Fentanyl

Fentanyl Citrate

AHFS Class: Opiate Agonists (28:08.08)

VA Class: CN101

View the associated Essentials monograph.

Introduction

Fentanyl is a synthetic phenylpiperidine-derivative opiate agonist.

Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Fentanyl citrate is a strong analgesic used preoperatively, during surgery, and in the immediate postoperative period for its analgesic action. In addition, the drug may be used to prevent or relieve tachypnea and postoperative emergence delirium. Fentanyl citrate is used parenterally to provide preoperative anxiolysis and sedation and as a supplement to anesthesia. The drug 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. Fentanyl citrate may be used as a supplement to general or regional anesthesia, including neuroleptanalgesia in which it is often used in combination with droperidol. When attenuation of the response to surgical stress is especially important, fentanyl citrate may be administered with oxygen and a skeletal muscle relaxant to provide anesthesia without the use of additional anesthetic agents.

Fentanyl citrate buccal (transmucosal) lozenges (Actiq^®, generic oral transmucosal fentanyl citrate lozenges)²²⁷ and buccal (transmucosal) tablets (Fentora^®)^{230 234} are used for the management of breakthrough cancer pain in patients who are already being treated with, and are tolerant of, opiates used for chronic cancer pain.^{227 230 234} Patients are considered opiate tolerant if they have been receiving at least 60 mg of morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate for at least 1 week.^{227 230} Because of the risk of life-threatening respiratory depression (e.g., hypoventilation), fentanyl citrate buccal lozenges (Actiq^®, generic oral transmucosal fentanyl citrate lozenges) and buccal tablets (Fentora^®) are contraindicated in the management of acute or postoperative pain^{227 230 232} and should not be used in patients who are not opiate tolerant.^{227 230 232} Because the buccal tablets are more bioavailable than the buccal lozenges, buccal tablets and lozenges of fentanyl citrate must not be used interchangeably (e.g., on a mcg-per-mcg basis) in the treatment of breakthrough cancer pain.^{230 232} In order to avoid overdosage, caution must be exercised when patients are transferred from the buccal lozenges or from other fentanyl formulations to the buccal tablets.^{230 232} (See Buccal Tablets under Dosage: Intrabuccal [Transmucosal] Dosage, in Dosage and Administration.) The manufacturers state that fentanyl citrate buccal lozenges and buccal tablets should be administered only under the supervision of qualified clinicians who are experienced in the use of opiates for the management of cancer pain.^{227 230}

The efficacy of fentanyl citrate buccal lozenges (Actiq^®) for the management of breakthrough cancer pain has been studied in a double-blind, placebo-controlled, randomized study in cancer patients 18 years of age and older who were already receiving the equivalent dosage of at least 60 mg of oral morphine sulfate daily or at least 50 mcg of transdermal fentanyl per hour for the management of chronic cancer pain and who experienced at least one occurrence of breakthrough pain daily.^{227 228} Following titration to an effective dose of fentanyl citrate buccal lozenges (doses of fentanyl used were 200, 400, 600, 800, 1200, and 1600 mcg), patients received in a blind, randomized manner a sequence of 7 lozenges of fentanyl citrate and 3 lozenges of placebo (one lozenge per breakthrough episode).^{227 228} Buccal lozenges of fentanyl citrate were associated with substantially more pain relief than placebo.^{227 228} In addition, when fentanyl citrate buccal lozenges were used for breakthrough cancer pain, rescue drug therapy (e.g., administration of an analgesic agent previously used for breakthrough cancer pain) was required less frequently than when placebo was used for such breakthrough pain.²²⁸

The efficacy of fentanyl citrate buccal tablets (Fentora^®) for the management of breakthrough cancer pain has been studied in a double-blind, placebo-controlled, crossover study in patients 18 years of age and older who were already receiving the equivalent dosage of at least 60 mg of oral morphine sulfate or at least 50 mcg of transdermal fentanyl per hour for the management of chronic cancer pain and who experienced at least one occurrence of breakthrough pain daily.^{230 231} Following titration to an effective dose of fentanyl citrate buccal tablets (median fentanyl dose: 400 mcg; range: 100–800 mcg), patients received in a double-blind, randomized manner a sequence of 7 buccal tablets of fentanyl citrate and 3 buccal tablets of placebo (one tablet per breakthrough episode).^{230 231} Buccal tablets of fentanyl citrate were associated with substantially more pain relief than placebo.^{230 231} In addition, when fentanyl citrate buccal tablets were used for breakthrough cancer pain, rescue drug therapy (e.g., administration of an analgesic agent previously used for breakthrough cancer pain) was required less frequently than when placebo was used for such breakthrough pain.²³¹

Fentanyl also previously was available for restricted use as an intrabuccal (transmucosal) premedicant prior to anesthesia or for inducing conscious sedation prior to diagnostic or therapeutic procedures in a monitored anesthesia setting (Fentanyl Oralet^®). 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 only labeled for use in opiate-tolerant patients with chronic cancer pain.

Fentanyl is used transdermally for the management of persistent, moderate to severe chronic pain in patients requiring opiate analgesia.^{200 209 211 225} The transdermal system should be used only for the management of chronic pain (e.g., such as that associated with cancer) that cannot be managed adequately with less intensive analgesic therapy (e.g., acetaminophen/opiate combinations, nonsteroidal anti-inflammatory agents [NSAIAs], intermittent dosing with short-acting opiates) and only in patients who require continuous opiate administration for an extended period of time.^{221 222 225} Fentanyl transdermal system should be used only in patients who are already being treated with, and are tolerant of, opiates used for chronic pain and who require a total daily opiate dosage equivalent to 25 mcg or more of transdermal fentanyl per hour.²²⁵ Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate for at least 1 week.²²⁵ Because of the risk of life-threatening respiratory depression, fentanyl transdermal system should not be used in patients who are not opiate tolerant or for the management of acute pain or mild or intermittent chronic pain that can be managed with less potent analgesics or on an as-needed (“prn”) or short-term basis.^{221 222 225} Although fentanyl also has been employed transdermally for the management of postoperative pain†,^{200 201 202 203 204 205 206 207 208 210 222} such use, including that following outpatient surgery, is not recommended because of inadequate experience and the interindividual variations in absorption and disposition of the drug observed in controlled clinical trials²⁰⁰ and because of the inability to properly titrate transdermal dosage in such pain and the risk of serious or life-threatening respiratory depression.^{221 222}

Dosage and Administration

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Fentanyl citrate is administered by IM or IV injection or intrabucally (transmucosally) as a buccal lozenge or buccal tablet. Fentanyl is administered percutaneously by topical application of a transdermal system.²⁰⁰

Parenteral Administration

An opiate antagonist and facilities for administration of oxygen and controlled respiration should be available during and immediately following IV administration of fentanyl citrate.

Preservative-free injections of fentanyl citrate also have been injected or infused epidurally†; specialized techniques are required for administration of the drug 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 associated with epidural fentanyl citrate administration.

