Fentanyl Citrate

Pronunciation

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

Warning(s)

  • 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 (See REMS.) 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 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, 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.)

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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 and also see REMS.)

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/opiate combinations, 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 analgesic concentrations.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 opiate component of balanced anesthesia or total IV anesthesia (balanced anesthesia in which the IV anesthetic completely replaces the inhalation anesthetic).d e

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

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

Tachypnea and Delirium (Postoperative)

To prevent or relieve tachypnea and postoperative emergence delirium.b

Conscious Sedation

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

Fentanyl 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 Certification of clinicians and pharmacies is required before transmucosal immediate-release fentanyl preparations may be prescribed or dispensed. (See REMS.)

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 REMS and alsosee 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, slowlyd 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 possible with the first transdermal dose if the dose is overestimated.225

The manufacturers provide specific dosage recommendations for switching opiate-tolerant patients 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

Table 2: Transdermal Fentanyl Dose Based on Current Oral Opiate Dosage

Daily Dosage of Oral Opiate (in mg/day)

Transdermal Fentanyl (in mcg/hr)

Morphine sulfate

 

60–134

25

135–224

50

225–314

75

315–404

100

Oxycodone hydrochloride

 

30–67

25

67.5–112

50

112.5–157

75

157.5–202

100

Codeine phosphate

 

150–447

25

448–747

50

748–1047

75

1048–1347

100

Hydromorphone hydrochloride

 

8–17

25

17.1–28

50

28.1–39

75

39.1–51

100

Methadone hydrochloride

 

20–44

25

45–74

50

75–104

75

105–134

100

Table 3: Transdermal Fentanyl Dose Based on Current Parenteral Opiate Dosage

Daily Dosage of Parenteral Opiate (in mg/day)

Transdermal Fentanyl (in mcg/hr)

Morphine sulfate IV/IM

 

10–22

25

23–37

50

38–52

75

53–67

100

Oxycodone hydrochloride IV/IM

 

15–33

25

33.1–56

50

56.1–78

75

78.1–101

100

Hydromorphone hydrochloride IV

 

1.5–3.4

25

3.5–5.6

50

5.7–7.9

75

8–10

100

Meperidine hydrochloride IM

 

75–165

25

166–278

50

279–390

75

391–503

100

Methadone hydrochloride IM

 

10–22

25

23–37

50

38–52

75

53–67

100

Alternatively, to convert patients 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

Table 4: Equianalgesic Potency Conversion

Opiate Agonist

IM [Equianalgesic Dose (in mg)]

Oral [Equianalgesic Dose (in mg)]

Morphine sulfate

10

30 (based on clinical experience with chronic pain) to 60 (based on potency study in acute pain)

Codeine phosphate

130

200

Hydromorphone hydrochloride

1.5

7.5

Levorphanol tartrate

2

4

Meperidine hydrochloride

75

Methadone hydrochloride

10

20

Oxycodone hydrochloride

15

30

Oxymorphone hydrochloride

1

10 (rectal)

Doses in Table 4 are considered equivalent to 10 mg of IM morphine sulfate.225

Equivalencies were based on single-dose studies comparing IM doses of these drugs, and oral doses are those recommended when changing from IM to oral therapy with each drug.225

Table 5: Transdermal Fentanyl Dose Based on Daily Morphine Equivalence

Oral 24-hr Morphine (in mg/day)

Transdermal Fentanyl (in mcg/hr)

60–134

25

135–224

50

225–314

75

315–404

100

405–494

125

495–584

150

585–674

175

675–764

200

765–854

225

855–944

250

945–1034

275

1035–1124

300

Postpone the initial evaluation of maximum analgesia for ≥24 hours 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

Most patients are maintained adequately with transdermal systems applied at 72-hour intervals; however, some may require application of the systems at 48-hour intervals to maintain adequate analgesia.225 Before shortening the dosing interval for inadequate response to a given dose, evaluate a dose increase so that patients can be maintained on a 72-hour regimen if possible.225

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

Special Populations

Hepatic Impairment

Exercise caution.225 227 230 c d Use lowest possible dosage.230

Reduce initial parenteral dosage.c d

Insufficient information available to support recommendations regarding use of transdermal or buccal preparations.225 227 230 If used, caution advised.225 227 230

Renal Impairment

Exercise caution.225 227 230 c d Use lowest possible dosage.230

Reduce initial parenteral dosage.c d

Insufficient information available to support recommendations regarding use of transdermal or buccal preparations.225 227 230 If used, caution advised.225 227 230

Geriatric Patients

Reduce initial parenteral and transdermal doses; response to initial dosing should be considered in determining subsequent incremental doses.225 b d

Doses of buccal lozenges in patients >65 years of age generally are about 200 mcg lower than those required in younger patients;227 doses of buccal tablets are slightly lower than those required in younger patients.230 Exercise caution during dosage titration.227 230

Cautions for Fentanyl Citrate

Contraindications

  • Patients receiving MAO inhibitors.c

  • Known hypersensitivity to fentanyl or any ingredient or component (e.g., the adhesive in transdermal systems) of the respective formulation.225 227 230 d

  • Intrabuccal (transmucosal) preparations contraindicated in the management of acute pain (e.g., painful injuries, migraine or other headaches) or postoperative pain and in non-opiate-tolerant patients because of the risk of life-threatening respiratory depression.227 230 236 (See Buccal [Transmucosal] Tablets and Lozenges in Boxed Warning and also see REMS.)

  • Transdermal preparations contraindicated in acute or postoperative pain, in chronic pain that is mild or intermittent and manageable with less potent analgesics, and in patients not already receiving and tolerant of opiates because of the prolonged duration of effects and risk of serious or life-threatening respiratory depression.225 241 (See Transdermal Systems in Boxed Warning.)

