Fentanyl Citrate

Class: Opiate Agonists
VA Class: CN101
CAS Number: 990-73-8
Brands: Actiq, Duragesic, Fentora, Sublimaze

• Transdermal Systems


• 
  

  Indicated only for the management of persistent, moderate to severe pain that requires continuous, around the clock opiate administration for an extended period of time and that cannot be managed by other means (e.g., NSAIAs, opiate combination preparations, immediate-release opiates).²²⁵

  
  


• 
  

  Use only in opiate-tolerant patients who require a total daily opiate dosage equivalent to ≥25 mcg of transdermal fentanyl per hour.²²⁵ Opiate-tolerant patients are those who have been receiving ≥60 mg of oral morphine sulfate daily, ≥30 mg of oral oxycodone hydrochloride daily, ≥8 mg of oral hydromorphone hydrochloride daily, or equianalgesic dosage of another opiate for ≥1 week.²²⁵

  
  


• 
  

  Contraindicated because of potential for serious or life-threatening hypoventilation in patients not already opiate tolerant; in patients requiring opiate analgesia for only a short period of time; in the management of acute pain or postoperative pain, including in outpatient surgery or day surgeries (e.g., tonsillectomies); and in the management of mild or intermittent pain (e.g., use on an as-needed [“prn”] basis).²²⁵

  
  


• 
  

  Peak fentanyl concentrations occur 24–72 hours following application; serious or life-threatening hypoventilation (even in opiate-tolerant patients) may occur at any time, but particularly during initial application period and after increases in dosage.²²⁵ (See Respiratory Depression under Cautions.)

  
  


• 
  

  Risk of fatal overdose secondary to respiratory depression.²²⁵ Fatal overdose is possible with the first transdermal dose in patients being switched from other opiate preparations if the transdermal dose is overestimated.²²⁵ Due to long elimination half-life (17 hours), patients experiencing severe adverse effects (including overdosage) should be monitored and treated for ≥24 hours.²²⁵

  
  


• 
  

  Concomitant use with any CYP3A4 inhibitor may result in increased plasma fentanyl concentrations, which could increase or prolong adverse effects, potentially resulting in fatal respiratory depression.²²⁵ (See Interactions.) If used concomitantly, carefully monitor patients for an extended period and adjust dosage if warranted.²²⁵

  
  


• 
  

  Do not expose transdermal application site or surrounding area to direct external heat sources, since this could increase release of fentanyl from the transdermal system and potentially result in overdosage and death.²²⁵ Closely observe febrile patients and individuals whose core body temperature increases following strenuous exercise for manifestations of opiate toxicity; adjust dosage accordingly.²²⁵ (See Patients with Fever or Exposure to High Temperatures under Cautions.)

  
  


• 
  

  For transdermal use on intact skin only.²²⁵ Do not use transdermal system if the seal is broken or if the system is damaged, cut, or altered.²²⁵ Use of such systems may expose the patient or caregiver to the contents of the system and result in rapid release of fentanyl and absorption of a potentially fatal dose of the drug.²²⁵

  
  


• 
  

  Safety in children <2 years of age not established.²²⁵ Use in children ≥2 years of age only if opiate tolerant.²²⁵

  
  


• 
  

  Potential for abuse of fentanyl is similar to that of other opiates.²²⁵ Transdermal systems may be a particular target for abuse and diversion because of high fentanyl content.²²⁵ Clinicians should consider abuse potential when administering, prescribing, or dispensing fentanyl transdermal systems in situations where they are concerned about an increased risk of misuse, abuse, or diversion.²²⁵ Individuals at risk for opiate abuse include those with a personal or family history of substance abuse (e.g., alcohol or drug abuse or addiction) or psychiatric disorders (e.g., major depression).²²⁵ Assess patient for abuse or addiction potential before prescribing opiates; monitor for misuse, abuse, and addiction during therapy.²²⁵ Patients at risk of abuse may be treated with modified-release opiate preparations; however, intensive monitoring is needed.²²⁵

  
  

• Buccal (Transmucosal) Tablets and Lozenges


• 
  

  Serious adverse events, including deaths, have occurred because of improper patient selection (e.g., use in non-opiate-tolerant patients) and/or improper dosage in patients receiving the buccal tablets.²³⁰ Substitution of buccal tablets for any other fentanyl preparation may result in fatal overdosage.²³⁰ (See Dosage: Breakthrough Malignant [Cancer] Pain under Dosage and Administration.)