Intrabuccal (Transmucosal) Administration

Buccal lozenges (Actiq^®, generic oral transmucosal fentanyl citrate lozenges) and buccal tablets (Fentora^®) of fentanyl citrate should be administered only under the supervision of qualified clinicians who are experienced in the use of opiates for the management of cancer pain.^{227 230}

When fentanyl citrate buccal lozenges are used, the package should be cut open with scissors just prior to administration.^{213 224 227} The lozenge should be placed in the patient’s mouth (between the cheek and the lower gum) using the handle and the patient should be instructed 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 (See Pharmacokinetics: Absorption.) The lozenge occasionally may be moved from one side to the other using the handle.^{213 224 227} Buccal lozenges of fentanyl citrate usually should be consumed over a period of 15 minutes; longer or shorter consumption times may result in reduced efficacy compared with that reported in clinical trials.²²⁷

When fentanyl citrate buccal tablets are used, a single blister unit should be separated by tearing along the blister card perforations.^{230 236} Immediately prior to administration, the single blister unit should be opened by bending the unit along the indicated line and peeling the backing to expose the buccal tablet.^{230 236} The buccal tablet should not be pushed through the blister, since this may damage the buccal tablet.^{230 236} The tablets should not be split.^{230 236} The fentanyl citrate buccal tablet should be placed in the patient's buccal cavity (above a rear molar, between the upper cheek and gum), and the patient should be instructed not to suck, chew, or swallow the tablet; efficacy may be reduced if the buccal tablet is sucked, chewed, or swallowed rather than being administered as directed.^{230 234 236} (See Pharmacokinetics: Absorption.) The fentanyl citrate buccal tablet should be left between the patient's upper cheek and gum until it has disintegrated (generally 14–25 minutes);^{230 234 236} the disintegration time does not appear to affect early systemic exposure to the drug.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}

If signs of excessive opiate effects develop before the buccal lozenge is consumed completely or the buccal tablet has disintegrated completely, the remaining portion should be removed from the patient's mouth immediately, and future doses should be decreased.^{227 230 236} Because fentanyl citrate buccal lozenges and buccal tablets contain sufficient amounts of fentanyl citrate to be fatal to a child, patients and/or their caregivers should be strongly warned to keep these preparations out of the reach of children.^{227 230} (See Chemistry and Stability: Stability.) In addition, patients and/or their caregivers should be instructed to safely dispose of used lozenge units and partially used tablets or lozenges of the drug.^{227 230} (See Chemistry and Stability: Stability.)

Transdermal Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Patients receiving transdermal fentanyl should be carefully instructed in the proper use and disposal of the transdermal system.²⁰⁰

To expose the adhesive surface of the system, the protective-liner covering should be peeled and discarded just prior to application.²⁰⁰ The transdermal system is applied 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 The transdermal fentanyl system should not be folded so that only part of the system is exposed to the skin.²²⁵ When the transdermal system is applied to young children or to individuals with cognitive impairment, the system should be placed on the upper back to reduce the risk that the system could be removed and placed in the mouth.²²⁵

Hair at the application site should be clipped, not shaved, prior to application of the transdermal system;²⁰⁰ shaving may produce irritation, which could alter percutaneous absorption of the drug.²⁰⁴ If the site must be cleansed prior to application, only clear water should be used.²⁰⁰ Soaps, oils, lotions, alcohol, or any other agents that could irritate the skin or alter its characteristics should not be used.²⁰⁰

Patients should be advised to avoid exposing the application site to direct external heat sources (e.g., heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds) while wearing the transdermal system since temperature-dependent increases in percutaneous absorption of fentanyl from the system are possible under such conditions.^{222 225} (See Cautions.)

The transdermal system should not be altered (e.g., cut) in any way prior to application since controlled drug delivery cannot be ensured.²²² A system should not be used if the seal of the package is broken or if the system is cut or damaged, since use of cut or damaged systems may result in rapid release of fentanyl and absorption of a potentially lethal dose of the drug.²²⁵

Each fentanyl transdermal system may be worn continuously for 72 hours; subsequent systems should be applied to a different site after removal of the previous system.²²⁵

Patients should be advised to keep both used and unused fentanyl transdermal systems out of the reach of children and pets.^{200 225} (See Cautions.) The manufacturers recommend that, immediately following removal, used systems be folded so that the adhesive side adheres to itself and is then flushed down the toilet.²⁰⁰ In addition, following completion of a course of transdermal fentanyl therapy, any remaining transdermal systems should be discarded.²⁰⁰ The manufacturers recommend that any unused systems be removed from their packaging, folded carefully so that the adhesive side adheres to itself, and then flushed down the toilet.^{200 225} If the gel from the drug reservoir accidentally contacts the skin, the affected area should be washed with copious amounts of water; soap, alcohol, or other solvents should not be used to remove the gel since they actually may enhance percutaneous absorption of fentanyl from the gel.²⁰⁰

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Dosage of fentanyl and fentanyl citrate is expressed in terms of fentanyl. The drugs should be given in the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. Reduced dosage is indicated initially in poor-risk patients, in geriatric patients, and in patients receiving other CNS depressants. Doses as low as 25–33% of the usual parenteral dose should be employed when the drug is used in conjunction with other CNS depressants. Dosage adjustment for the concomitantly administered drug also may be necessary. When the transdermal system is used concomitantly with other CNS depressants, the dosage of one or both drugs should be substantially reduced.²²⁵

Parenteral Dosage

For use as a preoperative medication, 50–100 mcg of fentanyl is administered IM 30–60 minutes prior to surgery.

As an adjunct to general anesthesia, fentanyl may be given in low-dose, moderate-dose, or high-dose regimens. In the low-dose regimen which is used for minor but painful surgical procedures, an IV dose of 2 mcg/kg is administered; additional doses are usually not necessary. In the moderate-dose regimen which is used in more major surgical procedures, an initial IV dose of 2–20 mcg/kg is administered; additional doses of 25–100 mcg may be given IV or IM as necessary. In the high-dose regimen which may be used during open heart surgery or certain complicated neurosurgical or orthopedic procedures where surgery is more prolonged, an initial IV dose of 20–50 mcg/kg may be given; additional doses ranging from 25 mcg to one-half the initial dose may be administered as necessary.

To provide general anesthesia without additional anesthetic agents when attenuation of the response to surgical stress is especially important, fentanyl doses of 50–100 mcg/kg may be administered IV in conjunction with oxygen and a skeletal muscle relaxant; in some cases, doses up to 150 mcg/kg may be required.

As an adjunct to regional anesthesia, 50–100 mcg of fentanyl may be administered by IM injection or by slow IV injection over 1–2 minutes when additional analgesia is required.

For the control of postoperative pain, restlessness, tachypnea, and emergence delirium, 50–100 mcg of the drug may be administered IM every 1–2 hours as needed.

During the induction and maintenance phases of general anesthesia in children 2–12 years of age, a fentanyl dose of 1.7–3.3 mcg/kg is recommended.