  • Transdermal preparations also contraindicated in patients with substantial respiratory depression, especially in settings where equipment for monitoring and resuscitation is not available; in patients with acute or severe bronchial asthma; and in those with known or suspected paralytic ileus.225

Warnings/Precautions

Warnings

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

Supervised Administration

Administer only under the supervision of qualified clinicians who are experienced in the use of opiates for anesthesia or the management of pain, depending on use, and in the management of respiratory effects of potent opiates.225 227 230 d

Opiate antagonist and facilities for administration of oxygen and controlled respiration should be available during and immediately following IV administration.225 b d

Use intrabuccally only under the supervision of qualified clinicians who are experienced in the use of opiates for the management of cancer pain.227 230 (See REMS.)

Use transdermally only under the supervision of clinicians who are experienced in continuous administration of potent opiates for management of pain and in the detection and management of hypoventilation.225

Respiratory Depression

The major toxicity associated with fentanyl.225 227 230

Occurs most frequently in geriatric and debilitated patients, usually following large initial doses in nontolerant patients, or when given concomitantly with drugs that depress respiration.225 227 230

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

Observe patients who develop serious adverse effects with transdermal therapy closely for ≥24 hours after removal of the transdermal system since serum concentrations decline gradually and reach an approximate 50% reduction 17 hours after system removal.225

Patients who develop hypoventilation (respiratory depression) during transdermal therapy must be observed carefully; observe the degree of sedation and monitor the respiratory rate until respiration has stabilized.225

Use of transdermal systems or buccal tablets or lozenges in non-opiate-tolerant patients may result in fatal respiratory depression and is contraindicated.225 227 230 (See Boxed Warning.)

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

Death and life-threatening adverse effects reported in patients receiving fentanyl transdermally; attributed to inappropriate prescribing (e.g., use of transdermal fentanyl for postoperative pain, occasional or mild pain, or headaches) and incorrect use by patients (application of too many systems, application of heat to the system, replacement of systems too frequently).221 223 225 241 Use only for chronic pain in carefully selected patients who are opiate tolerant and are appropriately monitored.225

Death and life-threatening adverse effects reported in patients receiving the buccal tablets; attributed to improper patient selection (e.g., use of this formulation in patients who were not opiate tolerant), improper dosage, and/or improper substitution of the buccal tablets for other fentanyl formulations.230 232 233 (See Buccal [Transmucosal] Tablets and Lozenges in Boxed Warning and also see REMS.) Safe dosage conversion ratios established only for patients being transferred from fentanyl buccal lozenges to the buccal tablets; for opiate-tolerant patients being transferred from any other fentanyl preparation, initial dose of the buccal tablets should be 100 mcg.230 (See Dosage: Breakthrough Malignant [Cancer] Pain under Dosage and Administration.)

Use fentanyl with extreme caution in patients with COPD or cor pulmonale, and in those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.225 227 230 c d Further decreased respiratory drive and increased airway resistance may occur.d During anesthesia, this can be managed with assisted or controlled respiration.d

Interactions with Other CNS Depressants

Additive depressant effects may occur with concomitant use of other CNS depressants including other opiates, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcohol.225 227 230

Hypoventilation, hypotension, and profound sedation or coma may occur.225 227 230

When such combined therapy is contemplated, the dose of one or both agents should be reduced substantially.225 b (See Specific Drugs and Foods under Interactions.)

Interactions with CYP3A4 Inhibitors

Concomitant use of transdermal fentanyl with any CYP3A4 inhibitor and of fentanyl citrate buccal tablets or lozenges with potent or moderately potent CYP3A4 inhibitors may increase plasma fentanyl concentrations, increasing or prolonging opiate effects and potentially resulting in fatal respiratory depression.225 227 230 (See Interactions.)

Interactions with MAO Inhibitors

Severe and unpredictable potentiation by MAO inhibitor may occur.227 230 Do not use in patients who have received MAO inhibitors within 14 days.230 c

Dependence and Abuse

Physical and psychic dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.230 c (See Boxed Warning.)

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.225 227 230 After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.225 227

Patients with Fever or Exposure to High Temperatures

Closely observe patients who develop a fever during transdermal fentanyl therapy or whose core body temperature increases following strenuous exercise for manifestations of opiate toxicity and adjust dosage accordingly; drug absorption from fentanyl transdermal systems depends in part on the temperature of the skin and increases with increasing temperature.225 241 Serum fentanyl concentrations theoretically could increase by approximately one-third when body temperature increases to 40°C.225

Percutaneous absorption of fentanyl from the transdermal system may be increased if the application site or surrounding area is exposed to direct external heat sources (e.g., heating pads, electric blankets, heat or tanning lamps, saunas, hot tubs, hot baths, heated water beds, sunbathing) while the transdermal system is being worn; avoid such exposure.225 229 241

Accidental Exposure

Risk of serious or fatal adverse effects following accidental exposure to fentanyl transdermal systems (e.g., transfer of a transdermal system from an adult to a child while hugging, inadvertently sitting on a transdermal system, exposure of the caregiver’s skin to the drug during application or removal of the transdermal system).225 If accidental exposure occurs, remove system and wash area of contact with water.225 229 The accidentally exposed individual should seek medical attention immediately.225 229

Risk of choking or potentially fatal overdosage of fentanyl if transdermal system is placed in the mouth, chewed or swallowed, or used in other unintended ways.225

Head Injury and Increased Intracranial Pressure

May interfere with evaluation of CNS function, and respiratory depression produced by the drug may produce cerebral hypoxia and elevated CSF pressure not caused by the injury itself.c d