  
  


• 
  

  Do not use buccal tablets and lozenges interchangeably (e.g., on a mcg-per-mcg basis); buccal tablets are more bioavailable than buccal lozenges.^{230 232} Dosage adjustment required.^{230 232} (See Table 1 in Dosage and Administration.)

  
  


• 
  

  Buccal tablets and lozenges indicated only for the management of breakthrough malignant (cancer) pain in patients who already are receiving and tolerant of around-the-clock opiate therapy for their underlying persistent cancer pain.^{227 230}

  
  


• 
  

  Opiate-tolerant patients are those who have been receiving around-the-clock therapy with ≥60 mg of morphine sulfate daily, ≥25 mcg of transdermal fentanyl per hour, ≥30 mg of oral oxycodone hydrochloride daily, ≥8 mg of oral hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate for ≥1 week.^{227 230}

  
  


• 
  

  Buccal preparations contraindicated in the management of acute pain (e.g., injuries, migraine, other headaches) or postoperative pain because serious or life-threatening hypoventilation can occur at any dose in patients not chronically taking opiates.^{227 230}

  
  


• 
  

  Buccal preparations contraindicated in patients not already opiate tolerant.^{227 230} Deaths reported in non-opiate-tolerant patients.²³⁰

  
  


• 
  

  Buccal preparations intended for use only in cancer care and only by oncologists and pain specialists knowledgeable about the use of schedule II opiates in such patients.^{227 230}

  
  


• 
  

  Buccal tablets require special care in dosing.²³⁰ If breakthrough pain is not relieved after 30 minutes, the patient may take only 1 additional dose (using the same-strength tablet) and then must wait at least 4 hours before taking another dose.²³⁰ (See Dosage: Breakthrough Malignant [Cancer] Pain under Dosage and Administration.)

  
  


• 
  

  Instruct patients and their caregivers that the buccal tablets and lozenges contain fentanyl in an amount that can be fatal to a child.^{227 230} Instruct patients and their caregivers to keep the buccal tablets and lozenges out of reach of children and to discard open units properly.^{227 230}

  
  


• 
  

  Concomitant use of buccal preparations with potent or moderately potent CYP3A4 inhibitors may result in increased plasma fentanyl concentrations, which could potentially result in fatal respiratory depression.^{227 230} (See Interactions.)

  
  


• 
  

  Potential for abuse is similar to that of other opiates.^{227 230} Clinicians should consider abuse potential when administering, prescribing, or dispensing fentanyl buccal preparations in situations where they are concerned about an increased risk of misuse, abuse, or diversion.^{227 230}

  
  

REMS:

FDA approved a REMS for fentanyl to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of fentanyl and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Fentanyl Citrate

Pain (Acute)

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

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

Parenterally for severe but intermittent pain (e.g., renal colic) that can be treated with short-duration opiate analgesia.^c

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

Around-the-clock dosing of analgesics may be considered in the initial stages of acute pain to avoid wide swings in pain and sedation often associated with as-needed dosing regimens.^c

Because of the risk of life-threatening respiratory depression (e.g., hypoventilation), transdermal systems and buccal preparations are contraindicated in the management of acute or postoperative pain.^{221 225 227 230 232}

Malignant (Cancer) Pain

Transdermally for the management of persistent, moderate to severe chronic pain (e.g., associated with cancer) when continuous around-the-clock, strong opiate analgesia is indicated for an extended period of time.^{209 211 225} Use only in patients who are opiate tolerant.²²⁵ (See Transdermal Systems in Boxed Warning.)

Intrabuccally (transmucosally) for the management of breakthrough cancer pain only in patients who are already being treated with, and are tolerant of, opiates used around-the-clock for chronic cancer pain.^{227 230 234} (See Buccal [Transmucosal] Tablets and Lozenges in Boxed Warning.)

