FentaNYL

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); 500 mcg/50 mL (50 mL); 1000 mcg/ 20 mL (20 mL); 1250 mcg/250 mL (250 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 cm^2; 40 cm²]

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

Generic: 12 [delivers 12.5 mcg/hr] (5s); 25 [delivers 25 mcg/hr] (5s); 37.5 [delivers 37.5 mcg/hr]; 50 [delivers 50 mcg/hr] (5s); 62.5 [delivers 62.5 mcg/hr]; 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)

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

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

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

V_dss: 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)

Intranasal: 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)

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

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)

SubQ bolus injection: 10 hours (Capper 2010)

Transdermal device: Terminal: ~16 hours

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

Transmucosal products: 3 to 14 hours (dose dependent)

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

Buccal 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

Use in Specific Populations

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

Pain management, acute and chronic pain:

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

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

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

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

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

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

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

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

Oral morphine 60 mg/day, or

Transdermal fentanyl 25 mcg/hour, or

Oral oxycodone 30 mg/day, or

Oral hydromorphone 8 mg/day, or

Oral oxymorphone 25 mg/day, or

Oral hydrocodone 60 mg/day, or

Equianalgesic dose of another opioid for at least 1 week

Use: Off Label

Critically ill patients in the ICU (analgesia and sedation)yes

Based on the Society of Critical Care Medicine guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the intensive care unit, fentanyl is an effective and recommended agent for analgesia and sedation in critically ill patients SCCM [Devlin 2018].

Procedural sedation and analgesia, outside the operating roomc

Clinical expert opinion suggests fentanyl as an option for procedural sedation in adult patients outside of the operating room, along with other sedatives (eg, benzodiazepines, propofol, etomidate) Bahn 2005, Frank 2019.

Rapid sequence intubation (pretreatment)c

Clinical expert opinion recommends fentanyl as an option for pretreatment during rapid sequence intubation to prevent physiologic responses of intubation (ie, hypertension, tachycardia, increased intracranial pressure) in patients inside and outside the operating room Caro 2019, Groth 2018, Roberts 2019, Stollings 2014.

Contraindications

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

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

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

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

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

Injection: Septicemia; severe hemorrhage or shock; local infection at proposed injection site; disturbances in blood morphology and/or anticoagulant therapy or other concomitant drug therapy or medical conditions which could contraindicate the technique of epidural administration

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

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

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

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

Dosage and Administration

Dosing: Adult

Analgesia and sedation:

Critically ill patients in the ICU (analgesia and sedation) (off-label use): Note: Multimodal approaches (eg, a combination of analgesics and techniques) should typically be employed for pain control in this setting. Pain should be monitored using validated scales (eg, behavioral pain scale, critical-care pain observation tool) in ICU patients who are unable to self-report (SCCM [Devlin 2018]). In patients who are obese, standard non–weight-based initial dosing is preferred (Pandharipande 2019).

Intermittent dosing:

Loading dose: IV: 25 to 100 mcg or 1 to 2 mcg/kg; may repeat dose if severe pain persists and adverse effects are minimal at the time of expected peak effect (eg, ~5 minutes after administration) (Pandharipande 2019). Follow with intermittent maintenance dose or a continuous infusion.

Maintenance dose: IV: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (Pandharipande 2019; SCCM [Barr 2013]).

Continuous infusion:

IV: After initial loading dose (see Intermittent dosing: Loading dose), begin continuous infusion at an initial rate of 25 to 50 mcg/hour; titrate every 30 to 60 minutes to clinical effect (ie, pain control and/or sedation). Usual dosing range: 50 to 200 mcg/hour (some patients may require doses as high as 300 mcg/hour); weight-based dosing range: 0.7 to 10 mcg/kg/hour (Pandharipande 2019; SCCM [Barr 2013]). Note: Fentanyl can accumulate in lipid stores when used for extended periods of time and may result in prolonged sedation and reduced ability to liberate from mechanical ventilator (Pandharipande 2019). May administer an additional small bolus dose (eg, 25 mcg) prior to increasing the infusion rate (Peng 1999; Salomäki 1991).