Intrabuccal (Transmucosal) Dosage

Buccal Lozenges. Dosage of buccal lozenges of fentanyl citrate (Actiq^®, generic oral transmucosal fentanyl citrate lozenges) should be individualized based on clinical response to provide adequate analgesia and to minimize adverse effects.^{227 228}

When buccal lozenges of fentanyl citrate are used for the management of breakthrough cancer pain in adults who are already being treated with, and are tolerant of, opiates used for chronic cancer pain, the initial recommended dose is 200 mcg (of fentanyl).²²⁷ The manufacturer recommends that a total of 6 lozenges be prescribed initially and that all 6 lozenges be used before the dose of fentanyl is increased.²²⁷ Until the appropriate dose of fentanyl citrate is attained, it may be necessary to use more than 1 lozenge per episode of breakthrough cancer pain; the 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 The manufacturer states that, during the dosage titration phase, a maximum of 2 lozenges per breakthrough pain episode may be given, if necessary.²²⁷ If several consecutive breakthrough cancer pain episodes occur that require the use of more than 1 lozenge per episode, the dose should be increased to the next higher available strength, again prescribing only 6 lozenges.²²⁷

During the titration phase, each new dose should be evaluated over several breakthrough cancer pain episodes (generally 1–2 days) to determine efficacy and tolerability of the drug.²²⁷ Once the patient has been titrated to an adequate fentanyl dose (average breakthrough pain episode is treated with a single lozenge), the patient should limit consumption of fentanyl citrate to a maximum of 4 lozenges daily.²²⁷ If consumption of fentanyl citrate buccal lozenges needs to be increased to more than 4 lozenges daily, dosage of opiates used for chronic cancer pain should be reevaluated.²²⁷ If discontinuance of opiates is required, gradual downward tapering of the dose is recommended to avoid signs and symptoms associated with abrupt withdrawal.²²⁷

In clinical trials, geriatric (older than 65 years of age) patients were titrated to an adequate dose of fentanyl citrate buccal lozenges (Actiq^®) that generally was about 200 mcg (of fentanyl) lower than the dose required in younger patients.²²⁷ Safety and efficacy of fentanyl citrate buccal lozenges in geriatric patients have not been studied specifically to date; however, about 24% of the cancer patients included in clinical studies of this formulation were older than 65 years of age, and 6% of patients were older than 75 years of age.^{227 228} Although the safety profile of fentanyl citrate buccal lozenges in geriatric patients appeared to be similar to that observed in younger patients, greater sensitivity to the effects of IV fentanyl has been observed in geriatric patients compared with younger individuals,²²⁷ and the manufacturer states that caution should be used when individually titrating dosage of fentanyl citrate buccal lozenges in geriatric patients.²²⁷

Buccal Tablets. Dosage of buccal tablets of fentanyl citrate (Fentora^®) should be individualized based on clinical response to provide adequate analgesia and to minimize adverse effects.²³⁰

When fentanyl citrate buccal tablets are used for the management of breakthrough cancer pain in adults who are already being treated with, and are tolerant of, opiates used for chronic cancer pain, the inital recommended dose is 100 mcg (of fentanyl).^{230 232 234} For opiate-tolerant adults who are being transferred from fentanyl citrate buccal lozenges (Actiq^®, generic oral transmucosal fentanyl citrate lozenges) to fentanyl citrate buccal tablets for the management of breakthrough cancer pain, the increased bioavailability of the buccal tablets must be considered.^{230 232} (See Pharmacokinetics: Absorption.) Failure to appropriately adjust the intrabuccal fentanyl dosage in these patients may result in fatal overdosage.²³³ The manufacturer's dosage conversion recommendations for patients being transferred from the buccal lozenges to the buccal tablets are shown in Table 1.²³⁰ The manufacturer states that these doses should be considered starting doses for the buccal tablets and are not intended to represent equianalgesic doses.²³² If breakthrough pain is not relieved within 30 minutes following the intital dose of fentanyl citrate buccal tablets (i.e., within 30 minutes after the buccal tablet was initially placed in the mouth), the patient may take one additional tablet of the same dosage strength during that episode of breakthrough pain.²³² If the initial dose of the buccal tablets did not provide adequate analgesia, the fentanyl dose used for the next episode of breakthrough pain may be increased to the next dosage level.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 Pain

Current Fentanyl Dose (in mcg) Administered as Buccal Lozenge	Initial Fentanyl Dose (in mcg) Administered as Buccal Tablet
200	100
400	100
600	200
800	200
1200	400
1600	400

Dosage should be titrated to a level that provides adequate analgesia with minimal adverse effects.^{230 232} If the patient has 100- or 200-mcg tablets and requires titration to a higher dosage level, dosage may be increased by increasing the number of 100- or 200-mcg tablets, respectively, administered as one dose (e.g., a patient who received a dose of 100 mcg during the previous episode of breakthrough pain may receive a 200-mcg dose, administered as two 100-mcg tablets, with one tablet placed on each side of the mouth in the buccal cavity, for the current episode).^{230 232} Dosage may be titrated in this manner, such that one dose may include administration of 2–4 tablets of the same dosage strength.²³² Administration of more than 4 tablets simultaneously has not been evaluated.²³⁰ The manufacturer states that systemic exposure to fentanyl is slightly higher when the drug is administered as four 100-mcg buccal tablets than when it is administered as one 400-mcg buccal tablet; however, the clinical importance of this difference has not been established.²³⁰ During the dosage titration period, if a single dose of fentanyl citrate buccal tablets does not provide adequate pain relief, a second dose (same dosage strength) may be administered 30 minutes after the previous buccal tablet was initially placed in the mouth.^{230 232 234} The manufacturer states that no more than 2 doses of the buccal tablet formulation 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, patients should be strongly advised to use or discard all the buccal tablets of one strength prior to obtaining tablets of a different strength.^{230 232} During the dosage titration phase, each new dose should be evaluated over several breakthrough cancer pain episodes to determine efficacy and tolerability of the drug.²³⁰

Once the patient has been titrated to an adequate fentanyl dose, average breakthrough pain episodes generally should be treated effectively with a single buccal tablet.²³² On occasion during maintenance therapy, a second dose (an additional buccal tablet of the same strength) may be taken when a breakthrough pain episode is not relieved within 30 minutes after the first buccal tablet was placed in the mouth.^{230 232} However, if several consecutive episodes require administration of more than one intrabuccal dose for pain relief, the dose of fentanyl given as buccal tablets generally should be increased.^{230 232} Patients should be instructed that, after treating one episode of breakthrough pain with fentanyl citrate buccal tablets, they should wait at least 4 hours before taking an additional dose to treat a subsequent episode of breakthrough cancer pain.^{230 232 234} If the patient experiences more than 4 breakthrough pain episodes daily, the dosage of opiates used for chronic cancer pain should be reevaluated.^{230 232}

If discontinuance of opiates is required, gradual downward tapering of the dose is recommended to avoid signs and symptoms associated with abrupt withdrawal.^{225 227 230 236}

Dosage adjustment of fentanyl citrate buccal tablets does not appear to be necessary in patients with grade 1 mucositis; safety and efficacy of this formulation in patients with grade 2 or greater mucositis have not been established.²³⁰

In clinical trials, the dosage of fentanyl citrate buccal tablets (following titration to an adequate dosage level) tended to be slightly lower in geriatric (older than 65 years of age) patients than in younger patients.²³⁰ About 23% of the cancer patients included in clinical studies of fentanyl citrate buccal tablets were 65 years of age or older.²³⁰ Geriatric patients receiving fentanyl citrate buccal tablets reported a slightly higher frequency of vomiting, constipation, and abdominal pain than did younger patients; the manufacturer states that caution should be used when individually titrating dosage of fentanyl citrate buccal tablets in geriatric patients.²³⁰

Transdermal Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Dosage of transdermal fentanyl should be individualized according to the clinical status of the patient, desired therapeutic effect, and patient age and weight and should be assessed at periodic intervals.^{222 225} However, the most important factor to be considered in determining the appropriate dose is the degree of existing opiate tolerance.^{222 225} In selecting an appropriate initial dose of the transdermal system, consideration also must be given to 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.²²² Overestimation of the transdermal dose when tranferring opiate-tolerant patients from other opiate therapy to transdermal fentanyl therapy may result in fatal overdosage following the initial transdermal dose.²²⁵ Because fentanyl transdermal system has an average elimination half-life of 17 hours, patients who experience a serious adverse effect, including overdosage, should be monitored for at least 24 hours.²²⁵

