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Special Alerts

Transdermal Patches: Risk of Burns During MRI - March 2009

The U.S. Food and Drug Administration (FDA) has issued a public health advisory regarding the risk of burns associated with the use of transdermal medication patches containing aluminum or other metals during MRI screening. The package labeling for certain metal-containing patches includes a warning related to the risk of burns if the patches are not removed prior to MRI procedures. However, not all transdermal medication patches with metallic backings have this warning in the labeling. Although metal materials are present in certain patches, it may not be visible. The FDA is currently reviewing the components of all transdermal medication systems to ensure that proper warnings are present in the labeling of those patches that do contain metal materials. In the interim, the FDA recommends that healthcare professionals who refer patients to have an MRI procedure should identify patients who are wearing a transdermal medication patch prior to the scan. Those patients who are wearing a transdermal medication patch should be advised on the proper removal of the patch prior to the procedure as well as reapplication following the scan.

Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Medication Safety Issues

Sound-alike/look-alike issues:

FentaNYL may be confused with alfentanil, SUFentanil

Dosing of transdermal fentanyl patches may be confusing. Transdermal fentanyl patches should always be prescribed in mcg/hour, not size. Patch dosage form of Duragesic®-12 actually delivers 12.5 mcg/hour of fentanyl. Use caution, as orders may be written as “Duragesic 12.5” which can be erroneously interpreted as a 125 mcg dose.

Fentora® and Actiq® are not interchangeable; do not substitute doses on a mcg-per-mcg basis.

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Fentanyl transdermal system patches: Leakage of fentanyl gel from the patch has been reported; patch may be less effective; do not use. Thoroughly wash any skin surfaces coming into direct contact with gel with water (do not use soap).

Pronunciation

(FEN ta nil)

U.S. Brand Names

• Actiq®
• Duragesic®
• Fentora®
• Onsolis™
• Sublimaze®

Index Terms

• Fentanyl Citrate
• Fentanyl Hydrochloride
• OTFC (Oral Transmucosal Fentanyl Citrate)

Generic Available

Yes: Excludes buccal tablet

Canadian Brand Names

• Actiq®
• Duragesic MAT
• Duragesic®
• Fentanyl Citrate Injection, USP
• Novo-Fentanyl
• RAN™-Fentanyl Transdermal System
• ratio-Fentanyl

Pharmacologic Category

• Analgesic, Opioid
• Anilidopiperidine Opioid
• General Anesthetic

Pharmacologic Category Synonyms

• Narcotic Analgesic
• Opiate Analgesic
• Opioid, Anilidopiperidine
• Anesthetic, General

Use: Labeled Indications

Injection: Relief of pain, preoperative medication, adjunct to general or regional anesthesia

Iontophoretic transdermal system (Ionsys™): Short-term, in-hospital management of acute postoperative pain

Transdermal patch (eg, Duragesic®): Management of persistent moderate-to-severe chronic pain

Transmucosal lozenge (eg, Actiq®), buccal tablet (Fentora®): Management of breakthrough cancer pain in opioid-tolerant patients

Use: Dental

Adjunct in preoperative intravenous conscious sedation in patients undergoing dental surgery

Restrictions

C-II

Pregnancy Risk Factor

C/D (prolonged use or high doses at term)

Pregnancy Considerations

Fentanyl crosses the placenta and has been used safely during labor. Chronic use during pregnancy has shown detectable serum levels in the newborn with mild opioid withdrawal (case report). Transdermal patch, transmucosal lozenge, and buccal tablet (Fentora®) are not recommended for analgesia during labor and delivery.

Lactation

Enters breast milk/not recommended (AAP rates “compatible”)

Breast-Feeding Considerations

Fentanyl is excreted in low concentrations into breast milk. Breast-feeding is considered acceptable following single doses to the mother; however, no information is available when used long-term. Note: Transdermal patch, transmucosal lozenge, and buccal tablet (Fentora®) are not recommended in nursing women due to potential for sedation and/or respiratory depression.