Procedural sedation and analgesia:

Outside the operating room (alternative agent) (off-label use): IV: 0.5 to 1 mcg/kg every 2 minutes until desired level of sedation and analgesia achieved (Bahn 2005; Frank 2019); generally, the maximum total dose is 250 mcg. If administered with other sedatives (eg, etomidate, propofol, midazolam), do not exceed single doses of 0.5 mcg/kg (Frank 2019).

Analgesia during monitored anesthesia care or regional anesthesia: IV: Usual initial dose range: 0.5 to 2 mcg/kg, administered in incremental boluses of 25 to 50 mcg, titrated to effect. When used in combination with a sedative (eg, midazolam), consider dosage reduction (Rosero 2019). Note: Since an IV should be in place with anesthesia, the IM route is rarely used but still maintained as an option in the manufacturer's labeling. If IM route is used, the dose is equivalent to the recommended IV dose.

General anesthesia:

Preinduction: IV: 25 mcg; may repeat in increments of 25 mcg (typical total dose is ≤100 mcg) to provide pain relief or if patient requires a regional anesthesia procedure prior to surgery (Casserly 2019; Roberts 2019).

Induction: IV: 25 to 100 mcg (or 0.5 to 1 mcg/kg) (Casserly 2019; King 2019). Some use a high-dose opioid induction technique (eg, 10 to 25 mcg/kg) for select patients (eg, those with poor myocardial function) who will remain intubated for several hours postoperatively (Casserly 2019).

Maintenance:

Intermittent: IV: 25 to 50 mcg bolus as needed; may be used to provide supplemental analgesia during maintenance of general anesthesia with inhaled agents. For opioid-naive patients, do not exceed 1 mcg/kg/hour based on ideal body weight (Casserly 2019).

Continuous infusion: IV: 1 to 2 mcg/kg/hour as supplement to total IV anesthesia (TIVA) when controlled postoperative ventilation is planned (Casserly 2019).

Rapid sequence intubation (pretreatment) (off-label use): IV: Usual dose: 50 to 200 mcg (or 1 to 3 mcg/kg) over 30 to 60 seconds administered ~3 minutes prior to induction. In patients with tenuous hemodynamic status, use lower doses (eg, 1 mcg/kg [or 50 mcg]) or avoid use; in patients with elevated intracranial pressure, use higher doses (eg, 3 mcg/kg [or 200 mcg]) (Caro 2019; Groth 2018; Roberts 2019; Stollings 2014).

Pain management, severe pain: Note: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for pain. Maximize nonopioid analgesia, if appropriate, prior to initiation of opioid analgesia (CDC [Dowell 2016]; Hill 2018). Dosing provided is based on typical doses and some patients may require higher or lower doses. Individualize dosing and dosing intervals based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time. For acute non–cancer-related pain severe enough to require an opioid, do not prescribe fentanyl for use on an outpatient basis; consider the use of other oral opioids. Before starting opioid therapy for chronic pain, establish realistic treatment goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh risks (CDC [Dowell 2016]).

Acute pain (including ICU, postoperative, and other closely monitored settings):

Patient-controlled analgesia (alternative agent): Note: Generally, the preferred opioid for patients with severe kidney or hepatic dysfunction and/or for patients who are unable to tolerate morphine or hydromorphone (Mariano 2019).

IV:

Postoperative pain:

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

IV: 25 to 50 mcg every 5 minutes (moderate pain) or 50 to 100 mcg every 2 to 5 minutes (severe pain) until pain is relieved or unwanted side effects appear; after initial pain control, readdress postoperative analgesic regimen to optimize comfort (Casserly 2019).

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

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

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

Severe pain (nonoperative):

Intermittent dosing: IV, IM: 25 to 50 mcg or 0.35 to 0.5 mcg/kg every 30 to 60 minutes as needed (Pandharipande 2019; SCCM [Barr 2013]). Note: More frequent administration may be necessary when used by the IV route due to short duration of activity. IM route should only be used if IV administration is not available (eg, loss of IV access).

Chronic pain, including chronic cancer pain:

Note: Opioids, including fentanyl, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred, with the exception of chronic pain from sickle cell disease and end-of-life care. Opioids, including fentanyl, should only be considered in patients with chronic, noncancer pain who are expected to experience clinically meaningful improvement in pain and function that outweighs patient safety risks (CDC [Dowell 2016]; Dowell [CDC letter] 2019).

