitution of fentanyl buccal for any other fentanyl product may result in fatal overdose. Due to the risk of respiratory depression, fentanyl is contraindicated in the management of acute or postoperative pain, including headache/migraine, and in opioid-nontolerant patients.

Death has been reported in children who have accidentally ingested fentanyl. Fentanyl must be kept out of the reach of children.

The concomitant use of fentanyl with cytochrome P450 (CYP-450) 3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression.

Medication errors: Substantial differences exist in the pharmacokinetic profile of fentanyl buccal 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.

When dispensing, do not substitute a fentanyl buccal prescription for other fentanyl products.

Abuse potential: Fentanyl is an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentanyl can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing fentanyl in situations in which the health care provider or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, fentanyl is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program, health care providers (who prescribe to outpatients), as well as 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.

Intranasal:

Respiratory depression: Fatal respiratory depression has occurred in patients treated with fentanyl transmucosal immediate-release, including following use in opioid-nontolerant patients and improper dosing. The substitution of fentanyl intranasal for any other fentanyl product may result in fatal overdose. Because of the risk of respiratory depression, fentanyl intranasal is contraindicated in the management of acute or postoperative pain, including headache/migraine, and in opioid-nontolerant patients.

Fentanyl intranasal must be kept out of the reach of children.

The concomitant use of fentanyl intranasal with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression.

Medication errors: Substantial differences exist in the pharmacokinetic profile of fentanyl intranasal 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 intranasal.

When dispensing, do not substitute a fentanyl intranasal prescription for other fentanyl products.

Abuse potential: Fentanyl is an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentanyl intranasal can be abused in a manner similar to other opioid agonists, legal or illicit. Consider this when prescribing or dispensing fentanyl intranasal in situations in which the health care provider or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, fentanyl intranasal is available only through a restricted program required by the Food and Drug Administration, 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.

Sublingual:

Respiratory depression: Fatal respiratory depression has occurred in patients treated with fentanyl transmucosal immediate-release products, including following use in opioid-nontolerant patients and improper dosing. The substitution of fentanyl sublingual for any other fentanyl product may result in fatal overdose. Because of the risk of respiratory depression, fentanyl sublingual is contraindicated in the management of acute or postoperative pain, including headache/migraine and in opioid-nontolerant patients.

Death has been reported in children who have accidentally ingested fentanyl transmucosal immediate-release products. Fentanyl sublingual must be kept out of the reach of children.

The concomitant use of fentanyl sublingual with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression.

Medication errors: Substantial differences exist in the pharmacokinetic profile of fentanyl 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 sublingual.

When dispensing, do not substitute a fentanyl sublingual prescription for other fentanyl products.

Abuse potential: Fentanyl is an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentanyl can be abused in a manner similar to other opioid agonists, legal or illicit. Consider this when prescribing or dispensing fentanyl in situations in which the health care provider is concerned about an increased risk of misuse, abuse, or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, fentanyl sublingual is available only through a restricted program required by the Food and Drug Administration, 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

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 or conditions.

Life-threatening respiratory depression:

Transdermal patch: Serious, life-threatening, or fatal respiratory depression may occur with use of fentanyl, even when used as recommended. Monitor for respiratory depression, especially during initiation of fentanyl or following a dose increase. Because of the risk of respiratory depression, fentanyl is contraindicated for use as an as-needed analgesic, in nonopioid tolerant patients, in acute pain, and in postoperative pain.

Transdermal iontophoretic system (Ionsys): Use may result in potentially life-threatening respiratory depression and death. Only the patient should activate Ionsys dosing. Ionsys is for use only in patients in the hospital. Discontinue treatment with Ionsys before patients leave the hospital.

Risk Evaluation and Mitigation Strategy (REMS) Program (Ionsys only): Because of potentially life-threatening respiratory depression resulting from accidental exposure, Ionsys is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Ionsys REMS Program.