Contraindications

Hypersensitivity to fentanyl or any component of the formulation

Transdermal system: Severe respiratory disease or depression including acute asthma (unless patient is mechanically ventilated); paralytic ileus; patients requiring short-term therapy, management of intermittent pain

Transmucosal buccal tablets (Fentora®), lozenges (eg, Actiq®), and/or transdermal patches (eg, Duragesic®): Contraindicated in the management of acute or postoperative pain and in patients who are not opioid tolerant

Warnings/Precautions

Boxed warnings:

• Abuse/misuse/diversion: See “Other warnings/precautions” below.

• Transmucosal: See “Dosage form specific issues” and "Concurrent drug therapy issues" below.

• Transdermal patches: See “Special populations" and "Dosage form specific issues” below.

Concerns related to adverse effects:

• Opioid agonist toxicities: Shares the toxic potentials of opiate agonists, and precautions of opiate agonist therapy should be observed.

• Opioid-nontolerant patients should not receive some formulations/strengths of fentanyl, including buccal tablets (Fentora®), lozenges (Actiq®), or transdermal patches. Patients are considered opioid-tolerant if they have been receiving at least:

60 mg of oral morphine/day, or

25 mcg of transdermal fentanyl/hour, or

30 mg of oxycodone/day, or

8 mg oral hydromorphone/day, or

Equianalgesic dose of another opioid for at least 1 week.

• Respiratory depression: [U.S. Boxed Warning] Actiq®, Duragesic®, Fentora®: May cause potentially life-threatening hypoventilation, respiratory depression, and/or death; Actiq®, Duragesic®, Fentora® should only be prescribed for opioid-tolerant patients. Risk of respiratory depression increased in elderly patients, debilitated patients, and patients with conditions associated with hypoxia or hypercapnia; usually occurs after administration of initial dose in nontolerant patients or when given with other drugs that depress respiratory function.

Disease-related concerns:

• Bradycardia: Use with caution when administering to patients with bradycardia or bradyarrhythmias.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Opioids may obscure the clinical course of head injury.

• Hepatic impairment: Use with caution in patients with hepatic dysfunction.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

Concurrent drug therapy issues:

• CNS depressants: When using with other CNS depressants, reduce dose of one or both agents.

• CYP3A4 inhibitors: [U.S. Boxed Warning]: Use with strong or moderate CYP3A4 inhibitors; may result in increased effects and potential respiratory depression.

Special populations:

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose.

•Pediatrics: Safety and efficacy have not been established in children <16 years of age for the lozenge and <18 years of age for the buccal tablet. [U.S. Boxed Warning]: Safety and efficacy of the transdermal patch have been limited to children ?2 years of age who are opioid-tolerant.

Dosage form specific issues:

• Injection: May cause muscle rigidity; usually occurs following high doses; respiratory depression may persist beyond analgesic effect; monitor closely.

•Transmucosal: Lozenge (eg, Actiq®), buccal tablet (Fentora®): [U.S. Boxed Warning]: Should be used only for the care of opioid-tolerant cancer patients with breakthrough pain and is intended for use by specialists who are knowledgeable in treating cancer pain. Not approved for use in management of acute or postoperative pain. [U.S. Boxed Warning]: Buccal tablet and lozenge preparations contain an amount of medication that can be fatal to children. Keep all units out of the reach of children and discard any open units properly. Patients and caregivers should be counseled on the dangers to children including the risk of exposure to partially-consumed units.

•Transmucosal: Buccal tablet (Fentora®): [U.S. Boxed Warning]: Due to the higher bioavailability of fentanyl in Fentora®, when converting patients from oral transmucosal fentanyl citrate (OTFC, Actiq®) to Fentora®, do not substitute Fentora® on a mcg-per-mcg basis for any other fentanyl product. [U.S. Boxed Warning]: Fentora® is contraindicated in the management of acute or postoperative pain, including headache/migraine. Serious adverse events, including death, have been reported when used inappropriately (improper dose or patient selection). [U.S. Boxed Warning]: Patients using Fentora® who experience breakthrough pain may only take one additional dose using the same strength and must wait four hours before taking another dose.