Use with extreme caution, if at all, in patients with severe CNS depression, anoxia, hypercapnia, respiratory depression, or in those susceptible to the intracranial effects of CO2 retention225 227 230 c or who are especially prone to respiratory depression such as comatose patients or those with head injury, brain tumor, or elevated CSF pressure.c

Major Toxicities

Musculoskeletal Effects

Muscle rigidity, particularly involving the respiratory muscles.d Concomitant neuromuscular blocking agents before or simultaneous with anesthetic use of fentanyl can reduce the risk.d

Dental Decay

Dental decay, including caries, tooth loss, and gum line erosion, has occurred in patients receiving fentanyl citrate buccal lozenges, despite routine oral hygiene in some patients.227 (See Buccal Tablets and Lozenges under Advice to Patients.) Each fentanyl citrate buccal lozenge contains 2 g of sugar.227

General Precautions

Care should be exercised and the initial dosage of the opiate agonist should be reduced in patients with toxic psychosis and in neonates and geriatric or debilitated patients.c

CNS Effects

May impair mental alertness and/or physical coordination needed to perform potentially hazardous activities such as driving or operating machinery; warn patient about possible adverse CNS effects of opiate agonists.230 b

Cardiac Arrhythmia

Because of cholinergic effects, may cause bradycardia.230 c d Caution in patients with cardiac bradyarrhythmias.230 c d

Hypothyroidism

Use with caution and in reduced dosage in patients with hypothyroidism.c

Addison’s Disease

Use with caution and in reduced dosage in patients with Addison’s disease.c

Pancreatic and Biliary Disease

May cause spasm of the sphincter of Oddi.225 c Use with caution in patients with biliary tract disease, including acute pancreatitis.225 Opiates may increase serum amylase concentrations.225 c

Diabetes Mellitus

Each buccal lozenge contains 2 g of sugar.227

Cachectic or Debilitated Patients

Use transdermal fentanyl with caution, since clearance of the drug may be decreased and reduced fat stores or muscle wasting may alter the drug’s pharmacokinetics.225

Local (Oral Mucosal) Reactions

Application site reactions (e.g., paresthesia, pain, ulceration, irritation, bleeding) reported in patients receiving fentanyl citrate buccal tablets; tend to occur early during treatment and generally are self-limited.230

Specific Populations

Pregnancy

Category C.225 227 230 d

Lactation

Distributed into milk.225 227 230 Discontinue nursing or the drug because of potential risk (sedation, respiratory depression) to nursing infants.225 227 230

Pediatric Use

Safety and efficacy of parenteral and transdermal therapy not established in children <2 years of age.225 b d Administer transdermal systems to children only if they are opiate tolerant and ≥2 years of age.225

Safety and efficacy of buccal (transmucosal) lozenges not established in children <16 years of age.227

Safety and efficacy of buccal tablets not established in children <18 years of age.230

To reduce potential for accidental ingestion, carefully select application site in young children receiving transdermal fentanyl therapy and monitor the system for proper adhesion over the period of application.225 242

Transdermal systems and buccal lozenges and tablets contain fentanyl in amounts that can be fatal to a child.227 229 230 236 Fatal respiratory depression can occur if a transdermal system is accidentally or deliberately applied or ingested by a child or adolescent.225 If a child is accidentally exposed to a fentanyl transdermal system or accidentally ingests the buccal tablets or lozenges, parents or caregivers should seek immediate medical treatment for the child.227 229 236

Strongly warn patients and/or their caregivers to keep new and used transdermal systems and new and partially used buccal preparations in a secure location out of the reach of children.225 227 229 230 Specifically question patients and/or their caregivers about the presence of children in the patient’s home.227 234

Geriatric Use

Respiratory depression is the major toxicity of fentanyl in geriatric or debilitated patients, especially after large initial doses in non-opiate-tolerant patients or when given in conjunction with other drugs that depress respiration.225

Clearance of IV fentanyl may be reduced substantially in individuals ≥60 years of age.225 Geriatric patients may be more sensitive to effects of IV fentanyl.227

Use transdermal fentanyl with caution, since clearance of the drug may be decreased and reduced fat stores or muscle wasting may alter the drug’s pharmacokinetics.225

Increased frequency of certain adverse effects (e.g., vomiting, constipation, abdominal pain) reported in geriatric patients compared with younger patients receiving fentanyl citrate buccal tablets.230 Safety profile of the buccal lozenges in geriatric patients appears similar to that in younger patients; however, caution is advised because of greater sensitivity observed in geriatric patients receiving IV fentanyl.227

Caution when selecting and titrating dosage.225 227 230 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

May have a prolonged duration and cumulative effect in patients with hepatic dysfunction.225 c

Exercise caution and reduce initial parenteral dosage.c d Insufficient information available to support recommendations regarding use of transdermal or buccal preparations; if used, caution advised.225 227 230

Renal Impairment

May have a prolonged duration and cumulative effect in patients with renal dysfunction.225 c

Exercise caution and reduce initial parenteral dosage.c d Insufficient information available to support recommendations regarding use of transdermal or buccal preparations; if used, caution advised.225 227 230

Common Adverse Effects

Abdominal pain, headache, bradyarrhythmia, chest pain, nausea, vomiting, constipation, somnolence, confusion, asthenia, fatigue, dizziness, nervousness, hallucinations, anxiety, depression, euphoria, respiratory depression (hypoventilation, dyspnea, apnea), sweating, pruritus, urinary retention.225 227 230

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

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

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

Interactions for Fentanyl Citrate

Metabolized by CYP3A4.225 227 230

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Concomitant use with drugs that inhibit CYP3A4 activity may cause decreased clearance of fentanyl resulting in increased or prolonged opiate effects; exercise caution during concomitant use and adjust dosage as necessary.225 227 230 234 If potent or moderately potent CYP3A4 inhibitors are used concomitantly with intrabuccal fentanyl therapy, monitor patients for an extended period of time; increases in fentanyl dosage should be conservative.227 230 Use of any CYP3A4 inhibitor concomitantly with transdermal fentanyl results in increased plasma fentanyl concentrations and may potentially cause fatal respiratory depression; monitor patients receiving such concomitant therapy for an extended period of time and adjust dosage if needed.225