Do not use transdermally or intrabuccally in patients who are not opiate tolerant.^{225 227 230 232}

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

Analgesic therapy must be individualized and titrated according to patient response and tolerance.^c

Although consideration of the dependence potential of opiate agonists has often limited their effective use by many clinicians in terminally ill patients with severe, chronic pain, such consideration is irrelevant in the context of terminal illness.^c

Other Chronic Pain

Transdermally for the management of persistent, moderate to severe chronic pain in patients requiring continuous around-the-clock, strong opiate analgesia for an extended period of time.^{209 211 225} Use only in patients who are opiate tolerant.²²⁵ (See Transdermal Systems in Boxed Warning.)

Do not use transdermally for the management of mild or intermittent chronic pain that can be managed with less intensive analgesic therapy (e.g., acetaminophen/opiateCombinations, NSAIAs, intermittent dosing with short-acting opiates) or on an as-needed (“prn”) basis because of the risk of life-threatening respiratory depression.^{221 225}

Treatment of continuous or frequently recurring pain is best accomplished by the use of around-the-clock dosing regimens designed to prevent pain and minimize fluctuations in serum analgesicConcentrations.^d

As tolerance to initial dosage develops, larger doses may be given as necessary.^c

Alternative analgesic adjuncts such as tricyclic antidepressants or anticonvulsants also should be considered in the treatment of chronic nonmalignant pain (e.g., neurogenic pain).^c

During prolonged use, especially when opiate agonists are self-administered, precautions should be taken to prevent unnecessary increases in dosage.^c

Anesthesia

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

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

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

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

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

Tachypnea and Delirium (Postoperative)

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

Conscious Sedation

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

Fentanyl Citrate Dosage and Administration

Administration

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

Administer intrabuccally (transmucosally) as a lozenge or buccal tablet.^{227 230 b}

Administer percutaneously by topical application of a transdermal system.²²⁵

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

Intrabuccal (Transmucosal) Administration

Carefully instruct patients in the proper use and disposal of the buccal (transmucosal) lozenges and buccal tablets.^{227 230 236} (See Buccal Tablets and Lozenges under Advice to Patients.)

If signs of excessive opiate effects develop before the lozenge or buccal tablet is consumed completely, remove the remaining portion from the patient’s mouth immediately and decrease future doses.^{227 230 236}

Buccal Lozenges

Cut lozenge package open with scissors just prior to administration.^{213 224 227}

Place the lozenge in the patient’s mouth (between the cheek and the lower gum) using the handle, and instruct the patient to suck, and not bite or chew, the lozenge; efficacy may be reduced if the lozenge is chewed and swallowed rather than being administered as directed.²²⁷ The lozenge occasionally may be moved from one side to the other using the handle.^{213 224 227}

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

Buccal Tablets

Bend and tear along the blister card perforations to separate a single blister unit.^{230 236} Just prior to administration, bend along the indicated line on a single blister unit and peel the backing to remove the buccal tablet; do not attempt to push the buccal tablet through the blister.^{230 236}

Do not split buccal tablets.^{230 236}

Place the buccal tablet in the patient’s mouth (above a rear molar, between the upper cheek and gum) and instruct the patient not to suck, chew, or swallow the buccal tablet; efficacy may be reduced if the buccal tablet is sucked, chewed, or swallowed rather than being administered as directed.^{230 234 236} Alternate sides of the mouth with each dose.²³⁰

If the buccal tablet has not completely disintegrated after 30 minutes, the remnants may be swallowed with a glass of water.^{230 234 236} Disintegration time does not appear to affect early systemic exposure to the drug.²³⁰

IV Administration

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

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

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

Dilution

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

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

Rate of Administration

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

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

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

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

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

IM Injection

Administer by IM injection.^b

Transdermal (Percutaneous) Administration

Carefully instruct patients in the proper use and disposal of the transdermal system.^{225 241} (See Transdermal Systems under Advice to Patients.)

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.^{225 242}

Apply the transdermal system to a dry, intact, nonirritated, nonirradiated flat surface on the chest, back, flank, or upper arm by firmly pressing the system by hand for 30 seconds with the adhesive side touching the skin and ensuring that contact is complete, particularly around the edges.^{225 242} Do not fold the transdermal system so that only part of the system is exposed to the skin.²²⁵ When applied to young children or to individuals with cognitive impairment, place transdermal system on the upper back to reduce the risk that the system could be removed and placed in the mouth.^{225 242}

Clip, not shave, hair at the application site prior to application;^{225 242} shaving may be irritating, which could alter percutaneous drug absorption.²⁰⁴