•Transdermal patch: [U.S. Boxed Warning]: Indicated for the management of persistent moderate-to-severe pain when around the clock pain control is needed for an extended time period. Should only be used in patients who are already receiving opioid therapy, are opioid tolerant, and who require a total daily dose equivalent to 25 mcg/hour transdermal patch. Contraindicated in patients who are not opioid tolerant, in the management of short-term analgesia, or in the management of postoperative pain. Should be applied only to intact skin. Use of a patch that has been cut, damaged, or altered in any way may result in overdosage. Serum fentanyl concentrations may increase approximately one-third for patients with a body temperature of 40°C secondary to a temperature-dependent increase in fentanyl release from the patch and increased skin permeability. [U.S. Boxed Warning]: Avoid exposure of application site and surrounding area to direct external heat sources. Patients who experience fever or increase in core temperature should be monitored closely. Patients who experience adverse reactions should be monitored for at least 24 hours after removal of the patch.

Other warnings/precautions:

• Abuse/misuse/diversion: [U.S. Boxed Warning]: Healthcare provider should be alert to problems of abuse, misuse, and diversion.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Rapid infusion: Inject slowly over 3-5 minutes; rapid I.V. infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest; nondepolarizing skeletal muscle relaxant may be required.

• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

Adverse Reactions

>10%:

Cardiovascular: Bradycardia, edema

Central nervous system: CNS depression, confusion, dizziness, drowsiness, headache, sedation

Gastrointestinal: Nausea, vomiting, constipation, xerostomia

Local: Application-site reaction erythema

Neuromuscular & skeletal: Chest wall rigidity (high dose I.V.), muscle rigidity, weakness

Ocular: Miosis

Respiratory: Dyspnea, respiratory depression

Miscellaneous: Diaphoresis

1% to 10%:

Cardiovascular: Cardiac arrhythmia, chest pain, flushing, hyper-/hypotension, orthostatic hypotension, pallor, palpitation, peripheral edema, syncope, tachycardia, vasodilation

Central nervous system: Abnormal dreams, abnormal thinking, agitation, amnesia, anxiety, chills, depression, euphoria, fatigue, fever, hallucinations, hypoesthesia, insomnia, lethargy, migraine, nervousness, paranoid reaction, stupor, vertigo

Dermatologic: Alopecia, bruising, cellulitis, erythema, hyperhidrosis, papules, pruritus, rash

Endocrine & metabolic: Breast pain, dehydration, hyper-/hypocalcemia, hyper-/hypoglycemia, hypoalbuminemia, hypokalemia, hypomagnesemia

Gastrointestinal: Abdominal pain, abnormal taste, anorexia, biliary tract spasm, diarrhea, dyspepsia, dysphagia (buccal tablet), flatulence, GI hemorrhage, gingival pain (buccal tablet), gingivitis (lozenge), glossitis (lozenge), ileus, periodontal abscess (lozenge/buccal tablet), stomatitis (lozenge/buccal tablet), weight loss

Genitourinary: Dysuria, urinary incontinence, urinary retention, vaginitis, vaginal hemorrhage

Hematologic: Anemia, leukopenia, neutropenia, thrombocytopenia

Hepatic: Ascites, jaundice

Local: Application site pain, application site irritation

Neuromuscular & skeletal: Abnormal coordination, abnormal gait, arthralgia, back pain, myalgia, neuropathy, paresthesia, rigors, tremor

Renal: Renal failure

Respiratory: Apnea, asthma, bronchitis, cough, epistaxis, hemoptysis, hypoventilation, hypoxia, nasopharyngitis, pharyngolaryngeal pain, pharyngitis, pneumonia, rhinitis, sinusitis, upper respiratory infection, wheezing

