Fentanyl (Systemic)

AHFS Class: Opiate Agonists (28:08.08)

VA Class: CN101

View the associated AHFS monograph.

Brands: Actiq^® , Duragesic^® , Sublimaze^®; also available generically.

Introduction

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

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.

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 system and intrabuccal (transmucosal) lozenges are contraindicated in the management of acute or postoperative pain.^{221 222 225 227}

Malignant (Cancer) Pain

Transdermally for the management of persistent, moderate to severe chronic pain (e.g., associated with cancer) when continuous, strong opiate analgesia is indicated for an extended period of time.^{200 209 211 225} Use only in patients who are opiate tolerant.²²⁵ (See Transdermal System in Boxed Warning.)

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

Do not use transdermally or intrabuccally (transmucosally) in patients who are not opiate tolerant.^{225 227}

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

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

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, strong opiate analgesia for an extended period of time.^{200 209 211 225} Use only in patients who are opiate tolerant.²²⁵ (See Transdermal System 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.^{221 222 225}

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 intrabuccal preparation (Actiq^®) is labeled only for use in opiate-tolerant patients with chronic cancer pain.^b

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.

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

Administer intrabuccally (transmucosally) as a lozenge.^{b 227}

Administer percutaneously by topical application of a transdermal system.²⁰⁰

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

Administer intrabuccal (transmucosal) lozenges only under the supervision of qualified clinicians who are experienced in the use of opiates for the management of malignant (cancer) pain.²²⁷

Cut 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

If signs of excessive opiate effects develop before the lozenge is consumed completely, remove the remaining portion from the patient’s mouth immediately and decrease future doses.²²⁷

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

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

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

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

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

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

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

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

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

Administer by IM injection.^b

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.

Carefully instruct patients in the proper use and disposal of the transdermal system.²⁰⁰ (See Advice to Patients.)

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.²⁰⁰

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 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

Clip, not shave, hair at the application site prior to application;²⁰⁰ 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;²⁰⁰ do not use soaps, oils, lotions, alcohol, or any other agents that could irritate the skin or alter its characteristics.²⁰⁰

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 result in rapid release of fentanyl and absorption of a potentially lethal dose of the drug.²²⁵

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

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

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.

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

Doses as low as 25–33% of the usual parenteral dose should be employed when fentanyl citrate injection is used in conjunction with other CNS depressants; dosage adjustment for the concomitantly administered drug also may be necessary.^b

When the transdermal system is used concomitantly with other CNS depressants, dosage of one or both drugs should be substantially reduced.²²⁵

Individualize dosage of intrabuccal (transmucosal) lozenges according to the clinical status of the patient, desired therapeutic effect, and age.^{227 228}

Individualize dosage of transdermal fentanyl according to the clinical status of the patient, desired therapeutic effect, and age and weight; assess dosage at periodic intervals.^{222 225} The most important factor in determining the appropriate dose is the degree of existing opiate tolerance.^{222 225}

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 System 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.²²² 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 1 and 2 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 1 or 2, calculate the opiate analgesic requirements during the previous 24 hours.^{200 225} Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using Table 4.^{200 225} Finally, calculate the equivalent dose of transdermal fentanyl 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 the first dose.²²⁵ Use the lowest possible dose providing acceptable analgesia.²⁰⁰ For transdermal doses >100 mcg/hour, apply multiple systems at different sites simultaneously.²⁰⁰ 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.^{200 222} Many patients are likely to require upward dosage titration.^{200 222} If analgesia is inadequate, dosage may be titrated upward after 72 hours.^{200 222} Give supplemental doses of a short-acting opiate as needed during the initial application period and subsequently thereafter as necessary to relieve breakthrough pain.^{200 222 225}

> Dosage Adjustment to Achieve Adequate Analgesia. Transdermal— If analgesia is inadequate after initial application of a transdermal system, dosage may be titrated upward after 72 hours.^{200 222} Initial transdermal dose may be increased after 72 hours based on the daily dose of supplemental opiates 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, 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).^{200 222} 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.²²² It generally takes ≥17 hours 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}

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

Table 1: Approximate Plasma Fentanyl Concentrations Required in Balanced Anesthesia with Nitrous Oxide^f

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.