Only clear water should be used if the site needs cleaning before transdermal application;^{225 242} do not use soaps, oils, lotions, alcohol, or any other agents that could irritate the skin or alter its characteristics.^{225 242}

Do not use transdermal system if the seal of the package is broken or if the system is altered in any way (e.g., cut, damaged), since use of altered systems may expose the patient or caregiver to the contents of the system and result in rapid release of fentanyl and absorption of a potentially lethal dose of the drug.^{225 229}

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

If a system should inadvertently come off during the period of use, apply a new system to a different skin site and leave in place for 72 hours.^{225 229 242} The edges of the system may be taped in place with first-aid tape if the patient experiences difficulty with system adhesion.^{225 229 242} If adhesion problems persist, an adhesive film dressing (e.g., Bioclusive, Tegaderm) may be applied over the system.^{225 229 242}

Patients may bathe, shower, or swim while wearing transdermal systems.²⁴²

Epidural Administration

Preservative-free injections have been injected or infused epidurally†; specialized techniques are required for administration by this route, and such administration should be performed only by qualified individuals familiar with the techniques of administration, dosages, and special patient management problems.^b

Dosage

Available as fentanyl and fentanyl citrate; dosage expressed in terms of fentanyl.^b

Give the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence.^b

Reduced dosage is indicated initially in poor-risk patients, in geriatric patients, and in patients receiving other CNS depressants.^b (See Geriatric Patients under Dosage and Administration and also see Specific Drugs and Foods under Interactions.)

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

Pediatric Patients

Anesthesia and Analgesia

IV or IM

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

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

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

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

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

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

Chronic Malignant (Cancer) Pain and Other Chronic Pain

Initial Dose Selection in Patients Being Switched to Transdermal Fentanyl Therapy

Transdermal

Use transdermal system only in children ≥2 years of age who are opiate tolerant.²²⁵ Risk of fatal respiratory depression when administered to patients not already opiate tolerant.²²⁵ (See Transdermal Systems in Boxed Warning.)

When selecting the initial transdermal dose, consider the daily dose, potency, and characteristics (e.g., pure or partial agonist activity) of the opiate the patient has been receiving and the reliability of potency estimates, which may vary by route, used to calculate an equivalent transdermal dose.²²⁵ Fatal overdose possible with the first transdermal dose if the dose is overestimated.²²⁵

The manufacturers provide specific dosage recommendations for switching opiate-tolerant children ≥2 years of age from certain oral or parenteral opiates to transdermal fentanyl (see Table 2 and Table 3);²²⁵ the manufacturers consider these initial dosages of transdermal fentanyl to be conservative estimates.²²⁵ Do not use the dosage conversion guidelines in Tables 2 and 3 to convert patients from transdermal fentanyl to oral or parenteral opiates, since dosage of oral or parenteral opiates may be overestimated.²²⁵

Alternatively, to convert children ≥2 years of age who currently are receiving other opiate therapy or dosages that are not listed in Table 2 or 3, calculate the opiate analgesic requirements during the previous 24 hours.²²⁵ Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using Table 4.²²⁵ Finally, calculate the equivalent dose of transdermal fentanyl using Table 5.²²⁵ The manufacturers state that this calculated initial dose of transdermal fentanyl may underestimate dosage requirements in about 50% of patients.²²⁵ However, this conservative initial dosage is recommended to reduce the risk of overdosage with the first dose.²²⁵

Use the lowest possible dose providing acceptable analgesia.²²⁵

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

If severe adverse effects (including overdosage) occur, monitor and treat patient for ≥24 hours because of long elimination half-life (17 hours).²²⁵

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

Postpone the initial evaluation of maximum analgesia for ≥24 hours after initiation of therapy because of gradual percutaneous absorption from the initially applied system.²²⁵

Many patients are likely to require upward dosage titration.²²⁵ If analgesia is inadequate, dosage may be titrated upward after 3 days.²²⁵

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

Dosage Adjustment to Achieve Adequate Analgesia

Transdermal

If analgesia is inadequate after initial application of a transdermal system, dosage may be titrated upward after 3 days.²²⁵ Initial transdermal dose may be increased after 3 days based on the daily dose of supplemental opiates during the second and third day after initial application.²²⁵