Miscellaneous: Hiccups, flu-like syndrome, lymphadenopathy, speech disorder

<1%, postmarketing, and/or case reports: Abdominal distention, amblyopia, allergic reaction, anaphylaxis, angina, anorgasmia, aphasia, bladder pain, blurred vision, bronchospasm, CNS excitation or delirium, cold/clammy skin, dental caries (lozenge), depersonalization, DVT, dysesthesia, ejaculatory difficulty, emotional lability, eructation, esophageal stenosis, exfoliative dermatitis, fecal impaction, flank pain, gum line erosion (lozenge), gum hemorrhage (lozenge), hematuria, hostility, hyper-/hypotonia, laryngospasm, libido decreased, moniliasis (lozenge/buccal tablet), mouth ulceration (lozenge/buccal tablet), myasthenia, nocturia, oliguria, pancytopenia, paradoxical dizziness, physical and psychological dependence with prolonged use, pleural effusion, polyuria, pustules, speech disorder, stertorous breathing, seizure, sputum increased, tooth loss (lozenge), urinary tract spasm, urticaria, vertigo

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

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

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Beta-Blockers: Anilidopiperidine Opioids may enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

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

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of FentaNYL. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of FentaNYL. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

MAO Inhibitors: Anilidopiperidine Opioids may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Avoid use of fentanyl (and other anilidopiperidine opioids when possible) in patients who have used a monoamine oxidase inhibitor within the past 14 days due to reports of unpredictable but severe adverse effects. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of FentaNYL. Risk C: Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: St John's wort may decrease fentanyl levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Storage

Injection formulation: Store at controlled room temperature of 20°C to 25°C (68°F to 77°F). Protect from light.

Transdermal patch: Do not store above 25°C (77°F).

Transmucosal (buccal tablets, lozenge): Store at controlled room temperature of 20°C to 25°C (68°F to 77°F). Protect from freezing and moisture.

Compatibility

Stable in D₅W, NS.

Y-site administration: Compatible: Alatrofloxacin, amphotericin B cholesteryl sulfate complex, atracurium, cisatracurium, diltiazem, dobutamine, dopamine, enalaprilat, epinephrine, esmolol, etomidate, furosemide, gatifloxacin, heparin, hydrocortisone sodium succinate, hydromorphone, labetalol, levofloxacin, linezolid, lorazepam, midazolam, milrinone, morphine, nafcillin, nicardipine, nitroglycerin, norepinephrine, pancuronium, potassium chloride, propofol, ranitidine, remifentanil, sargramostim, thiopental, vecuronium, vitamin B complex with C.

Compatibility in syringe: Compatible: Atracurium, atropine, bupivacaine with ketamine, butorphanol, chlorpromazine, cimetidine, clonidine with lidocaine, dimenhydrinate, diphenhydramine, droperidol, heparin, hydromorphone, hydroxyzine, meperidine, metoclopramide, midazolam, morphine, ondansetron, pentazocine, perphenazine, prochlorperazine edisylate, promazine, promethazine, ranitidine, scopolamine. Incompatible: Pentobarbital.

Compatibility when admixed: Compatible: Bupivacaine. Incompatible: Fluorouracil, methohexital, pentobarbital, thiopental.

Mechanism of Action

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

Pharmacodynamics/Kinetics

Onset of action: Analgesic: I.M.: 7-8 minutes; I.V.: Almost immediate; Transmucosal: 5-15 minutes

Peak effect: Transmucosal: Analgesic: 15-30 minutes

Duration: I.M.: 1-2 hours; I.V.: 0.5-1 hour; Transmucosal: Related to blood level; respiratory depressant effect may last longer than analgesic effect

Absorption:

Transdermal: Initial application: Gradually absorbed for the first 12-24 hours, followed by a constant absorption for the remainder of the dosing interval

Transmucosal, buccal tablet: Rapid, ~50% from the buccal mucosa; remaining 50% swallowed with saliva and slowly absorbed from GI tract.