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

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

Conversion from continuous IV infusion of fentanyl: In patients who have adequate pain relief with IV fentanyl infusion, may convert to transdermal dosing at a rate equivalent to the IV rate using a 2-step taper of the infusion to be completed over 12 hours after the patch is applied. Six hours after the application of the first patch, decrease the infusion to 50% of the original rate; discontinue infusion 12 hours after patch application (Kornick 2001).

Titration: Do not titrate more frequently than every 3 days after the initial application or every 6 days thereafter. Short-acting opioids may be required until analgesic efficacy is established and/or as supplements for breakthrough pain. The number and quantity of supplemental doses should be closely monitored. When increasing the dose, base the new dose on the daily requirement of supplemental opioids required by the patient during the second or third day of initial application. For example, if 24-hour oral morphine requirement for breakthrough pain is 50 mg, then may increase transdermal fentanyl dose by 25 mcg/hour (McPherson 2016).

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

Note: Using the manufacturer's recommended dose conversion guidelines, based upon the daily oral morphine dose, may underestimate the transdermal fentanyl strength required and result in the need for supplemental immediate-release opioid therapy for breakthrough pain or in the patient experiencing withdrawal syndrome (Skaer 2004). The manufacturers recommend a ratio of approximately 45 mg/24 hours of oral morphine to a 12 mcg/hour fentanyl dosage (US labeling) or the ratio of 45 to 59 mg/24 hours of oral morphine to a 12 mcg/hour fentanyl dosage (Canadian labeling). Below is a less conservative dosing conversion strategy based on a 2:1 ratio of oral morphine to transdermal fentanyl (McPherson 2016; Portenoy 2019). For the more conservative dose conversion strategy, see the manufacturer's labeling. The table is only to be used for the conversion from current opioid therapy to transdermal fentanyl. Do not use this table to convert from transdermal fentanyl to another opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). This is not a table of equianalgesic doses.

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

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

Cancer pain, breakthrough:

Transmucosal:

Note: For patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Dose titration should be done if patient requires more than 1 dose per breakthrough pain episode for several consecutive episodes. Patients experiencing >4 breakthrough pain episodes per day should have the dose of their long-term opioid reevaluated. Patients must remain on around-the-clock opioids during use (Portenoy 2019).

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

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

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

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

Buccal 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 in each subsequent 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 use more than 4 of the 200 mcg films (800 mcg) simultaneously (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 1,200 mcg film (maximum dose: 1,200 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 30 minutes after 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 1,200 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 (except Actiq); individually titrate to provide adequate analgesia while minimizing adverse effects. For patients previously using the transmucosal lozenge (Actiq), the initial dose should be selected using the conversions listed; see Conversion from lozenge (Actiq) to buccal tablet (Fentora).

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

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

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

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

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

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

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

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

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

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

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

Sublingual:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Discontinuation of pain management therapy:

When reducing the dose or discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal tapering schedule has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reduction per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2019). When discontinuing transdermal fentanyl and not converting to another opioid, particularly in patients who are physically opioid dependent, use a gradual downward titration (eg, decrease the dose by 25% every 2 to 4 weeks) (manufacturer's labeling). Upon system removal of transdermal fentanyl, ≥17 hours are required for a 50% decrease in fentanyl levels. Individualize discontinuation to minimize withdrawal, while considering patient-specific goals and concerns, as well as the opioid’s pharmacokinetics. Slower tapers may be appropriate after long-term use (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2019). In patients who continue to take chronic opioid therapy but no longer require fentanyl for breakthrough pain, fentanyl can usually be discontinued without a taper.

Neuraxial analgesia:

Epidural: Note: Reserve use for patients with severe acute pain (eg, after major abdominal surgery, cancer pain, during labor and delivery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (APS [Chou 2016]). Use a preservative-free formulation intended for neuraxial use (Mariano 2019).

Single dose: 25 to 100 mcg; may provide adequate relief for up to 8 hours. May repeat with additional 100 mcg boluses on demand (US labeling) or alternatively may administer by a continuous infusion (APS 2008; Canadian labeling).

Continuous infusion: 25 to 100 mcg/hour (fentanyl alone). When combined with a local anesthetic (eg, bupivacaine), fentanyl requirement is less (APS 2008; Manion 2011).

Intrathecal: Note: Reserve use for patients with severe acute pain (eg, after major abdominal surgery, cancer pain, during labor and delivery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (APS [Chou 2016]). Use a preservative-free formulation intended for neuraxial use (Mariano 2019).