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

Conversion of supplemental opiate requirements to transdermal dose should be based on a ratio of 45 mg of oral morphine sulfate (during a 24-hour period) to each 12.5-mcg/hour delivery from the fentanyl transdermal system.²²⁵

Discontinuance of Transdermal Fentanyl Therapy

Transdermal

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

It generally takes ≥17 hours for serum fentanyl concentrations to decline by 50% following removal of the system.²²⁵ Symptoms of withdrawal (e.g., nausea, vomiting, diarrhea, anxiety, shivering) may occur in some patients following conversion to another opiate agonist or discontinuance of the fentanyl transdermal system.^{225 229}

Adults

Analgesia

IM or IV

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

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

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

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

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

Anesthesia

Adjunct to General Anesthesia

IV or IM

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

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

Moderate-dose, used in more major surgical procedures: Initially, 2–20 mcg/kg IV; additional doses of 25–100 mcg IV or IM as necessary.^{b d}

High-dose, used during open heart surgery or certain complicated neurosurgical or orthopedic procedures where surgery is more prolonged: Initially, 20–50 mcg/kg IV; additional doses ranging from 25 mcg to one-half the initial dose IV as necessary.^{b d}

IV Infusion

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

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

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

Approximate Plasma Fentanyl Concentrations Required in Balanced Anesthesia with Nitrous Oxidef

Noxious and surgical stimulus level (1–10 scale)	1-2	3–5	6–8	9–10
Plasma fentanyl (ng/mL)	1–2	3–6	4–10	6–20

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

General Anesthesia without Additional Anesthetic Agent

IV

Attenuation of the response to surgical stress: 50–100 mcg/kg in conjunction with oxygen and a skeletal muscle relaxant; doses up to 150 mcg/kg may be required.^b

Adjunct to Regional Anesthesia

IV or IM

50–100 mcg IM or by slow IV injection over 1–2 minutes when additional analgesia is required.^b

Postoperative Pain, Restlessness, Tachypnea, and Emergence Delirium

IM

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

Breakthrough Malignant (Cancer) Pain

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

Adults who are already being treated with, and are tolerant of, opiates: Initially, 200 mcg for breakthrough episode.²²⁷

Prescribe 6 lozenges initially, all of which should be used for various breakthrough episodes before the dose is increased.²²⁷

May be necessary to use >1 lozenge per episode of breakthrough cancer pain until the appropriate dose is attained; an additional lozenge may be administered 15 minutes after the previous lozenge has been consumed (i.e., 30 minutes after the first lozenge initially was placed in the mouth).²²⁷

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

Increase dose to the next higher available strength after several consecutive breakthrough cancer pain episodes require the use of >1 lozenge per episode; again, prescribe only 6 lozenges of the new strength.²²⁷

During titration phase, evaluate each new dose over several breakthrough cancer pain episodes (generally 1–2 days) to determine efficacy and tolerability of the drug.²²⁷

Once titrated to an adequate dose (average breakthrough pain episode is treated with a single lozenge), the patient should limit consumption to a maximum of 4 lozenges daily.²²⁷

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

Discontinuance of opiates: Gradually taper the dose of the opiate to avoid manifestations associated with abrupt withdrawal.²²⁷

Intrabuccal (Buccal tablets [Fentora])

Consider the increased bioavailability of the buccal tablets when transferring opiate-tolerant patients from fentanyl citrate buccal lozenges (e.g., Actiq) to fentanyl citrate buccal tablets.^{230 232} (See Bioavailability under Pharmacokinetics.) Fatal overdosage may occur if the buccal tablets are substituted on a mcg-per-mcg basis for the buccal lozenges or for any other fentanyl preparation.²³⁰

Instruct patients being transferred from the buccal lozenges to the buccal tablets to discontinue use of the buccal lozenges and to dispose of any remaining lozenges.²³⁰

Dosage conversion recommendations are available for opiate-tolerant patients being transferred from fentanyl citrate buccal lozenges to fentanyl citrate buccal tablets (see Table 1).²³⁰

Safe conversion regimens for opiate-tolerant patients being transferred from other fentanyl preparations (i.e., transdermal, parenteral, other oral formulations) have not been established.²³⁰ For all opiate-tolerant patients other than those being transferred from fentanyl citrate buccal lozenges, the initial recommended dose of the buccal tablets is 100 mcg for breakthrough episode.^{230 232 234}