No systematic evaluation of transdermal fentanyl as initial opiate agonist therapy in the management of chronic pain has been completed to date; most patients in clinical studies were converted to transdermal therapy from other opiate therapy.^{200 222} Efficacy of the fentanyl transdermal system labeled as delivering 12.5 mcg/hour as an initial dose also has not been determined.²²⁵ Therefore, fentanyl transdermal systems should be used only in patients who are opiate tolerant.²²⁵ (See Uses.) Use of transdermal fentanyl in patients who are not opiate tolerant may result in life-threatening respiratory depression.²²⁵ Geriatric, cachectic, or debilitated patients should not receive initial transdermal doses exceeding 25 mcg/hour unless they currently are receiving a continuous daily opiate dose equivalent to 25 mcg/hour of transdermal fentanyl.^{200 225} Children initiating transdermal fentanyl therapy at a dose of 25 mcg/hour should be opiate tolerant and currently receiving the equivalent of at least 60 mg of oral morphine sulfate daily.²²⁵

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

Alternatively, to convert patients who currently are receiving other opiate therapy or dosages that are not listed in Table 2 or 3, the opiate analgesic requirements during the previous 24 hours should be calculated, an equianalgesic 24-hour dosage of oral morphine sulfate should be calculated using Table 4, and the equivalent dose of transdermal fentanyl should be calculated using Table 5.^{200 225} 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 administration of the first dose.²²⁵ The lowest possible dose providing acceptable analgesia should be used.²⁰⁰ For transdermal doses exceeding labeled delivery rates of 100 mcg/hour, multiple systems can be applied at different sites simultaneously.²⁰⁰

The manufacturers state that doses in Table 4 are considered equivalent to 10 mg of IM morphine sulfate.^{200 222} These 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.^{200 222}

In clinical trials, the ranges of daily oral morphine doses noted above were used as a basis for converting patients to transdermal fentanyl.²²² Although controlled clinical studies are not available, it is customary in clinical practice to consider the doses of opiates given IV, IM, or subcutaneously to be equivalent; however, differences in some pharmacokinetic parameters (e.g., peak concentrations achieved, time to peak) may exist.²²²

Most patients are maintained adequately with fentanyl transdermal systems applied at 72-hour intervals, although some patients may require application of the systems at 48-hour intervals to maintain adequate analgesia.^{200 222} However, dosing intervals of less than 72 hours have not been evaluated in children and adolescents and therefore cannot be recommended for use in this population.²²⁵ Because of the gradual percutaneous absorption of fentanyl from the initially applied system, the initial evaluation of maximum analgesia should be postponed for at least 24 hours.^{200 222} If inadequate analgesia is achieved, dosage may be titrated upward after 72 hours.^{200 222} Before shortening the dosing interval in patients not responding adequately to a given dose, an increase in dose should be evaluated so that patients can be maintained on a 72-hour regimen if possible.²²² Supplemental doses of a short-acting opiate analgesic should be used as needed during the initial application period and subsequently thereafter as necessary to relieve breakthrough pain.^{200 222 225}

The manufacturers state that the conversion factor used in determining equianalgesic morphine sulfate doses is conservative; therefore, many patients are likely to require upward dosage titration after initial application of a transdermal dose.^{200 222} The initial transdermal dose may be increased after 72 hours based on the daily dose of supplemental opiate analgesics during the second and third day after initial application.^{200 222} Because subsequent equilibrium with an increased dose may require up to 6 days to achieve, the manufacturers recommend that further upward titration in dose based on supplemental opiate analgesic requirements be made no more frequently than every 6 days (i.e., after two 72-hour application periods with a given dose).^{200 222} The manufacturers recommend that conversion of supplemental opiate requirements to transdermal fentanyl dose be based on a ratio of 45 mg of oral morphine sulfate (during a 24-hour period) to each 12.5-mcg/hour labeled delivery of fentanyl from the transdermal system.²²⁵

To convert to another opiate, the manufacturers recommend that the fentanyl transdermal system be removed and dosage of the other opiate titrated according to patient toleration and response.²²² It generally takes 17 hours or longer for serum fentanyl concentrations to decline by 50% following removal of the system.^{200 222} 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} When opiate therapy is discontinued, it should be done so gradually to avoid precipitation of withdrawal symptoms.²⁰⁰

Cautions

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Fentanyl shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed. (See Cautions in the Opiate Agonists General Statement 28:08.08.)

The most serious adverse effect of fentanyl is respiratory depression.^{225 227 230} Respiratory depression resulting in hypoventilation occurred in 4 or 2% of patients receiving fentanyl transdermally for postoperative or cancer pain, respectively, in clinical trials.²²² In postmarketing experience, fatal hypoventilation secondary to inappropriate use of fentanyl transdermal system has been reported,^{221 222 223} and the manufacturers warn that the system should be used only for chronic pain in carefully selected patients who are opiate tolerant and are appropriately monitored.^{222 225} (See Uses.) Death and life-threatening adverse effects also have been reported during postmarketing surveillance in patients receiving fentanyl citrate buccal tablets and have been 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.^{232 233} The manufacturers of buccal preparations of fentenyl citrate (lozenges, buccal tablets) warn that these preparations should be used only for treatment of breakthough pain in patients with cancer who are opiate tolerant.^{227 230 232} (See Uses.) Dosage must be carefully adjusted in patients being transferred from other fentanyl preparations (including fentanyl citrate buccal lozenges) to fentanyl citrate buccal tablets.^{230 232} (See Buccal Tablets under Dosage: Intrabuccal [Transmucosal] Dosage, in Dosage and Administration.)

In addition to the usual adverse effects associated with opiate therapy, local adverse effects associated with topical application of transdermal systems of fentanyl include erythema, papules, pruritus, and edema at the site of application.^{200 203 206 212 222} Erythema at the site of application is common and may persist for 6 hours or longer following removal of the transdermal system;^{203 206 212} exfoliative dermatitis and pustules have been reported occasionally.²²²

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 Frequent consumption of sugar-containing products has been associated with an increased risk of dental decay.²²⁷ Each fentanyl citrate buccal lozenge contains 2 g of sugar.²²⁷ Dry mouth is frequently associated with the use of opiate agonists (e.g., fentanyl) and may add to this risk.²²⁷ Patients should be instructed to inform their dentist that they are receiving this preparation, so that appropriate dental care is provided.²²⁷

Application site reactions, ranging from paresthesia to ulceration and bleeding, occurred in 10% of patients receiving fentanyl citrate buccal tablets in clinical trials.²³⁰ The most common application site reactions were pain, ulcer, and irritation, each occurring in 3–4% of patients receiving this preparation of fentanyl.²³⁰ Such reactions tended to occur early during treatment and generally were self-limited.²³⁰

Anaphylaxis and hypersensitivity reactions have been reported in patients receiving fentanyl citrate buccal lozenges.²²⁷

Fentanyl citrate appears to cause a lower incidence of nausea and vomiting than do other opiate agonists. Skeletal and thoracic muscle rigidity occur frequently, especially following rapid IV administration of fentanyl. Muscular rigidity may be associated with reduced pulmonary compliance and/or apnea, laryngospasm, and bronchoconstriction and may be managed by use of assisted or controlled respiration or, if necessary, by IV administration of a neuromuscular blocking agent. Bradycardia may occur following administration of fentanyl and may be controlled with atropine. Fentanyl should be used with caution in patients with cardiac bradyarrhythmias.