Single dose: 15 to 25 mcg; may provide adequate relief for up to 6 hours. When combined with a local anesthetic (eg, bupivacaine), fentanyl dose requirement is less (eg, 10 to 15 mcg instead of 15 to 25 mcg) (APS 2008; d’Arby Toledano 2019).

Dosing: Geriatric

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

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

Dosing: Pediatric

Note: Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance.

Infants, Children and Adolescents <18 years of age:

Acute, short-term uses:

Acute pain: Opioid-naïve:

Infants: Limited data available: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 2 to 4 hour intervals; in opioid-tolerant or younger infants, titration to higher doses may be required (up to 4 mcg/kg/dose) (Hegenbarth 2008; Nelson 1996; WHO 2012)

Children: Limited data available in <2 years of age: IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 30- to 60-minute intervals; in opioid-tolerant children, titration to higher doses may be required. Note: Usual adolescent starting dose is 25 to 50 mcg (Hegenbarth 2008; Nelson 1996; WHO 2012).

Adolescents <18 years: Note: After the first dose, if severe pain persists and adverse effects are minimal at the time of expected peak effect, may repeat dose (APS 2008)

<50 kg: Initial: IV: 0.5 to 1 mcg/kg/dose may repeat every 1 to 2 hours although some patients may require more frequent dosing (eg, 30-minute intervals) (APS 2008; Berde 2002)

≥50 kg: Initial: IV: 25 to 50 mcg every 1 to 2 hours although some patients may require more frequent dosing (eg, 30-minute intervals) (APS 2008; Berde 2002)

Analgesia for minor procedures/sedation:

Parenteral:

Infants and Children: Limited data available in <2 years of age: IM, IV: 1 to 2 mcg/kg/dose; administer 3 minutes before the procedure; maximum dose: 50 mcg/dose; may repeat ¹/₂ original dose every 3 to 5 minutes if necessary; titrate to effect (Cramton 2012; Krauss 2006; Zeltzer 1990)

Adolescents <18 years: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg, repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5-minute intervals if needed. Note: Higher doses are used for major procedures.

Intranasal (using parenteral preparation): Limited data available: Infants and Children weighing ≥10 kg: Intranasal: 1.5 mcg/kg once (maximum: 100 mcg/dose); reported range: 1 to 2 mcg/kg; some studies that used an initial dose of 1.5 mcg/kg allowed for additional incremental doses of 0.3 to 0.5 mcg/kg to be administered every 5 minutes, not to exceed a total dose of 3 mcg/kg depending on pain type and severity (Borland 2002; Borland 2005; Borland 2007; Chung 2010; Cole 2009; Crellin 2010; Herd 2009; Manjushree 2002; Saunders 2010)

Anesthesia, general; adjunct:

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

Adolescents <18 years: IV:

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

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

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

Anesthesia, general without additional anesthetic agents: Adolescents <18 years: IV: 50 to 100 mcg/kg/dose with O₂ and skeletal muscle relaxant

Anesthesia, regional; adjunct: Adolescents <18 years: IM, IV: 50 to 100 mcg; Note: An IV should be in place with regional anesthesia so the IM route is rarely used but still maintained as an option in the manufacturer's labeling.

Continuous analgesia/sedation:

Infants and Children: Limited data available in <2 years of age: Initial IV bolus: 1 to 2 mcg/kg followed by continuous IV infusion at initial rate: 1 mcg/kg/hour; titrate to effect; usual range: 1 to 3 mcg/kg/hour; some patients may require higher rates (5 mcg/kg/hour) (WHO 2012)

Adolescents <18 years:

≤50 kg: Initial IV bolus: 0.5 to 2 mcg/kg followed by continuous IV infusion at initial rate: 0.5 to 2 mcg/kg/hour based on expert recommendations for children and pediatric patients ≤50 kg (APS 2008; Berde 2002; WHO 2012)

>50 kg: Initial IV bolus: 25 to 100 mcg/dose followed by continuous IV infusion at initial rate: 25 to 200 mcg/hour based on expert recommendations for pediatric patients and experience in adult patients (APS 2008; Berde 2002; Liu 2003; Peng 1999)