CYP3A4 inducers: Induce metabolism and may cause increased clearance of fentanyl resulting in decreased opiate effects; exercise caution during concomitant use and adjust dosage as necessary.225 230 234

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

May inhibit fentanyl metabolism and decrease clearance resulting in increased opiate effects225

Monitor patients receiving transdermal fentanyl for an extended time; dosage adjustment may be necessary225

Amphetamines

Dextroamphetamine may enhance opiate agonist analgesiac

May be used to therapeutic advantage

Antibiotics, macrolide (clarithromycin, erythromycin, troleandomycin)

May inhibit fentanyl metabolism and decrease clearance resulting in increased opiate effects225 227 230

Monitor patients receiving fentanyl transdermal systems or buccal tablets or lozenges for an extended time;225 227 230 dosage adjustment may be necessary;225 increases in fentanyl dosage should be conservative227 230

Anticoagulants

Opiate agonists have been reported to potentiate the anticoagulant activity of coumarin anticoagulantsc

Antidepressants, MAO inhibitors

Severe and unpredictable potentiation by MAO inhibitors227 230 d

Do not use in patients who have received MAO inhibitors within 14 days227 230 c

Antidepressants, tricyclic

May potentiate the effects of tricyclic antidepressants c

Use concomitantly with caution; dosage adjustment may be necessary225

Antifungals, azole (fluconazole, itraconazole, ketoconazole)

May inhibit fentanyl metabolism and decrease clearance resulting in increased opiate effects225 227 230

Monitor patients receiving fentanyl transdermal systems or buccal tablets or lozenges for an extended time;225 227 230 dosage adjustment may be necessary;225 increases in fentanyl dosage should be conservative227 230

Aprepitant

May increase plasma fentanyl concentration resulting in increased opiate effects225 227 230

Monitor patients receiving fentanyl transdermal systems or buccal tablets or lozenges for an extended time;225 227 230 dosage adjustment may be necessary;225 increases in fentanyl dosage should be conservative227 230

Calcium-channel blocking agents (diltiazem, verapamil)

May increase plasma fentanyl concentration resulting in increased opiate effects225 227 230

Monitor patients receiving fentanyl transdermal systems or buccal tablets or lozenges for an extended time;225 227 230 dosage adjustment may be necessary;225 increases in fentanyl dosage should be conservative227 230

Carbamazepine

May induce fentanyl metabolism and increase clearance resulting in decreased opiate effects225

Use concomitantly with caution; dosage adjustment may be necessary225

CNS depressants (e.g., other opiates, general anesthetics, tranquilizers, sedatives and hypnotics, alcohol)

May potentiate the effects of other CNS depressantsc

Use with great caution and in reduced dosagec

Transdermal fentanyl: Substantially reduce dosage of one or both drugs225

Parenteral fentanyl: Fentanyl doses as low as 25–33% of the usual parenteral dose should be employed; dosage adjustment for the concomitantly administered drug also may be necessaryb

Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesiac

Diuretics

Opiate agonists may decrease the effects of diuretics in patients with CHFc

Droperidol

Decreased pulmonary artery pressure may occurd

Hypotension or hypertension may occurd

May interfere with postoperative EEG monitoring (slow return to normal)

Exercise caution during concomitant used

Grapefruit, grapefruit juice

May inhibit fentanyl metabolism and increase plasma fentanyl concentration225 227 230

Avoid grapefruit and grapefruit juice during intrabuccal therapy227 230

If consumed during transdermal fentanyl therapy, monitor patient for an extended time; dosage adjustment may be necessary225

HIV protease inhibitors (fosamprenavir, nelfinavir, ritonavir)

May inhibit fentanyl metabolism and decrease clearance resulting in increased opiate effects225 227 230

Monitor patients receiving fentanyl transdermal systems or buccal tablets or lozenges for an extended time;225 227 230 dosage adjustment may be necessary;225 increases in fentanyl dosage should be conservative227 230

Nefazodone

May inhibit fentanyl metabolism and decrease clearance resulting in increased opiate effects225 227 230

Monitor patients receiving fentanyl transdermal systems or buccal tablets or lozenges for an extended time;225 227 230 dosage adjustment may be necessary;225 increases in fentanyl dosage should be conservative227 230

Nitrous oxide

Cardiovascular depression at relatively high fentanyl dosagesd

Exercise caution during concomitant used

Phenytoin

May induce fentanyl metabolism and increase clearance resulting in decreased opiate effects225

Use concomitantly with caution; dosage adjustment may be necessary225

Rifampin

May induce fentanyl metabolism and increase clearance resulting in decreased opiate effects225

Use concomitantly with caution; dosage adjustment may be necessary225

Skeletal muscle relaxants

May enhance the neuromuscular blocking action of skeletal muscle relaxantsc

Fentanyl Citrate Pharmacokinetics

Absorption

Bioavailability

Well absorbed percutaneously following topical application of a transdermal system201 202 203 225 and transmucosally following intrabuccal administration via sucking of a lozenge matrix or administration of a buccal tablet.213 214 227 230

When administered as a buccal tablet rather than a buccal lozenge, a larger fraction of the administered dose is absorbed transmucosally (48% versus 22%), peak plasma concentration is achieved earlier (47 versus 91 minutes), and systemic exposure to the drug is approximately 30–50% greater.230 235