The manufacturers state that use of fentanyl is not recommended in patients who have received monoamine oxidase inhibitors within 14 days. Because fentanyl undergoes metabolism via cytochrome P-450 (CYP) isoenzyme 3A4 in the liver and the intestinal mucosa, concomitant use of potent or moderately potent inhibitors of CYP3A4 (including certain macrolide antibiotics [e.g., clarithromycin, erythromycin, troleandomycin], certain azole-derivative anti-infective agents [e.g., fluconazole, itraconazole, ketoconazole], most HIV protease inhibitors [e.g., amprenavir, fosamprenavir, nelfinavir, ritonavir], aprepitant, diltiazem, nefazodone, and verapamil) may increase bioavailability and decrease clearance of fentanyl (possibly resulting in increased or prolonged opiate effects, including potentially fatal respiratory depression).^{225 227 230 234} Conversely, concomitant use of drugs that induce CYP3A4 may reduce efficacy of fentanyl.^{225 230 234} Patients receiving potent or moderately potent CYP3A4 inhibitors concomitantly with transdermal or intrabuccal fentanyl therapy should be monitored for an extended period of time and dosage should be adjusted if needed.^{225 227 230} Manufacturers of buccal preparations (lozenges, buccal tablets) of fentanyl citrate recommend that concomitant ingestion of grapefruit and grapefruit juice be avoided.^{227 230}

The manufacturers state that the high concentration of fentanyl contained in the transdermal systems may make this preparation a target for diversion and abuse.²²⁵ Patients should be instructed to keep fentanyl transdermal systems in a secure place to prevent theft or misuse in the home or workplace.²²⁵ Patients should be informed of the risk of severe or fatal respiratory depression if fentanyl transdermal system is used in individuals for whom the drug was not prescribed.²²⁵ Health-care professionals should contact the professional licensing board or controlled substance authority in their states for information about prevention and detection of abuse or diversion of fentanyl transdermal systems.²²⁵

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Because the absorption of topically applied fentanyl from the transdermal systems depends in part on the temperature of the skin, increasing with increased temperature, patients who develop a fever while using the transdermal system should be observed closely for manifestations of opiate toxicity, and dosage of the drug should be adjusted accordingly.^{200 222} Pharmacokinetic modeling indicates that absorption theoretically could increase by approximately one-third when body temperature increases to 40°C.^{200 222} In addition, patients wearing a transdermal system of the drug should be advised to avoid exposing the application site to direct external heat sources.²²² (See Transdermal Administration under Dosage and Administration: Administration.)

Peak serum concentrations of fentanyl occur between 24–72 hours after application of the transdermal system; serious or life-threatening respiratory depression may occur at any time, but especially during the initial application period and after increases in dosage.²²⁵ Because serum fentanyl concentrations decline slowly following removal of the transdermal system,^{200 201 202 203 205 207 208} patients who develop adverse effects should be observed closely for at least 24 hours after removal of the system.^{200 225} It is particularly important that patients who develop hypoventilation (respiratory depression) during use of the transdermal system be observed carefully; the degree of sedation should be observed and the respiratory rate monitored until respiration has stabilized.²⁰⁰

Serious or fatal adverse effects have occurred after accidental exposure to fentanyl transdermal systems (including transfer of a transdermal system from an adult to a child while hugging, inadvertently sitting on a transdermal system, and exposure of the caregiver's skin to the drug during application or removal of the transdermal system).²²⁵ If individuals other than the patient for whom the transdermal system was prescribed accidentally come in contact with the gel from the system or if the transdermal system accidentally adheres to the individual, the system should be removed and the area of contact should be washed with water.²²⁵ The accidentally exposed individual should seek medical attention immediately.²²⁵ Placement of fentanyl transdermal systems in the mouth, chewing or swallowing transdermal systems, or using these systems in other unintended ways may cause choking or potentially fatal overdosage of fentanyl.²²⁵

The manufacturer's patient information (e.g., medication guide) should be provided to the patient each time fentanyl transdermal system or fentanyl citrate buccal tablets or lozenges are dispensed.^{227 229 236}

Because of the prolonged duration of effects and risk of serious or life-threatening respiratory depression associated with fentanyl transdermal system, this dosage form is not recommended for use in acute or postoperative pain, in chronic pain that is mild or intermittent and manageable with less potent analgesics, or in patients not already receiving and tolerant of opiates;^{221 222} the manufacturer states that such uses are contraindicated.²²⁵ Use of the transdermal system also is contraindicated in patients with substantial respiratory depression, especially in settings where equipment for monitoring and resuscitation is not available, in patients with severe bronchial asthma, and in those with known or suspected paralytic ileus.²²⁵

Because of the risk of life-threatening respiratory depression (e.g., hypoventilation), buccal preparations (lozenges, buccal tablets) of fentanyl citrate are contraindicated in the management of acute or postoperative pain and should not be used in patients who are not opiate tolerant.^{227 230} The manufacturer states that buccal lozenges and buccal tablets of fentanyl citrate should be administered only under the supervision of qualified clinicians who are experienced in the use of opiates for the management of cancer pain.^{227 230}

For additional information on cautions associated with the use of buccal preparations (lozenges, buccal tablets) of fentanyl citrate or transdermal fentanyl, see Uses.

Pediatric Precautions

Safety and efficacy of parenteral fentanyl citrate and transdermal fentanyl have not been established in children younger than 2 years of age. Fentanyl transdermal system should be used in children only if they are 2 years of age or older and are opiate tolerant.²²⁵ To reduce the potential for accidental ingestion, the application site in young children receiving transdermal fentanyl therapy should be carefully selected and caregivers should monitor the system for proper adhesion over the period of application.^{225 229} (See Transdermal Administration under Dosage and Administration: Administration.) Because of the high potential for fatal respiratory depression if a system is accidentally or deliberately applied or ingested by a child or adolescent, patients and/or caregivers must be instructed to keep new and used fentanyl transdermal systems in a secure location out of the reach of children.²²⁵ If a child is accidentally exposed to a fentanyl transdermal system, parents or caregivers should seek immediate medical treatment for the child.²²⁹

Safety and efficacy of buccal lozenges of fentanyl citrate have not been established in children younger than 16 years of age;²²⁷ safety and efficacy of buccal tablets of fentanyl citrate have not been established in children younger than 18 years of age.²³⁰ Clinicians must specifically question patients and/or their caregivers about the presence of children in the patient’s home, since the buccal lozenges and buccal tablets contain sufficient amounts of fentanyl citrate to be fatal to a child.^{227 230 234} Therefore, patients and/or their caregivers should be strongly warned to keep buccal preparations of fentanyl citrate out of the reach of children.^{227 230} (See Chemistry and Stability: Stability.)

Pregnancy and Lactation

Pregnancy

Safe use of fentanyl or fentanyl citrate during pregnancy has not been established; therefore, the drugs should not be administered to pregnant women unless the possible benefits outweigh the potential risks.

Lactation

Since fentanyl may cause sedation and serious respiratory depression and the drug is distributed into milk, fentanyl should not be used in nursing women, because of the potential for serious adverse reactions to the drug in nursing infants.^{227 230}

See Drug Interactions in the associated General Statement for more information.