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

Table 1: Initial Dosage Recommendations for Adults Being Transferred from Fentanyl Citrate Buccal Lozenges to Fentanyl Citrate Buccal Tablets for Management of Breakthrough Cancer Pain230

Current Fentanyl Dose Administered as Buccal Lozenge	Initial Fentanyl Dose Administered as Buccal Tablet
200 mcg	100 mcg (as one 100-mcg tablet)
400 mcg	100 mcg (as one 100-mcg tablet)
600 mcg	200 mcg (as one 200-mcg tablet)
800 mcg	200 mcg (as one 200-mcg tablet)
1200 mcg	400 mcg (as two 200-mcg tablets)
1600 mcg	400 mcg (as two 200-mcg tablets)

If breakthrough pain is not relieved within 30 minutes after the initial buccal tablet dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.^{230 232} After treating 1 episode of breakthrough pain with the buccal tablets, the patient must wait ≥4 hours before treating a subsequent episode of breakthrough pain with the buccal tablets.²³⁰

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

Instruct patients to record use of buccal tablets over several episodes of breakthrough pain and to discuss their experience with their clinician to decide whether dosage adjustment is warranted.²³⁰

During dosage titration, 1 dose may include administration of 1–4 tablets of the same strength.²³⁰ Administer no more than 4 tablets simultaneously.²³⁰ Manufacturer states that the only time patients should take >1 tablet as a single dose (e.g., two 100-mcg tablets for a single 200-mcg dose) is during dosage titration.²³⁰

Patients receiving an initial dose of 100 mcg who require titration to a higher dosage level may increase buccal tablet dosage to 200 mcg (two 100-mcg tablets, with one tablet placed on each side of the mouth in the buccal cavity) with the next episode of breakthrough pain.²³⁰ Those who require a further increase in dosage may place two 100-mcg tablets on each side of the mouth in the buccal cavity (total of four 100-mcg tablets).²³⁰ If dosages >400 mcg (i.e., dosages of 600 or 800 mcg) are required, titrate dosage using multiples of 200-mcg tablets.²³⁰

In patients who initiated buccal tablet therapy with the 200-mcg tablets (i.e., those who were transferred from fentanyl citrate buccal lozenge dosages of ≥600 mcg [see Table 1]), titrate buccal tablet dosage using multiples of 200-mcg tablets.²³⁰

During dosage titration period, if breakthrough pain is not relieved within 30 minutes after the initial dose of buccal tablets, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.^{230 232 234} Manufacturer states that no more than 2 doses may be given during a single episode of breakthrough pain, even if the patient continues to experience pain after the second dose is administered.^{230 232}

To reduce the risk of overdosage during titration, strongly advise patients to use or discard all the buccal tablets of one strength prior to obtaining tablets of a different strength.^{230 232}

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

Once titrated to an adequate dosage, breakthrough pain episodes generally should be treated effectively with 1 buccal tablet.^{230 232} On occasion during maintenance therapy, when a breakthrough pain episode is not relieved within 30 minutes after the first buccal dose, the patient may take only 1 additional dose of the same strength during that episode of breakthrough pain.²³⁰

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

After treating 1 episode of breakthrough pain with fentanyl citrate buccal tablets, patient must wait ≥4 hours before taking an additional dose of buccal tablets to treat a subsequent episode of breakthrough cancer pain.^{230 232 234}

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

Dosage adjustment does not appear to be necessary in patients with grade 1 mucositis; safety and efficacy in patients with grade 2 or greater mucositis not established.²³⁰

Discontinuance of opiates: Gradually taper the dose of the opiate to avoid manifestations associated with abrupt withdrawal.^{225 227 230 236}

Chronic Malignant (Cancer) Pain and Other Chronic Pain

Initial Dose Selection in Patients Being Switched to Transdermal Fentanyl Therapy

Transdermal

Use transdermal system only in patients who are opiate tolerant.²²⁵ Risk of fatal respiratory depression when administered to patients not already opiate tolerant.²²⁵ (See Transdermal Systems in Boxed Warning.)

When selecting the initial transdermal dose, consider the daily dose, potency, and characteristics (e.g., pure or partial agonist activity) of the opiate the patient has been receiving and the reliability of potency estimates, which may vary by route, used to calculate an equivalent transdermal dose.²²⁵ Fatal overdose p