Accidental exposure: 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. Accidental exposure to an intact iontophoretic system (Ionsys) or to the hydrogel component, especially in children, through contact with skin or contact with mucous membranes, can result in a fatal overdose of fentanyl.

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.

Cytochrome P450 3A4 interaction: The concomitant use of fentanyl with all cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects 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.

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 and death. Patients wearing fentanyl systems who develop fever or increased core body temperature due to strenuous exertion are also at risk for increased fentanyl exposure and may require an adjustment in the dose of fentanyl to avoid overdose and death.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypotension/syncope: May cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; risk is increased in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume; monitor these patients for signs of hypotension after initiating therapy. Avoid Ionsys in patients with circulatory shock; may cause vasodilation that can further reduce cardiac output and blood pressure.

• Opioid agonist toxicities: Shares the toxic potentials of opioid agonists, and precautions of opioid agonist therapy should be observed.

• Respiratory depression: [US Boxed Warning] Abstral, Actiq, Duragesic, Fentora, Ionsys, Lazanda, Onsolis, Subsys: May cause serious, life-threatening, or fatal respiratory depression, even when used as recommended. Monitor closely for respiratory depression, especially during initiation or dose escalation. Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis, or Subsys should only be prescribed for opioid-tolerant patients. Risk of respiratory depression increased in elderly patients, debilitated patients, and patients with conditions associated with hypoxia or hypercapnia; usually occurs after administration of initial dose in nontolerant patients or when given with other drugs that depress respiratory function. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

Disease-related concerns:

• Adrenal 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 sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan, 2013).

• Allergic rhinitis: Nasal spray: 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 the nasal spray 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 when administering to patients with bradycardia or bradyarrhythmias (may produce further bradycardia).

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Opioids may obscure the clinical course of head injury. Use of some products may be contraindicated in these patients (refer to Contraindications field). Ionsys is not for use in patients who are not alert and able to follow directions; avoid use in patients with impaired consciousness or coma.

• Hepatic impairment: Use with caution in patients with hepatic dysfunction.

• 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]).

• 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 or higher mucositis; use with caution in patients with grade 1 mucositis, and closely monitor for respiratory and CNS depression.

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

• Respiratory disease: Monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating with fentanyl; even therapeutic doses may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients. Use of some products may be contraindicated in patients with respiratory disease (refer to Contraindications field).

• Seizures: May aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control.

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

Concurrent drug therapy issues:

• CYP3A4 interactions: [US Boxed Warning]: Use with strong or moderate CYP3A4 inhibitors may result in increased effects and potentially fatal respiratory depression. In addition, discontinuation of a concomitant CYP 3A4 inducer may result in increased fentanyl concentrations. Monitor patients receiving any CYP 3A4 inhibitor or inducer.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

Special populations:

• Cachectic or debilitated patients: Use with caution in debilitated or cachectic patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Elderly: Use with caution in the elderly; 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]).

• Neonates: Neonatal withdrawal syndrome: Transdermal patch (Duragesic): [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

• Pediatric: Buccal film, buccal tablet, nasal spray, sublingual tablet, sublingual spray, and lozenge: [US Boxed Warning]: Preparations contain an amount of medication that can be fatal to children. Keep all used and unused products out of the reach of children at all times and discard products properly. Patients and caregivers should be counseled on the dangers to children including the risk of exposure to partially-consumed products.

Dosage form specific issues:

• Injection: Inject slowly over 3 to 5 minutes; rapid IV infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest; nondepolarizing skeletal muscle relaxant may be required.

• Transmucosal (buccal film/tablet, sublingual spray/tablet, lozenge) and nasal spray:

- [US Boxed Warning]: Transmucosal and nasal fentanyl formulations are contraindicated in the management of acute or postoperative pain and in opioid nontolerant patients. Should be used only for the care of opioid-tolerant cancer patients with breakthrough pain and is intended for use by specialists who are knowledgeable in treating cancer pain.