See Acute Toxicity in the associated General Statement for more information.

Pharmacology

Fentanyl citrate shares the actions of the opiate agonists. When given 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. In controlled clinical trials employing an acute pain model in opiate-naive (nontolerant) patients, a fentanyl transdermal system dosage of 100 mcg/hour provided analgesia approximately equivalent to that of 60 mg of IM morphine sulfate daily.²²² Although pharmacodynamically similar to meperidine and morphine, fentanyl exhibits little hypnotic activity, and histamine release rarely occurs.

Pharmacokinetics

Absorption

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Fentanyl is well absorbed percutaneously following topical application of a transdermal system to a flat surface on the upper torso.²⁰⁰ The drug also is well absorbed transmucosally following intrabuccal administration via a lozenge matrix or buccal tablet containing fentanyl citrate.^{213 214 227 230}

Following parenteral administration, the action of fentanyl is more prompt and less prolonged than that of morphine or meperidine. The onset of action following IV administration is rapid; peak analgesia occurs within several minutes and the duration of analgesia is 30–60 minutes after a single dose of up to 100 mcg. Following IM administration of fentanyl citrate, the onset of action occurs within about 7–15 minutes and the duration of action is 1–2 hours. Respiratory depressant effects may persist longer than analgesia. Residual effects of one dose of fentanyl citrate may potentiate the effects of subsequent doses. It has been suggested that redistribution is the main cause of the brief analgesic effect of fentanyl.

In opiate-naive (nontolerant) patients, minimum effective analgesic serum fentanyl concentrations range from 0.2–2 ng/mL.^{222 224} Adverse effects of the drug generally increase as serum concentrations exceed 2 ng/mL.²²² While respiratory depression (e.g., hypoventilation) can occur throughout the therapeutic range of fentanyl serum concentrations, the risk of such depression increases as concentrations exceed 2 ng/mL in opiate-naive patients, especially those with underlying pulmonary conditions.²²² CNS depression becomes prominent as serum fentanyl concentrations exceed 3 ng/mL in opiate-naive patients,²²² and anesthesia and profound respiratory depression generally occur at concentrations of 10–20 ng/mL.²²⁴ With continued use, tolerance to the pharmacologic and adverse effects of the drug develop, but the rate of development of tolerance exhibits considerable interindividual variation.²²² Serum concentrations of the drug may be useful clinically, but they should not be relied on as sole indicators of efficacy or toxicity since they do not reflect individual patient sensitivity to fentanyl.²²²

Fentanyl transdermal systems (Duragesic^®, Sandoz and Watson transdermal systems) are designed to deliver fentanyl at a nearly constant rate of 25 mcg/hour per 10 cm²; however, the actual amount of drug delivered to the skin during the period of application exhibits interindividual variation, and the labeled rate on each system corresponds to the average amount of drug delivered across average skin to systemic circulation per hour.^{200 201 222} Following initial application of a transdermal system of fentanyl, initial release of the drug saturates skin sites beneath the system, and a depot of drug concentrates in the upper layers of the skin.^{200 201 222} Serum fentanyl concentrations increase slowly following topical application of the system, reaching a plateau between 12–24 hours and then remaining relatively constant, but with some fluctuation, during the remainder of the application period (up to 72 hours total);^{200 201 202 204 222} peak serum concentrations of the drug generally occur 24–72 hours after initial application.²²² Although the transdermal system was applied for 24-hour periods in most published studies,^{201 202 203 204 205 206 207} data provided by the manufacturer are for application for 72-hour periods.^{200 208}

Steady-state serum fentanyl concentrations achieved with sequential applications of transdermal systems exhibit considerable interindividual variation, depending on individual variation in skin permeability and body clearance of the drug.^{200 201} With sequential, continuous use, serum fentanyl concentrations continue to increase with the first few transdermal system applications.²²² Transdermal systems manufactured by Mylan and labeled as delivering 12.5, 25, 50, 75, or 100 mcg of fentanyl per hour have been shown to be bioequivalent to the respectively labeled delivery concentrations of Duragesic^® transdermal systems. The manufacturers state that peak serum concentrations of the drug following the initial 72-hour application average 0.3, 0.6, 1.4, 1.7, or 2.5 ng/mL following topical application of transdermal systems labeled as delivering 12.5, 25, 50, 75, or 100 mcg/hour, respectively.²²⁵ Following use of fentanyl 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 Following discontinuance of transdermal therapy, serum fentanyl concentrations decline gradually with an average half-life of about 17 (range: 13–22) hours; the slower decline in serum concentrations relative to that following IV administration results from the continued absorption of residual drug from the skin.^{200 201 202 203 205 207 208} Longer apparent elimination half-lives (e.g., 30–40 hours or longer) have been observed in some patients.^{203 204 208 209} In one study in which transdermal systems designed to deliver 75 mcg/hour were applied for 24 hours, it was estimated that approximately 30–40% of the total dose was not yet absorbed at the time the system was removed.²⁰⁴

Following intrabuccal administration of fentanyl citrate in a lozenge matrix, the drug is absorbed transmucosally from the buccal mucosa, and also from the GI tract (for any portion of the dose that is swallowed in saliva during sucking of the lozenge matrix).^{213 214 224 227} Thus, systemic absorption of intrabuccally administered drug is characterized by an initial rapid phase from the buccal mucosa and a more prolonged phase from the GI tract; the absorption characteristics of the lozenge result in sustained plasma concentrations of the drug.^{213 214 224} In addition, both the profile of systemic blood fentanyl concentrations achieved and bioavailability of the drug are variable and depend on the relative fractions of the dose that are absorbed from the buccal mucosa and the GI tract.^{213 214 224 227}

Generally, approximately 25% of a dose of fentanyl administered as a buccal lozenge is absorbed rapidly from the buccal mucosa and the remaining portion is swallowed with the saliva and then absorbed slowly from the GI tract.^{213 214 224 227} However, considerable interindividual variability exists, in part because of the influence of the rate of sucking and saliva production on dissolution of the drug, but principally because of variability in the amount of saliva that is swallowed rather than remaining in the oral cavity for contact with mucosal surfaces.²¹⁴ Considerable interindividual variability is particularly evident with this dosage form in the time and magnitude of peak serum concentrations achieved and in the serum half-life of the drug.²²⁴ Drug that is absorbed systemically via the oral mucosa bypasses first-pass metabolism in the liver and the intestinal mucosa, whereas that which is swallowed, either dissolved in saliva or as chewed lozenge, undergoes extensive first-pass metabolism and thus lower bioavailability and lower peak serum concentrations may occur compared with those absorbed by the oral mucosa.^{213 214 227} In general, the combined systemic bioavailability of fentanyl following administration of the lozenge is approximately 50%,^{213 214 227} being approximately equally divided between rapid transmucosal absorption and more prolonged GI absorption.^{213 214 227} In a limited number of adults receiving single 15-mcg/kg doses in one study, systemic bioavailability relative to IV administration averaged 52% with the lozenge versus 32% with an oral solution.²¹⁴ In addition, transmucosal absorption is more rapid than GI absorption, with peak plasma fentanyl concentrations from the lozenge and oral solution occurring within a median of approximately 23 and 101 minutes, respectively.^{213 214 224} In adults receiving a single 15-mcg/kg dose, peak serum concentrations of the drug occurred at a median of 23 (range: 19–30) minutes and averaged 2.7 (range: 1.4–4.6) ng/mL, and oral bioavailability averaged 50% (range: 36–71%).^{224 227}