Buccal lozenge: Bioavailability averages about 50%.227 Generally, approximately 25% absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with saliva and then absorbed slowly from the GI tract.213 214 224 227

Buccal tablet: Bioavailability averages about 65%.230 Generally, approximately 50% absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with saliva and then absorbed slowly from the GI tract.230 The time required for the buccal tablet to fully disintegrate does not appear to affect early systemic exposure to the drug.230

Transdermal systems are designed to deliver fentanyl at a nearly constant rate of 25 mcg/hour per 10 cm2 (Duragesic, Actavis, Sandoz, and Watson transdermal systems) or 25 mcg/hour per 6.25 cm2 (Mylan transdermal system); however, actual amount of drug delivered to the skin exhibits interindividual variation.201 225 237 238 239 240 Mylan transdermal systems labeled as delivering 12.5, 25, 50, 75, or 100 mcg of fentanyl per hour are bioequivalent to the respectively labeled delivery concentrations of Duragesic.244

Transdermal system: Peak concentration attained within 24–72 hours after initial application.225 With sequential, continuous use, serum concentrations continue to increase with the first few transdermal system applications.225

Serum concentrations of transdermally administered fentanyl theoretically could increase by approximately one-third when body temperature increases to 40°C.225

Application of a polyurethane film dressing (Bioclusive) over a Duragesic 100-mcg/hour transdermal system did not alter the pharmacokinetics of the drug.225

Following use of transdermal systems in non-opiate-tolerant children 1.5–5 years of age, plasma fentanyl concentrations were about twice the concentrations achieved in adults; however, pharmacokinetic parameters in older children were similar to those in adults.225

Onset

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

IM administration: About 7–15 minutes.b

Intrabuccal administration (lozenge): About 5–15 minutes; peaks within 20–50 minutes.213 215 216

Intrabuccal administration (tablet): About 10 minutes.235

Duration

IV administration, analgesia: 0.5–1 hours.b

IM administration, analgesia: 1–2 hours.b

Respiratory depressant effects may persist longer than analgesia.b

Special Populations

Following administration of single 200-mcg buccal tablet, systemic exposure to fentanyl in patients with grade 1 mucositis appears to be similar to that in patients without mucositis.230

Distribution

Extent

IV administration: Distributes rapidly from blood into the lungs and skeletal muscle and more slowly into deeper fat compartments;213 then redistributes slowly from these tissues into systemic circulation.213

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

Fentanyl crosses the placenta225 227 230 and is distributed into breast milk.225 227 230

Plasma Protein Binding

80–85% bound, principally to α1-acid glycoprotein but also to albumin and lipoproteins.213 224 227 230

Elimination

Metabolism

Metabolized extensively in the liver and the intestinal mucosa via CYP3A4;230 b also undergoes hydrolysis.b

Transdermally administered fentanyl does not appear to be metabolized in the skin.201 225

Elimination Route

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

Half-life

IV: About 7.1 hours.214

Oral: About 7.8 hours.214

Buccal: 2.6–11.7 hours.214 227 230

Transdermal: About 17 hours.201 202 203 205 207 208 225 229

Stability

Storage

Buccal (Transmucosal)

Tablets and Lozenges

20–25°C (may be exposed to 15–30°C) in a secure place away from children.227 230 Protect from freezing and moisture.227 230 Once buccal tablet has been removed from the blister package, do not store for use at a later time since tablet integrity may be compromised or accidental exposure may occur.230 236

Parenteral

Injection

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

Topical

Transdermal Systems

≤25°C in a secure place away from children and pets.225 229 Apply the system to the skin immediately after removal from the individually sealed package; discard if the seal was previously broken.225 229

Discard cut, damaged, or altered transdermal systems since proper controlled release of the drug cannot be ensured.225 229 242 (See Transdermal Systems in Boxed Warning.)

Compatibility

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

Parenteral

Hydrolyzed in acidic solutions.b

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Bupivacaine HCl

Bupivacaine HCl with Clonidine HCl

Ropivacaine HCl

Incompatible

Fluorouracil

Variable

Lidocaine HCl

Y-Site CompatibilityHID

Compatible

Abciximab

Amiodarone HCl

Amphotericin B cholesteryl sulfate complex

Argatroban

Atracurium besylate

Atropine sulfate

Bivalirudin

Dexamethasone sodium phosphate

Diazepam

Diltiazem HCl

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Doxapram HCl

Enalaprilat

Epinephrine HCl

Esmolol HCl

Etomidate

Fenoldopam mesylate

Furosemide

Haloperidol lactate

Heparin sodium

Hetastarch in lactated electrolyte injection (Hextend)

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Ketorolac tromethamine

Labetalol HCl

Lansoprazole

Levofloxacin

Linezolid

Lorazepam

Metoclopramide HCl

Midazolam HCl

Milrinone lactate

Morphine sulfate

Nafcillin sodium

Nicardipine HCl

Nitroglycerin

Norepinephrine bitartrate

Oxaliplatin

Pancuronium bromide

Phenobarbital sodium

Potassium chloride

Propofol

Ranitidine HCl

Remifentanil HCl

Sargramostim

Scopolamine HBr

Thiopental sodium

Vecuronium bromide

Vitamin B complex with C

Incompatible

Azithromycin

Phenytoin sodium

Actions

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

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

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

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

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

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

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

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

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

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

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

Advice to Patients

  • Provide manufacturer’s patient information (e.g., medication guide) to the patient each time fentanyl transdermal system or fentanyl citrate buccal tablets or lozenges are dispensed.225 227 229 230 236 (See REMS.)