- [US Boxed Warning]: Substantial differences exist in the pharmacokinetic profile of fentanyl products. Do not convert patients on a mcg-per-mcg basis from one fentanyl product to another fentanyl product; the substitution of one fentanyl product for another fentanyl product may result in a fatal overdose.

- [US Boxed Warning]: Available only through the TIRF REMS ACCESS program, a restricted distribution program with outpatients, prescribers who prescribe to outpatients, pharmacies (inpatient and outpatient), and distributor-required enrollment.

• Transdermal device:

- [US Boxed Warning]: Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Ionsys REMS Program.

- [US Boxed Warning]: For use only in patients in the hospital. Discontinue treatment before patients leave the hospital. Only the patient should activate Ionsys dosing. Accidental exposure to an intact Ionsys device or to the hydrogel component, especially by children, through contact with skin or contact with mucous membranes, 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:

- [US Boxed Warning]: Transdermal patch is contraindicated for use as an as-needed analgesic, in the management of acute or postoperative pain, or in patients who are opioid nontolerant. Monitor closely for respiratory depression during use, particularly during initiation of therapy or after dose increases. Should only be prescribed by health care professionals who are knowledgeable in the use of potent opioids in the management of chronic pain.

- [US Boxed Warning]: Exposure of application site and surrounding area to direct external heat sources (eg, heating pads, electric blankets, heat or tanning lamps, sunbathing, hot tubs) may increase fentanyl absorption and has resulted in fatalities. Patients who experience fever or increase in core body temperature should be monitored closely. 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.

- [US Boxed Warning]: Accidental exposure to fentanyl transdermal patch has resulted in fatal overdose in children and adults. Strict adherence to recommended handling and disposal instructions is necessary to prevent accidental exposures. 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.

- Should be applied only to intact skin. Use of a patch that has been cut, damaged, or altered in any way may result in overdosage. 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. May contain conducting metal (eg, aluminum); remove patch prior to MRI.

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Users are exposed to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient’s risk prior to prescribing; monitor all patients for development of these behaviors or conditions. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). Other factors associated with increased risk include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) 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 anticonvulsants 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]).

• 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.

• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

Monitoring Parameters

Respiratory and cardiovascular status, blood pressure, heart rate; signs of misuse, abuse, or addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan, 2013)

Transdermal patch: Monitor for 24 hours after application of first dose

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): 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]).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Fentanyl crosses the placenta.

Fentanyl injection may be used for the management of pain during labor (ACOG 2002). When used for pain relief during labor, opioids may temporarily affect the heart rate of the fetus (ACOG 2002). Transient muscular rigidity has been observed in the neonate with fentanyl; symptoms of respiratory or neurological depression were not different than those observed in infants of untreated mothers.

[US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur; monitoring of the neonate is recommended. The minimum effective dose should be used if opioids are needed (Chou 2009). Symptoms characteristic of neonatal abstinence syndrome have been observed following chronic fentanyl use in pregnant women. Neonatal abstinence syndrome following opioid exposure may present with autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow 2012; Hudak 2012).

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

Transdermal patch, transdermal iontophoretic system (Ionsys), transmucosal lozenge, nasal spray (Lazanda), sublingual tablet, sublingual spray (Subsys), buccal tablet (Fentora), and buccal film (Onsolis) are not recommended for analgesia during labor and delivery.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, diarrhea, headache, sensation of cold, lack of appetite, insomnia, sweating a lot, abdominal pain, or tingling of mouth. Have patient report immediately to prescriber slow breathing, shallow breathing, difficulty breathing, severe dizziness, passing out illogical thinking, severe nausea, vomiting, severe constipation, loss of strength and energy, shortness of breath, angina, tachycardia, bradycardia, severe fatigue, seizures, severe mouth irritation, mouth sores, severe application site irritation, swelling of arms or legs, or swelling of hands or feet (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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