> Buccal (Transmucosal) (Actiq^®)— 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.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 more than 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.²²⁷ Increase dose to the next higher available strength after several consecutive breakthrough cancer pain episodes require the use of more than 1 lozenge per episode; again, prescribe only 6 lozenges of the new strength.²²⁷ 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 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 for chronic cancer pain.²²⁷ Discontinuance of opiates: Gradually downward taper the dose of the opiate to avoid manifestations associated with abrupt withdrawal.²²⁷ Geriatric (>65 years of age) patients have been titrated to an adequate lozenge dose that generally was about 200 mcg lower than the dose required in younger patients.²²⁷ Use caution when individually titrating transmucosal dosage in geriatric patients.²²⁷

Chronic Malignant (Cancer) Pain and Other Chronic Pain.

> Initial Dose Selection in Patients Being Switched to Transdermal Fentanyl Therapy. Transdermal— 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.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 System 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.²²² Fatal overdose possible with the first transdermal dose if the dose is overestimated.²²⁵ Geriatric, cachectic, or debilitated patients should not receive initial transdermal doses >25 mcg/hour unless they currently are receiving a continuous daily opiate dose equivalent to 25 mcg/hour of transdermal fentanyl.^{200 225} 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 1 and 2 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 1 or 2, calculate the opiate analgesic requirements during the previous 24 hours.^{200 225} Then calculate an equianalgesic 24-hour dosage of oral morphine sulfate using Table 4.^{200 225} Finally, calculate the equivalent dose of transdermal fentanyl using Table 4.^{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 the first dose.²²⁵ Use the lowest possible dose providing acceptable analgesia.²⁰⁰ For transdermal doses >100 mcg/hour, apply multiple systems at different sites simultaneously.²⁰⁰ 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

	Equianalgesic Dose (in mg)
Opiate Agonist	IM	Oral
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.^{200 222} 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}

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.^{200 222} Many patients are likely to require upward dosage titration.^{200 222} If analgesia is inadequate, dosage may be titrated upward after 72 hours.^{200 222} Give supplemental doses of a short-acting opiate as needed during the initial application period and subsequently thereafter as necessary to relieve breakthrough pain.^{200 222 225}

> Dosage Adjustment to Achieve Adequate Analgesia. Transdermal— 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.If analgesia is inadequate after initial application of a transdermal system, dosage may be titrated upward after 72 hours.^{200 222} Initial transdermal dose may be increased after 72 hours based on the daily dose of supplemental opiates 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, 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).^{200 222} 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.^{200 222} 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.²²²

> Discontinuance of Transdermal Fentanyl Therapy. Transdermal— 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.To convert to another opiate, remove the transdermal system and titrate the dosage of the other opiate according to patient toleration and response.²²² It generally takes ≥17 hours 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}

Special Populations

Exercise caution and reduce initial dosage.^{225 c d}

Exercise caution and reduce initial dosage.^{225 c d}

Initial doses should be reduced in geriatric patients; response to initial dosing should be considered in determining subsequent incremental doses.^{b d d 227}

Buccal (transmucosal) dosage (Actiq^®): Geriatric (>65 years of age) doses generally are about 200 mcg lower than those required in younger patients.²²⁷ Exercise caution during individual dosage titration.²²⁷

Geriatric, cachectic, or debilitated patients should not receive initial transdermal doses >25 mcg/hour unless they currently are receiving a continuous daily opiate dose equivalent to 25 mcg of transdermal fentanyl per hour.²²⁵

Cautions

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 d 227}

• Transdermal and buccal (transmucosal) preparations contraindicated in the management of acute or postoperative pain and in non-opiate-tolerant patients because of the risk of life-threatening respiratory depression (e.g., hypoventilation).^{225 227} (See Boxed Warning for additional information on contraindications with these preparations.)