  • Importance of informing patients that fentanyl is a drug of abuse.225 227 229 230 236 Instruct patients to keep the transdermal systems and buccal tablets and lozenges in a secure place to prevent theft or misuse in the home or workplace.225 227 229 230 236 Risk of severe or fatal respiratory depression if misused or used in individuals for whom the drug was not prescribed.225 227 229 230 236

  • Importance of informing patients that fentanyl may impair mental and/or physical ability required for performance of potentially hazardous tasks;225 227 229 230 236 avoid driving or operating heavy machinery until effects on individual are known.225 227 229 230 236

  • Importance of informing patients that fentanyl should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers).225 227 229 230 236

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.225 227 229 230 236

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.225 227 229 230 236

  • Importance of seeking immediate medical attention if signs or symptoms of overdosage (e.g., difficulty breathing; slow, shallow breathing; slow heart rate; extreme drowsiness with slowed breathing; cold, clammy skin; seizures or hallucinations; feelings of faintness, dizziness, or confusion) occur.227 229 236

  • Potential for severe constipation to occur.225 227 229 236

  • Importance of not abruptly discontinuing fentanyl following prolonged opiate therapy.225 227 229

  • Importance of informing patients of other important precautionary information.225 227 230 (See Cautions.)

  • Buccal Tablets and Lozenges
  • Importance of using buccal tablets and lozenges exactly as prescribed and only if opiate tolerant.227 230 236 (See REMS.) Do not substitute buccal tablets for buccal lozenges, or buccal tablets or lozenges for other fentanyl preparations, without consulting clinician.227 236

  • Importance of adhering to prescribed dosage and instructions for administration.227 230 236

  • Importance of using or discarding all the buccal tablets of one strength prior to obtaining buccal tablets of a different strength.230 232

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

  • Importance of questioning patients and/or their caregivers about the presence of children in the patient’s home, since the buccal tablets and lozenges contain sufficient amounts of fentanyl to be fatal to a child.227 230

  • Importance of warning patients and/or their caregivers to keep the buccal tablets and lozenges out of the reach of children and to safely dispose of partially used units.227 230 236

  • Proper disposal of partially consumed buccal lozenges involves dissolving any remaining lozenge under hot running tap water until the matrix is gone and then discarding the handle in a trash receptacle that is out of reach of children.227

  • Proper disposal of remaining unused buccal lozenges involves cutting open the package with scissors, holding the lozenge by its handle over a toilet bowl and cutting the drug matrix off the handle with wire-cutting pliers, flushing the toilet twice after up to 5 units have been cut and deposited in the toilet, and then discarding the handle in a trash receptacle that is out of reach of children.227

  • Proper disposal of remaining unused buccal tablets involves removing the buccal tablets from their blister packages and flushing the tablets down the toilet.230 236

  • Handles, blister packages, and cartons should not be flushed down the toilet, but disposed of according to instructions provided by the manufacturer.227 230 236

  • If patients and/or their caregivers need additional assistance with disposal of unused lozenges or buccal tablets, contact the manufacturer at 800-896-5855 or, alternatively, the local office of the DEA.227 230

  • Transdermal Systems
  • Importance of using transdermal systems exactly as prescribed and only if opiate tolerant.225 229

  • Importance of adhering to prescribed dosage and instructions for administration.229 242

  • Risk of serious or fatal adverse effects following accidental exposure to fentanyl transdermal systems.225 229 (See Accidental Exposure under Cautions.)

  • Importance of questioning patients and/or their caregivers about the presence of children in the patient’s home, since the transdermal systems contain sufficient amounts of fentanyl to be fatal to a child.225

  • Importance of warning patients and/or their caregivers to keep the transdermal systems out of the reach of children and pets and to safely dispose of used units.225 229 242

  • Importance of not using transdermal systems that have been altered in any way (e.g., cut, damaged, folded so that only part of the system is exposed).225 229 242

  • Instruct patients to carefully fold used transdermal systems immediately following removal so that the adhesive side adheres to itself and then flush them down the toilet.225 242

  • Instruct patients who have completed their course of transdermal therapy to discard any remaining unused systems by removing them from their packaging, folding them so that the adhesive side adheres to itself, and flushing them down the toilet.225 229 242

  • If gel from the drug reservoir of the transdermal system accidentally contacts the skin, the area should be washed with copious amounts of water.225 229 242 Do not use soap, alcohol, or other solvents since percutaneous absorption of the drug may be enhanced.225 242

  • Advise patients to avoid exposing the application site or surrounding area to direct external heat sources (e.g., heating pads, electric blankets, heat or tanning lamps, saunas, hot tubs, hot baths, heated water beds, sunbathing) while wearing the transdermal system since temperature-dependent increases in percutaneous absorption of fentanyl from the system are possible under such conditions.225 229 Importance of contacting clinician if a high fever occurs or if body temperature increases following strenuous exercise during transdermal fentanyl therapy.225 229

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.225 227 230

Certification of clinicians and pharmacies is required before transmucosal immediate-release fentanyl preparations may be prescribed or dispensed. (See REMS.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fentanyl

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Transdermal System

12.5 mcg/hour (1.25 mg/5 cm2 Duragesic and Sandoz or 1.28 mg/3.13 cm2 Mylan)*

Duragesic (C-II)

Janssen

Fentanyl Transdermal System (C-II)

25 mcg/hour (2.5 mg/10 cm2 Actavis, Duragesic, Sandoz, and Watson or 2.55 mg/6.25 cm2 Mylan)*

Duragesic (C-II)

Janssen

Fentanyl Transdermal System (C-II)

50 mcg/hour (5 mg/20 cm2 Actavis, Duragesic, Sandoz, and Watson or 5.1 mg/12.5 cm2 Mylan)*

Duragesic (C-II)

Janssen

Fentanyl Transdermal System (C-II)

75 mcg/hour (7.5 mg/30 cm2 Actavis, Duragesic, Sandoz, and Watson or 7.65 mg/18.75 cm2 Mylan)*