Endotracheal intubation, emergent: Limited data available: Infants and Children: IV: 1 to 5 mcg/kg/dose (Hegenbarth 2008)

Preoperative sedation: Adolescents <18 years: IM, IV: 50 to 100 mcg administered 30 to 60 minutes prior to surgery or slow IV: 25 to 50 mcg given shortly before induction (Barash 2009)

Patient-controlled analgesia (PCA): Limited data available: Children ≥5 years and Adolescents <18 years; opioid-naïve: Note: PCA has been used in children as young as 5 years; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naïve. Assess patient and pain control at regular intervals and adjust settings if needed (APS 2008): IV:

Patient weight ≤50 kg:

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

Children <12 kg: 10 mcg/mL

Children 12 to 30 kg: 25 mcg/mL

Children >30 kg: 50 mcg/mL

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

Lockout: Usual initial: 5 doses/hour

Lockout interval: Range: 6 to 8 minutes

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

Patient weight >50 kg:

Usual concentration: 50 mcg/mL

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

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

Usual basal rate: ≤50 mcg/hour

Chronic uses or opioid-tolerant patients (eg, cancer pain):

Chronic pain, moderate to severe (opioid-tolerant): Transdermal patch: Duragesic: Children ≥2 years and Adolescents <18 years who are opioid-tolerant receiving at least 60 mg oral morphine equivalents per day: Note: Discontinue or taper all other around-the-clock or extended release opioids when initiating therapy with fentanyl transdermal patch:

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

Conversion from continuous infusion of fentanyl: In patients who have adequate pain relief with a fentanyl infusion, fentanyl may be converted to transdermal dosing at a rate equivalent to the intravenous rate. Based on experience in adults, a two-step taper of the infusion to be completed over 12 hours may be considered (Kornick 2001) after the patch is applied. The infusion is decreased to 50% of the original rate 6 hours after the application of the first patch, and subsequently discontinued twelve hours after application.

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

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

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

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

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

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

Table has been converted to the following text.

US Labeling: Dose Conversion Guidelines: Recommended Initial Duragesic Dose Based Upon Daily Oral Morphine Dose^a,b,c

• 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 1,034 mg morphine oral/day = 275 mcg/hour Duragesic
• 1,035 to 1,124 mg morphine oral/day = 300 mcg/hour Duragesic

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

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

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

Table has been converted to the following text.

US Labeling: Dose Conversion Guidelines^a

• 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

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

Cancer pain; breakthrough: Transmucosal lozenge: Actiq: Adolescents ≥16 years: Note: For patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Patients must remain on around-the-clock opioids during use.

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

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

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

Adolescents ≥ 18 years:

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:

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

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: 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) (APS 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).

Cancer pain; breakthrough: Transmucosal: Opioid-tolerant patients: 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/day should have the dose of their long-term opioid re-evaluated. Patients must remain on around-the-clock opioids during use.

Lozenge (eg, 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 (eg, 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 1,200 mcg film (maximum dose: 1,200 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 1,200 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 tablets (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, a second 100 mcg dose may be administered (maximum of 2 doses per breakthrough pain episode). 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. 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. 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 1,200 to 1,600 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 using the recommended titration steps. (Note: Must wait at least 2 hours before treating another episode with nasal spray.) Dose titration steps: 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 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.

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/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, one additional 100 mcg dose may be given 30 minutes after administration of the first dose. A maximum of two 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 per episode (one 200 mcg unit); if no relief with 200 mcg dose, increase to 400 mcg per episode (one 400 mcg unit); if no relief with 400 mcg dose, increase to 600 mcg dose per episode (one 600 mcg unit); if no relief with 600 mcg dose, increase to 800 mcg dose per episode (one 800 mcg unit); if no relief with 800 mcg dose, increase to 1,200 mcg dose per episode (two 600 mcg units); if no relief with 1,200 mcg dose, increase to 1,600 mcg per episode (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, one additional dose using the same strength may be administered (maximum: Two 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/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: 100 mcg for all patients unless patient already using Actiq; see Conversion from lozenge (Actiq) to sublingual tablet (Abstral); if pain is unrelieved, a second dose may be given 30 minutes after administration of the first dose. A maximum of two doses can be given per breakthrough pain episode. Must wait at least 2 hours before treating another episode.