• Transdermal preparations also contraindicated in patients with mild or intermittent pain; in those who require opiate analgesia for a short period of time; in individuals 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

Warnings/Precautions

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.

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 on the respiratory effects of potent opiates.^{225 d 227}

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

Respiratory Depression. The major toxicity associated with fentanyl.²²⁵

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

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

Observe patients who develop 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.^{200 225}

Patients who develop hypoventilation (respiratory depression) during use of the transdermal system must be observed carefully; observe the degree of sedation and monitor the respiratory rate until respiration has stabilized.²⁰⁰

Use of transdermal systems or intrabuccal (transmucosal) lozenges in non-opiate-tolerant patients may result in fatal respiratory depression and is contraindicated.^{225 227} (See Boxed Warning.)

Use 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 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

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

When such combined therapy is contemplated, the dose of one or both agents should be reduced substantially.^{225 b} (See Dosage under Dosage and Administration.)

Interactions with CYP3A4 Inhibitors. Concomitant use with potent CYP3A4 inhibitors may increase plasma fentanyl concentrations, increasing opiate effects.^{225 227} Hypoventilation, hypotension, and profound sedation or coma may occur.^{225 227} (See Interactions.)

Dependence and Abuse. Physical and psychic dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.^c (See Transdermal System in Boxed Warning.)

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

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 The accidentally exposed individual should seek medical attention immediately.²²⁵

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 retention^{225 227 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

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.

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 buccal (transmucosal) fentanyl, despite routine oral hygiene in some patients.²²⁷ (See Advice to Patients.) Each intrabuccal (transmucosal) fentanyl citrate lozenge contains 2 g of sugar.²²⁷

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.^b

Cardiac Arrhythmia. Because of cholinergic effects, may cause bradycardia.^{c d} Caution in patients with cardiac bradyarrhythmias.^{c d}

Patients with Fever or Exposure to High Temperatures. Observe patients who develop a fever while using a transdermal system closely for manifestations of opiate toxicity, and adjust dosage accordingly because drug absorption depends in part on the temperature of the skin, increasing with increased temperature.^{200 222}

Percutaneous absorption of fentanyl from the transdermal system may be increased if the application site is exposed to direct external heat sources (e.g., heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds) while the transdermal system is being worn.^{222 225}

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 intrabuccal (transmucosal) lozenge contains 2 g of sugar.²²⁷

Pregnancy.

Category C.^{225 d 227}

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

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 intrabuccal (transmucosal) lozenges not established in children <16 years of age.²²⁷

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.^{225 229}

Because of the risk of fatal respiratory depression following accidental or deliberate exposure, instruct patients and/or caregivers 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.²²⁵

Clinicians must specifically question patients and/or their caregivers about the presence of children in the patient’s home, since the lozenges and transdermal patches contain sufficient amounts of fentanyl to be fatal to a child.^{225 227}

Strongly warn patients and/or their caregivers to keep the intrabuccal (transmucosal) lozenges and transdermal systems out of the reach of children.^{200 225 227}

Geriatric Use. Clearance may be reduced substantially in individuals >60 years of age.²²⁵

Geriatric, cachectic, or debilitated patients should not receive initial transdermal doses >25 mcg/hour unless they currently are receiving a continuous daily opiate dose equivalent to 25 mcg of transdermal fentanyl per hour.²²⁵

Caution when individually titrating transmucosal dosage (Actiq^®) in geriatric patients.²²⁷ Geriatric (>65 years of age) patients have been titrated to an adequate dose of Actiq^® that generally was about 200 mcg lower than the dose required in younger patients.²²⁷