Duragesic (C-II)

Janssen

Fentanyl Transdermal System (C-II)

100 mcg/hour (10 mg/40 cm2 Actavis, Duragesic, Sandoz, and Watson or 10.2 mg/25 cm2 Mylan)*

Duragesic (C-II)

Janssen

Fentanyl Transdermal System (C-II)

Fentanyl Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Buccal (Transmucosal)

Lozenge (solid drug matrix on a handle)

200 mcg (of fentanyl)

Actiq (C-II)

Cephalon

Oral Transmucosal Fentanyl Citrate (C-II)

400 mcg (of fentanyl)

Actiq (C-II)

Cephalon

Oral Transmucosal Fentanyl Citrate (C-II)

600 mcg (of fentanyl)

Actiq (C-II)

Cephalon

Oral Transmucosal Fentanyl Citrate (C-II)

800 mcg (of fentanyl)

Actiq (C-II)

Cephalon

Oral Transmucosal Fentanyl Citrate (C-II)

1200 mcg (of fentanyl)

Actiq (C-II)

Cephalon

Oral Transmucosal Fentanyl Citrate (C-II)

1600 mcg (of fentanyl)

Actiq (C-II)

Cephalon

Oral Transmucosal Fentanyl Citrate (C-II)

Tablet

100 mcg (of fentanyl)

Fentora (C-II)

Cephalon

200 mcg (of fentanyl)

Fentora (C-II)

Cephalon

300 mcg (of fentanyl)

Fentora (C-II)

Cephalon

400 mcg (of fentanyl)

Fentora (C-II)

Cephalon

600 mcg (of fentanyl)

Fentora (C-II)

Cephalon

800 mcg (of fentanyl)

Fentora (C-II)

Cephalon

Parenteral

Injection

50 mcg (of fentanyl) per mL

Fentanyl Citrate Injection (C-II; with preservatives or preservative-free)

Sublimaze (C-II; preservative-free)

Taylor

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Actiq 1600MCG Lollipop (CEPHALON): 20/$2,627.02 or 30/$3,940.54

Actiq 200MCG Lollipop (CEPHALON): 20/$927.31 or 30/$1,390.97

Actiq 400MCG Lollipop (CEPHALON): 20/$1,194.94 or 30/$1,792.41

Actiq 600MCG Lollipop (CEPHALON): 20/$1,436.93 or 30/$2,155.39

Actiq 800MCG Lollipop (CEPHALON): 20/$1,671.84 or 30/$2,507.77

Duragesic-100 100MCG/HR Patches (JANSSEN): 5/$459.97 or 10/$906.01

Duragesic-12 12MCG/HR Patches (JANSSEN): 5/$95.99 or 10/$189.32

Duragesic-25 25MCG/HR Patches (JANSSEN): 5/$115.00 or 10/$228.98

Duragesic-50 50MCG/HR Patches (JANSSEN): 5/$205.78 or 10/$411.57

Fentanyl 100MCG/HR Patches (SANDOZ): 5/$215.99 or 10/$425.98

Fentanyl 12 (12.5)MCG/HR Patches (MYLAN): 5/$95.99 or 10/$190.96

FentaNYL 25MCG/HR Patches (MYLAN): 5/$66.66 or 10/$133.33

Fentanyl 50MCG/HR Patches (SANDOZ): 5/$129.99 or 10/$259.99

FentaNYL 75MCG/HR Patches (MYLAN): 5/$195.98 or 10/$379.98

FentaNYL Citrate 1200MCG Lollipop (MALLINCKRODT PHARM): 10/$299.95 or 30/$799.93

FentaNYL Citrate 1600MCG Lollipop (MALLINCKRODT PHARM): 20/$770.59 or 30/$1,155.89

FentaNYL Citrate 400MCG Lollipop (WATSON LABS): 20/$399.95 or 30/$599.93

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

201. Varvel JR, Shafer SL, Hwang SS et al. Absorption characteristics of transdermally administered fentanyl. Anesthesiology. 1989; 70:928-34. [IDIS 256148] [PubMed 2729633]

202. Holley FO, van Steennis C. Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodynamics of constant-rate IV and transdermal delivery. Br J Anaesth. 1988; 69:608-13.

203. Gourlay GK, Kowalski SR, Plummer JL et al. The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain. 1989; 37:193-202. [PubMed 2748192]

204. Plezia PM, Kramer TH, Linford J et al. Transdermal fentanyl: pharmacokinetics and preliminary clinical evaluation. Pharmacotherapy. 1989; 9:2-9. [IDIS 386010] [PubMed 2646620]

205. Bell SD, Larijani GE, Goldberg ME et al. Evaluation of transdermal fentanyl for multi-day analgesia in postoperative patients. Anesthesiology. 1988; 69(Suppl 3A):A362.

206. Caplan RA, Ready LB, Oden RV et al. Transdermal fentanyl for postoperative pain management: a double-blind placebo study. JAMA. 1989; 261:1036-9. [IDIS 250311] [PubMed 2915410]

207. Duthie DJR, Rowbotham DJ, Wyld R et al. Plasma fentanyl concentrations during transdermal delivery of fentanyl to surgical patients. Br J Anaesth. 1988; 60:614-8. [IDIS 247231] [PubMed 3377943]

208. Larijani GE, Bell SD. Goldberg ME et al. Pharmacokinetics of fentanyl following transdermal application. Anesthesiology. 1988; 69(Suppl 3A):A363.