Following intrabuccal administration of the fentanyl citrate lozenge, sedative, anxiolytic, and analgesic effects generally are apparent within 5–15 minutes, achieving a peak within 20–50 minutes;^{213 215 216} however, while consumption of the lozenge generally is complete within 10–20 minutes,²¹³ pharmacologic effects (e.g., respiratory depression) can persist for several hours after a dose.²¹³ The manufacturers state that in a limited number of adults, mean peak serum concentrations and area under the plasma concentration-time curve (AUC) of fentanyl increased in proportion to the dose from the commercially available 200-, 400-, 800-, and 1600-mcg of fentanyl lozenges.²²⁷ Following intrabuccal administration of fentanyl citrate lozenges in healthy individuals (after a standardized consumption time of 15 minutes), mean peak serum concentrations of fentanyl were attained within 40 (range: 20–120), 25 (range: 20–240), 25 (range: 20–120), and 20 (range: 20–480) minutes, respectively, and were 0.39 ng/mL following a single 200-mcg dose of fentanyl, 0.75 ng/mL following a single 400-mcg dose of fentanyl, 1.55 ng/mL following a single 800-mcg dose of fentanyl, and 2.51 ng/mL following a single 1600-mcg dose of fentanyl, respectively.²²⁷

Following intrabuccal administration of fentanyl citrate buccal tablets, the drug is absorbed transmucosally from the buccal mucosa and also from the GI tract (for any portion of the dose that is swallowed).²³⁰ In general, the combined systemic bioavailability of fentanyl following administration of the buccal tablet is approximately 65%, being approximately equally divided between rapid transmucosal absorption and more prolonged GI absorption.²³⁰ Peak plasma fentanyl concentrations generally are attained within 1 hour following administration of fentanyl citrate buccal tablets.²³⁰ Following administration of the buccal tablets in healthy individuals, systemic exposure to fentanyl generally increased proportionally with the dose over the range of 100–800 mcg.²³⁰ Following administration of single 100-, 200-, 400-, and 800-mcg doses of fentanyl (as buccal tablets) in healthy individuals, peak serum concentrations of the drug were attained within 45 (range: 25–181), 40 (range: 20–180), 35 (range: 20–180), and 40 (range: 25–180) minutes, respectively, and averaged 0.25, 0.4, 0.97, and 1.59 ng/mL, respectively.²³⁰ The time required for the tablet to fully disintegrate following intrabuccal administration does not appear to affect early systemic exposure to the drug.²³⁰ Following administration of a single 200-mcg dose of fentanyl as a buccal tablet, systemic exposure data for patients with grade 1 mucositis appeared to be similar to such data for patients without mucositis.²³⁰

In a crossover study comparing the bioavailability of fentanyl citrate buccal tablets with that of fentanyl citrate buccal lozenges, the buccal tablet was more bioavailable than the lozenge (absolute bioavailability: 65% versus 47%).^{230 235} The tablet and lozenge formulations differed in both the rate and extent of absorption.^{230 235} When the dose was administered as a buccal tablet rather than a lozenge, a larger fraction of the administered dose was absorbed transmucosally (48% versus 22%).^{230 235} The peak plasma concentration was achieved earlier with the buccal tablet (47 minutes) than with the lozenge (91 minutes), and dose-normalized systemic exposure to the drug was approximately 30% greater when the dose was administered as a buccal tablet rather than a lozenge.^{230 235} In another bioavailability study, systemic exposure to fentanyl reportedly was about 50% greater with the buccal tablet compared with the lozenge.²³⁰

Distribution

Following IV administration, fentanyl distributes rapidly from blood into the lungs and skeletal muscle and more slowly into deeper fat compartments.²¹³ The drug then redistributes slowly from these tissues into systemic circulation.²¹³ Large single doses or repeated doses can result in substantial accumulation of the drug, potentially resulting in an extended duration of effect.^{213 224}

Fentanyl is 80–85% protein bound in plasma, principally to α₁-acid glycoprotein but also to albumin and lipoproteins.^{213 224 227 230} The free fraction of fentanyl in plasma increases with acidosis.^{213 224} The mean volume of distribution of the drug at steady state has been reported to be 4 L/kg.²²⁷

Fentanyl is distributed into milk in humans.^{227 230}

Elimination

In one study, serum fentanyl concentrations decreased rapidly to about 20% of peak concentrations within 5 minutes after IV administration of the drug. Serum concentrations then decreased more slowly during the next 10–20 minutes and stabilized at low concentrations by 2 hours. Concentrations then decreased very slowly and the drug could be detected for at least 6 hours after administration. In a study comparing single 15-mcg/kg IV, oral, and buccal (transmucosal) doses in healthy adults, the elimination half-life of fentanyl averaged approximately 7.1, 7.8, and 7.7 hours, respectively.²¹⁴ The manufacturer states that the mean elimination half-life ranges from 2.6–11.7 hours in adults following intrabuccal (transmucosal) administration.^{224 227 230} Following administration as fentanyl transdermal system, the eliminate half-life of fentanyl averages 17 hours.^{225 229}

Fentanyl citrate is metabolized extensively in the liver and the intestinal mucosa. Animal studies indicate that the drug undergoes oxidation via the microsomal enzymes in the liver and intestinal mucosa (principally cytochrome P-450 [CYP] isoform 3A4) to form norfentanyl; the drug also undergoes hydrolysis to form 4-N-anilinopiperidine and propionic acid. Norfentanyl has been shown to be pharmacologically inactive in animal studies.^{227 230} Fentanyl is excreted in the urine as inactive metabolites and as unchanged drug. Less than 10% of a dose is excreted in urine unchanged and only about 1% is excreted in the feces as unchanged drug.^{227 230} In one study using ³H-labeled fentanyl citrate, about 20% of the total radioactivity was excreted in the urine within 8 hours and about 70% within 4 days. Fentanyl does not appear to be metabolized in skin.^{200 201} Data from clinical studies and from studies using a human keratinocyte cell assay indicate that about 92% of a dose delivered from the transdermal system is accounted for as unchanged drug in systemic circulation.^{200 201} Total plasma clearance of fentanyl is reported to be about 8.3 mL/minute per kg (range: 5–11.7 mL/minute per kg.)²²⁷

Chemistry and Stability

Chemistry

Fentanyl is a synthetic phenylpiperidine-derivative opiate agonist. The drug is commercially available for parenteral and intrabuccal (transmucosal) use as the citrate salt and for transdermal use as the base.

Fentanyl citrate occurs as a white, crystalline powder and is sparingly soluble in water and soluble in alcohol. The commercially available injections have a pH of 4–7.5.