Dose titration: If titration required, increase in 100 mcg increments (up to 400 mcg) over consecutive breakthrough episodes. If titration requires >400 mcg/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, one additional dose using the same strength may be administered (maximum: 2 doses 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 one tablet in the appropriate strength per episode. If pain is unrelieved with maintenance dose, 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/day. Consider increasing the around-the-clock, long-acting opioid therapy in patients experiencing >4 breakthrough pain episodes/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 following tables, the appropriate initial dose can be determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage equivalent and titrated to minimize adverse effects and provide analgesia. Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily fentanyl requirement and provide breakthrough pain relief with rescue medication (eg, immediate release opioid) than to overestimate requirements. With the initial application, the absorption of transdermal fentanyl requires several hours to reach plateau; therefore, transdermal fentanyl is inappropriate for management of acute pain. Change patch every 72 hours.

Conversion from continuous infusion of fentanyl: In patients who have adequate pain relief with a fentanyl infusion, fentanyl may be converted to transdermal dosing at a rate equivalent to the intravenous rate. 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 12 hours after application.

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

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

Frequency of application: The majority of patients may be controlled on every 72-hour administration; however, a small number of adult patients 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: The conversion factors in these tables are only to be used for the conversion from current opioid therapy to Duragesic (US labeling). 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.

Table has been converted to the following text.

US Labeling: Dose Conversion Guidelines: Recommended Initial Duragesic Dose Based Upon Daily Oral Morphine Dose^a,b

• 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 1,034 mg morphine oral/day = 275 mcg/hour Duragesic
• 1,035 to 1,124 mg morphine oral/day = 300 mcg/hour Duragesic

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

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

Table has been converted to the following text.

US Labeling: Dose Conversion Guidelines^a

• 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

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

Reconstitution

Continuous IV infusion: May further dilute in NS or D5W

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.

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

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

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

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

Buccal 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.

Intranasal: 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. 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.

Storage

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

Intranasal: 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, transdermal patch, transmucosal (buccal film, buccal tablet, lozenge, sublingual spray, sublingual tablet): Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect transmucosal products from freezing and moisture. Keep all products out of the reach of children.

Drug Interactions

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

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

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

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

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

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

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

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

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

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

Beta-Blockers: Opioids (Anilidopiperidine) may enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) 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

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

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

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

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

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

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

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

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

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

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

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

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

CYP3A4 Inducers (Moderate): May decrease the serum concentration of FentaNYL. Exceptions: St John's Wort. 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. Exceptions: Nefazodone. Consider therapy modification

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

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

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

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

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

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists 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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

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

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

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

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

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

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

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

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

Gastrointestinal Agents (Prokinetic): Opioid Agonists 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 (High risk with Inhibitors). Avoid combination

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

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

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

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

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

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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 (High risk with Inhibitors). Monitor therapy

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

Pegvisomant: Opioid Agonists 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 Opioid Agonists. 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

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

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

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

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

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

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

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, sedated state

Endocrine & metabolic: Dehydration

Gastrointestinal: Constipation, nausea, vomiting

Local: Application site erythema (transdermal device)

Neuromuscular & skeletal: Asthenia

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, vasodilation

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, night sweats, pallor, papule (application site, transdermal device), 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, lower limb cramp, limb pain, myalgia, tremor

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

Renal: Renal failure syndrome

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

Miscellaneous: Fever

<1%, postmarketing, and/or case reports: Allergic dermatitis, anaphylactoid shock, anaphylaxis, angina pectoris, bradycardia, bronchoconstriction, candidiasis, chest wall rigidity, clonus, contact dermatitis, crusted skin, cyanosis, decreased libido, dental caries, dermatitis, drug dependence (physical and psychological; with prolonged use), eczema, emotional lability, eructation, esophageal stenosis, exfoliative dermatitis, falling, fecal impaction, flank pain, flushing, genitourinary tract spasm, gingival hemorrhage, gingival recession, hematuria, hiccups, hostility, hyperesthesia, hypoglycemia, hypogonadism (Brennan 2013; Debono 2011), impaired consciousness, increased bronchial secretions, joint swelling, local hemorrhage, local hypersensitivity reaction, localized infection, local skin hyperpigmentation (lasted 2 to 3 weeks), local tissue necrosis, loss of consciousness, miosis, muscle rigidity (transient; observed in infants whose mothers were treated with IV fentanyl), muscle spasm, muscle twitching, myasthenia, nocturia, oliguria, pancytopenia, pleural effusion, polyuria, respiratory depression, respiratory distress, seizure, sexual disorder, skin erosion, Stevens-Johnson syndrome, swelling, swollen tongue, tonic-clonic epilepsy, tooth loss, upper abdominal pain, urticaria, voice disorder

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: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.
• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur, including following use in opioid non-tolerant patients and improper dosing. 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 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.
• Serotonin syndrome: May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs), lithium, St John's wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea).