209. Miser AW, Narang PK, Dothage JA et al. Transdermal fentanyl for pain control in patients with cancer. Pain. 1989; 37:15-21. [PubMed 2726274]

210. Rowbotham DJ, Wyld R, Peacock JE et al. Transdermal fentanyl for the relief of pain after upper abdominal surgery. Br J Anaesth. 1989; 63:56-9. [IDIS 256938] [PubMed 2669904]

211. Simmonds MA, Blain C, Richenbacher J et al. A new approach to the administration opiates: TTS (fentanyl) in the management of pain in patients with cancer. J Pain Symptom Management. 1988; 3:S18.

212. Gourlay GK, Kowalski SR, Plummer JL et al. The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems. Pain. 1990; 40:21-8. [PubMed 2339011]

213. Abbott Laboratories. Fentanyl Oralet oral transmucosal fentanyl citrate prescribing information. North Chicago, IL; 1993 Oct.

214. Streisand JB, Varvel JR, Stanski DR et al. Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology. 1991; 75:223-9. [IDIS 286271] [PubMed 1859010]

215. Friesen RH, Lockhart CH. Oral transmucosal fentanyl citrate for preanesthetic medication of pediatric day surgery patients with and without droperidol as a prophylactic anti-emetic. Anesthesiology. 1992; 76:46-51. [IDIS 298766] [PubMed 1729935]

216. Goldstein-Dresner MC, Davis PJ, Kretchman E et al. Double-blind comparison of oral transmucosal fentanyl citrate with oral meperidine, diazepam, and atropine as preanesthetic medication in children with congenital heart disease. Anesthesiology. 1991; 74:28-33. [IDIS 276763] [PubMed 1986659]

217. Ashburn MA, Lind GH, Gillie MH et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of postoperative pain. Anesth Analg. 1993; 76:377-81. [IDIS 310157] [PubMed 8424519]

218. Lind GH, Marcus MA, Mears SL et al. Oral transmucosal fentanyl citrate for analgesia and sedation in the emergency department. Ann Emerg Med. 1991; 20:1117-20. [PubMed 1928885]

219. Fine PG, Marcus M, De Boer AJ et al. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain. 1991; 45:149-53. [PubMed 1876422]

220. The United States pharmacopeia, 22nd rev, and The national formulary, 17th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1990:1934.

221. Wyman JR. Fentanyl. HHS News. P94-2. Rockville, MD: Food and Drug Administration; 1994 Jan 18.

223. Wolfe S (Public Citizen’s Health Research Group, Washington, DC). Letter to David Kessler, Commissioner, Food and Drug Administration, regarding Oralet (fentanyl lollipop). 1994 Jan 25.

224. Abbott Laboratories. Fentanyl Oralet (oral transmucosal fentanyl citrate) prescribing information. North Chicago, IL; 1998 May.

225. Janssen Pharmaceutica. Duragesic (fentanyl transdermal system) prescribing information. Titusville, NJ; 2008 Feb.

226. Schechter NL, Weisman SJ, Rosenblum M et al. The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics. 1995; 95:335-9. [IDIS 343938] [PubMed 7862469]

227. Cephalon, Inc. Actiq (oral transmucosal fentanyl citrate lozenge) prescribing information. Salt Lake City, UT; 2007 Feb.

228. Farrar JT, Cleary J, Rauck R et al. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst. 1998; 90:611-6. [IDIS 404597] [PubMed 9554444]

229. Janssen Pharmaceutica. Duragesic (fentanyl transdermal system) patient information. Titusville, NJ; 2008 Feb.

230. Cephalon, Inc. Fentora (fentanyl buccal tablet) prescribing information. Salt Lake City, UT; 2007 Oct.

231. Portenoy RK, Taylor D, Messina J et al. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006; 22:805-11. [PubMed 17057563]

232. Dayno JM. Dear healthcare professional letter: Important safety information for Fentora. Salt Lake City, UT: Cephalon, Inc.; 2007 Sep 10.

233. US Food and Drug Administration. FDA public health advisory: Important information for the safe use of Fentora (fentanyl buccal tablets). Rockville, MD; 2007 Sep 26. From FDA web site.

234. Anon. Fentanyl buccal tablet (Fentora) for breakthrough pain. Med Lett Drugs Ther. 2007; 49:78-9. [PubMed 17878889]

235. Darwish M, Kirby M, Robertson P Jr et al. Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate. J Clin Pharmacol. 2007; 47:343-50. [PubMed 17322146]

236. Cephalon, Inc. Fentora (fentanyl buccal tablet) medication guide. Salt Lake City, UT; 2007 Oct.

237. Actavis. Fentanyl transdermal system prescribing information. Sunrise, FL; 2007 Aug.

238. Sandoz, Inc. Fentanyl transdermal system prescribing information. Broomfield, CO; 2007 Mar.

239. Watson Laboratories, Inc. Fentanyl transdermal system prescribing information. Corona, CA; 2006 Nov.

240. Mylan Pharmaceuticals, Inc. Fentanyl transdermal system prescribing information. Morgantown, WV; 2008 Feb.

241. US Food and Drug Administration. FDA public health advisory: Important information for the safe use of fentanyl transdermal system (patch). Rockville, MD; 2007 Dec 21. From FDA website.

242. Janssen. Duragesic (fentanyl transdermal system) instructions for applying a Duragesic patch. Titusville, NJ; 2008 Feb.

243. Janssen Pharmaceutica. Duragesic (fentanyl transdermal system) prescribing information. In: Physicians’ desk reference. 48th ed. Montvale, NJ: Medical Economics Company Inc; 1994(Suppl A):A90-4.

244. Approved Drug Products with Therapeutic Equivalence Evaluations (Electronic Orange Book). Accessed 2008 Nov 5. From FDA website.

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d. Marsam. Fentanyl citrate injection USP prescribing information. Cherry Hill, NJ; 1997 Jan.

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f. Bailey PL. Clinical Pharmacology and Applications of Opioid Agonists. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:96-103.

g. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:2466.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:699-707.

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