Fentanyl citrate buccal lozenges contain the drug in a solid drug (lozenge) matrix that is molded onto a radiopaque plastic holder;²²⁷ the holder, which is fracture resistant under normal conditions when used as directed,²²⁷ allows the matrix unit to be removed from the mouth when needed.²²⁷

Fentanyl citrate buccal tablets utilize the OraVescent^® drug delivery system, which generates a reaction that releases carbon dioxide when the tablet comes in contact with saliva.²³⁰ The transient pH changes accompanying the reaction are thought to facilitate tablet dissolution and enhance drug permeation through the buccal mucosa.²³⁰

The Duragesic^® transdermal system consists of an outer layer of polyester film; a drug reservoir of fentanyl in an alcohol and hydroxyethyl cellulose gel; a microporous ethylene-vinyl copolymer membrane that controls the rate of diffusion of the drug; and a final silicone adhesive layer that provides an initial release of drug.²⁰⁰ The Mylan transdermal system consists of an outer backing layer of polyolefin film and a fentanyl-containing silicone adhesive layer; the adhesive matrix releases fentanyl at a nearly constant amount per unit time. The Duragesic^® and Mylan transdermal formulations are bioequivalent for preparations labeled as delivering 12.5, 25, 50, 75, or 100 mcg/hour. The adhesive layer is covered by a protective strip which is removed prior to application.²⁰⁰ The amount of fentanyl released from each system per hour is proportional to the surface area, and such release is designed to occur at an average rate of 25 mcg/hour per 10 cm² (Duragesic^®, Sandoz and Watson transdermal systems) or 25 mcg/hour per 6.25 cm² (Mylan transdermal system) (see Pharmacokinetics: Absorption); the composition per unit area of all transdermal fentanyl systems is identical.²⁰⁰ Each Duragesic^® transdermal system also contains 0.1 mL of alcohol per 10 cm², but less than 0.2 mL is released from the system during normal use.²⁰⁰ Alcohol is present in the reservoir in part to enhance the rate of drug flow through the rate-limiting copolymer membrane and to increase the permeability of the skin to fentanyl.²⁰⁰ The Mylan formulation does not include an alcohol-containing drug reservoir.

Stability

Commercially available fentanyl citrate injections should be protected from light and stored at room temperatures of 15–30°C; brief exposure to temperatures up to 40°C does not adversely affect the injection. Fentanyl citrate is hydrolyzed in acidic solutions. Fentanyl citrate is reportedly physically incompatible with methohexital sodium, pentobarbital sodium, or thiopental sodium, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

The commercially available transdermal system of fentanyl should be stored at a temperature not exceeding 25°C; the system should be applied to the skin immediately after removal from the individually sealed package, and should be discarded if the seal was previously broken.²²⁵ Cut or damaged transdermal systems should be discarded since proper controlled release of the drug cannot be ensured and may lead to a rapid release of fentanyl with the potential for absorption of a lethal dose.^{222 225} Fentanyl transdermal systems should be stored in a secure place to prevent access by children or pets.²²⁵ (See Cautions.)

The commercially available fentanyl citrate buccal preparations (lozenges, buccal tablets) should be stored at temperatures of 20–25°C, but may be exposed to temperatures ranging from 15–30°C; the buccal preparations should be protected from freezing and moisture.^{227 230} Patients receiving buccal preparations of the drug should be advised regarding proper storage and disposal of these preparations.^{227 230} If patients and/or their caregivers need additional assistance with disposal of the preparations, the manufacturer may be contacted at 800-896-5855, or, alternatively, the local office of the Drug Enforcement Administration (DEA) may be contacted.^{227 230}

When fentanyl citrate buccal lozenges are used, patients and/or their caregivers should be given educational materials (e.g., welcome kit) provided by the manufacturer concerning proper storage and disposal techniques of the lozenges.²²⁷ In addition, patients and/or their caregivers should be instructed to properly dispose of completely or partially used units of the drug.²²⁷ After consumption of a lozenge unit is complete and the lozenge matrix is totally dissolved, the handle should be disposed of in a trash container that is out of the reach of children; any drug matrix remaining on the handle can be removed by placing the handle under warm running tap water until the drug matrix is completely dissolved.²²⁷ While all units should be disposed of immediately after use, unused portions of the preparation represent a special risk, since they are no longer protected by the child-resistant blister package, and they still may contain sufficient amounts of the drug to be fatal to a child.²²⁷ If unused portions of the drug cannot be disposed of immediately by the patients or their caregivers, they should be stored in a temporary storage bottle (supplied by the manufacturer) according to enclosed instructions and then be disposed of at least once a day.²²⁷ Unopened units of fentanyl citrate buccal lozenges that are no longer needed should be disposed of immediately by removing the lozenges from their blister packages (using scissors); once the lozenges are removed, they should be disposed of by cutting the matrix from the handles with wire-cutting pliers over a toilet bowl and then flushing them twice down the toilet.²²⁷ Handles, blister packages, and cartons should not be flushed down the toilet, but disposed of according to instructions provided by the manufacturer.²²⁷

Fentanyl citrate buccal tablets that are no longer needed should be disposed of immediately by removing the tablets from their blister packages and flushing the tablets down the toilet.^{230 236} Once a buccal tablet of fentanyl citrate has been removed from the blister, it should not be stored for use at a later time because the integrity of the dosage form may be compromised and because of the risk of accidental exposure to the drug.²³⁰

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, and dosage and administration of fentanyl citrate, see the Opiate Agonists General Statement 28:08.08.

Preparations

Fentanyl and fentanyl citrate preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.

Fentanyl

Routes	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; with <2 mL alcohol/10 cm2)	Janssen
			Fentanyl Transdermal System (C-II)	Mylan, Sandoz
		25 mcg/hour (2.5 mg/10 cm2 Duragesic®, Sandoz, and Watson or 2.55 mg/6.25 cm2 Mylan)*	Duragesic® (C-II; with <2 mL alcohol/10 cm2)	Janssen
			Fentanyl Transdermal System (C-II)	Mylan, Sandoz, Watson
		50 mcg/hour (5 mg/20 cm2 Duragesic®, Sandoz, and Watson or 5.1 mg/12.5 cm2 Mylan)*	Duragesic® (C-II; with <2 mL alcohol/10 cm2)	Janssen
			Fentanyl Transdermal System (C-II)	Mylan, Sandoz, Watson
		75 mcg/hour (7.5 mg/30 cm2 Duragesic®, Sandoz, and Watson or 7.65 mg/18.75 cm2 Mylan)*	Duragesic® (C-II; with <2 mL alcohol/10 cm2)	Janssen
			Fentanyl Transdermal System (C-II)	Mylan, Sandoz, Watson
		100 mcg/hour (10 mg/40 cm2 Duragesic®, Sandoz, and Watson or 10.2 mg/25 cm2 Mylan)*	Duragesic® (C-II; with <2 mL alcohol/10 cm2)	Janssen
			Fentanyl Transdermal System (C-II)	Mylan, Sandoz, Watson

* available by nonproprietary name

Fentanyl Citrate

Routes	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)	Watson
		400 mcg (of fentanyl)	Actiq® (C-II)	Cephalon
			Oral Transmucosal Fentanyl Citrate (C-II)	Watson
		600 mcg (of fentanyl)	Actiq® (C-II)	Cephalon
			Oral Transmucosal Fentanyl Citrate (C-II)	Watson
		800 mcg (of fentanyl)	Actiq® (C-II)	Cephalon
			Oral Transmucosal Fentanyl Citrate (C-II)	Watson
		1200 mcg (of fentanyl)	Actiq® (C-II)	Cephalon
			Oral Transmucosal Fentanyl Citrate (C-II)	Watson
		1600 mcg (of fentanyl)	Actiq® (C-II)	Cephalon
			Oral Transmucosal Fentanyl Citrate (C-II)	Watson
	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)	Baxter, Hospira
			Sublimaze® (C-II; preservative-free)	Taylor

Comparative Pricing

Pricing information provided by <