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).
• Allergic rhinitis: Intranasal: Allergic rhinitis is not expected to alter fentanyl absorption following nasal administration; however, use of nasal decongestants (eg, oxymetazoline) during episodes of rhinitis may result in lower peak concentrations and delayed T_max, therefore, titration of intranasal fentanyl is not recommended during use of nasal decongestants.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.
• Bradycardia: Use with caution in patients with bradycardia or bradyarrhythmias (may produce further bradycardia).
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO₂ retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Avoid transdermal (patch) in patients with severe hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).
• Obesity: Use with caution in patients who are morbidly obese.
• Oral mucositis: Sublingual spray (Subsys): Cancer patients with oral mucositis experienced increased fentanyl exposure following sublingual spray administration; avoid use in patients with ≥ grade 2 mucositis; use with caution in patients with grade 1 mucositis, and closely monitor for respiratory and CNS depression.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate seizures.
• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of oxycodone/acetaminophen and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.
• CYP3A4 interactions: [US Boxed Warning]: The concomitant use of fentanyl with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl and any CYP3A4 inhibitor or inducer.
• 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.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• 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]). Consider the use of alternative nonopioid analgesics in these patients.
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged 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 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. 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, intranasal, 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: IV: Inject slowly over 1 to 2 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 intranasal:

- [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 that result in clinically important differences in the extent of absorption of fentanyl. When prescribing or dispensing fentanyl, 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. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure.

- [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.

- Application site reactions, ranging from paresthesia to ulcerations and bleeding, occurred with buccal tablet (Fentora).

• Transdermal iontophoretic system (Ionsys):

- [US Boxed Warning]: Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Ionsys REMS Program. Healthcare facilities that dispense Ionsys must be certified in this program and comply with the REMS requirements.

- [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, 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 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 baths, hot tubs, heated water beds, saunas) may increase fentanyl absorption and has resulted in fatalities. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources. 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]: Deaths due to a fatal overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal patch. 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.

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

- 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:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances, and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.
• Abuse/misuse/diversion: [US Boxed Warning]: Use exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing fentanyl and monitor all patients regularly for the development of these behaviors and conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age and psychotropic medication use. 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]).
• Accidental exposure: [US Boxed Warning]: Accidental ingestion of even one dose, especially by children, can result in a fatal overdose of fentanyl. Fentanyl must be kept out of reach of children.
• 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.
• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Monitoring Parameters

Pain relief; respiratory and mental 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]).

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

Pregnancy

Pregnancy Considerations

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

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

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

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

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

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

Patient Education

What is this drug used for?

• It is used to ease pain.

All products other than injection and skin system (lonsys):

• This drug is not for mild pain or pain that only lasts a short time (like headaches, toothaches, or pain after surgery).
• This drug is only for use by people who have been taking pain drugs (opioids) and are used to their effects. Talk with the doctor.

Frequently reported side effects of this drug

• Dry mouth
• Nausea
• Vomiting
• Diarrhea
• Headache
• Sensation of cold
• Lack of appetite
• Trouble sleeping
• Sweating a lot
• Application site irritation
• Tingling of mouth

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Slow breathing
• Shallow breathing
• Difficult breathing
• Noisy breathing
• Severe dizziness
• Passing out
• Confusion
• Severe constipation
• Severe abdominal pain
• Severe loss of strength and energy
• Shortness of breath
• Chest pain
• Fast heartbeat
• Slow heartbeat
• Severe fatigue
• Seizures
• Depression
• Abnormal movements
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea.
• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss.
• Sexual dysfunction (males)
• No menstrual periods
• Decreased sex drive
• Trouble getting pregnant
• Mouth sores
• Swelling of arms or legs
• Swelling of hands or feet
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.