Hepatic Impairment. Exercise caution and reduce initial dosage.^{225 c d} May have a prolonged duration and cumulative effect in patients with hepatic dysfunction.^{225 c}

Renal Impairment. Exercise caution and reduce initial dosage.^{225 c d} May have a prolonged duration and cumulative effect in patients with renal dysfunction.^{225 c}

Common Adverse Effects

Common adverse effects include abdominal pain, headache, bradyarrhythmia, chest pain, nausea, vomiting, constipation, somnolence, confusion, asthenia, dizziness, nervousness, hallucinations, anxiety, depression, euphoria, respiratory depression (hypoventilation, dyspnea, apnea), sweating, pruritus, and urinary retention.²²⁵

May increase the risk of water intoxication in postoperative patients because of stimulation of vasopressin release.^c

Buccal (transmucosal) therapy: Nausea and vomiting also are frequent and are dose related.^{213 214 215 216 217 226} Facial pruritus and flushing occur frequently.^{213 214 215 216 217} Dental decay, including caries, tooth loss, and gum line erosion, has occurred despite routine oral hygiene in some patients.²²⁷ (See Advice to Patients.)

IV administration: Skeletal and thoracic muscle rigidity occur frequently.

Transdermal system: Respiratory depression resulting in hypoventilation is the most serious adverse reaction.²²² Adverse local effects associated with topical application include erythema (may persist for ≥6 hours after removal of the system), papules, pruritus, and edema at the site of application.^{200 203 206 212 222}

Interactions

Metabolized by CYP3A4.^{225 227}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Concomitant administration 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} If used concomitantly with transdermal fentanyl therapy, monitor patients 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.^{225 227}

Specific Drugs

Pharmacokinetics

Absorption

Well absorbed percutaneously following topical application of a transdermal system²⁰⁰ and transmucosally following intrabuccal administration via sucking of a lozenge matrix.^{213 214 227}

Lozenge: Averages about 52%.²¹⁴

Transmucosal: 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}

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

IM administration: About 7–15 minutes.^b

Intrabuccal administration: About 5–15 minutes; peaks within 20–50 minutes.^{213 215 216}

IV administration, analgesia: 0.5–1 hours.^b

IM administration, analgesia: 1–2 hours.^b

Respiratory depressant effects may persist longer than analgesia.^b

Transdermal, peak: Within 24–72 hours.²²²

Intrabuccal, peak: Within approximately 23 minutes.^{213 214 224}

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

Distribution

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 and is distributed into breast milk.^{225 227}

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

Elimination

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

Does not appear to be metabolized in the skin.^{200 201}

In the urine as inactive metabolites and as unchanged drug.^b

IV: About 7.1 hours.²¹⁴

Oral: About 7.8 hours.²¹⁴

Buccal: About 7.7 hours.²¹⁴

Transdermal: About 17 hours.^{200 201 202 203 205 207 208 225}

Stability

Storage

Injection. Protect from light at 15–30°C; brief exposure up to 40°C does not adversely affect the injection.^b

Hydrolyzed in acidic solutions.^b

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

Discard cut or damaged transdermal systems since proper controlled release of the drug cannot be ensured, and use of cut or damaged systems may result in rapid release of fentanyl and absorption of a potentially lethal dose of the drug.^{222 225}

Buccal (Transmucosal). 20–25°C (may be exposed 15–30°C).²²⁷ Protect from freezing and moisture.²²⁷

Compatibility

Solution Compatibility^HID .

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility.

Admixture Compatibility^HID

Compatible
Bupivacaine HCl
Bupivacaine HCl with Clonidine HCl
Ropivacaine HCl
Incompatible
Fluorouracil
Variable
Lidocaine HCl

Y-Site Compatibility^HID

Compatible
Abciximab
Amiodarone HCl
Amphotericin B cholesteryl sulfate complex
Argatroban
Atracurium besylate
Atropine sulfate
Bivalirudin
Dexamethasone sodium phosphate
Diazepam