Transmucosal, lozenge: Rapid, ~25% from the buccal mucosa; 75% swallowed with saliva and slowly absorbed from GI tract

Distribution: 4-6 L/kg; Highly lipophilic, redistributes into muscle and fat

Protein binding: 80% to 85%

Metabolism: Hepatic, primarily via CYP3A4

Bioavailability: Total (transmucosal and GI absorption): Buccal: 65% (range: 45% to 85%); Lozenge: 47% (range: 37% to 57%)

Half-life elimination:

I.V.: 2-4 hours

Transdermal patch: 17 hours (13-22 hours, half-life is influenced by absorption rate)

Transmucosal: Lozenge: 7 hours; Buccal tablet: 100-200 mcg: 3-4 hours, 400-800 mcg: 11-12 hours

Time to peak: Buccal tablet: 20-240 minutes (median: 47 minutes); Lozenge: 20-480 minutes (median: 20-40 minutes); Transdermal patch: 24-72 hours, after several sequential 72-hour applications, steady state serum concentrations are reached

Excretion: Urine 75% (primarily as metabolites, <7% to 10% as unchanged drug); feces ~9%

Dosage

Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses and dosage intervals should be titrated to pain relief/prevention. Monitor vital signs routinely. Single I.M. doses have a duration of 1-2 hours, single I.V. doses last 0.5-1 hour.

Minor procedures/analgesia (unlabeled use): I.V.:

Children 1-12 years: 0.5-2 mcg/kg/dose given 3 minutes prior to procedure; may repeat every 1-2 hours

Children >12 years: 0.5-2 mcg/kg/dose (maximum 50 mcg/dose) given 3 minutes prior to procedure; may repeat in 5 minutes if necessary; if more than 2 doses are needed, repeat with a maximum of 25 mcg/dose up to 5 times

Surgery:

Children ?2 years: Adjunct to anesthesia (induction and maintenance): Slow I.V.: 2-3 mcg/kg/dose every 1-2 hours as needed

Adults:

Premedication: I.M., slow I.V.: 50-100 mcg/dose 30-60 minutes prior to surgery

Adjunct to regional anesthesia: Slow I.V.: 25-100 mcg/dose over 1-2 minutes. Note: An I.V. should be in place with regional anesthesia so the I.M. route is rarely used but still maintained as an option in the package labeling.

Adjunct to general anesthesia: Slow I.V.:

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

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

High-dose: 20-50 mcg/kg/dose; Note: Fentanyl is rarely used, but is still maintained in the package labeling.

Pain management:

Children (unlabeled use): I.V.: 0.5-2 mcg/kg/dose given every 1-2 hours as needed; continuous infusion: 0.5-2 mcg/kg/hour; titrate to desired effects

Adults:

I.V. (unlabeled use): Bolus at start of infusion: 1-2 mcg/kg or 25-100 mcg/dose; continuous infusion rate: 1-2 mcg/kg/hour or 25-200 mcg/hour

Severe: I.M, I.V. (unlabeled): 50-100 mcg/dose every 1-2 hours as needed; patients with prior opiate exposure may tolerate higher initial doses

Patient-controlled analgesia (PCA) (unlabeled use): I.V.: Usual concentration: 10 mcg/mL

Basal rate: ?50 mcg/hour

Demand dose: Usual: 10 mcg; range: 10-50 mcg

Lockout interval: 5-10 minutes

Critically-ill patients (unlabeled dose): Slow I.V.: 25-100 mcg (based on ~70 kg patient) or 0.35-1.5 mcg/kg every 30-60 minutes as needed. Note: More frequent dosing may be needed (eg, mechanically-ventilated patients).

Continuous infusion: 50-700 mcg/hour (based on ~70 kg patient) or 0.7-10 mcg/kg/hour

Breakthrough cancer pain: For patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain; dosing should be individually titrated to provide adequate analgesia with minimal side effects. Dose titration should be done if patient requires more than 1 dose/breakthrough pain episode for several consecutive episodes. Patients experiencing >4 breakthrough pain episodes/day should have the dose of their long-term opioid re-evaluated.

Children ?16 years and Adults: Lozenge: Initial dose: 200 mcg; the second dose may be started 15 minutes after completion of the first dose. Consumption should be limited to ?4 units/day. Additional requirements suggest need for improved baseline therapy.

Adults: Buccal tablet (Fentora®): Initial dose: 100 mcg; a second 100 mcg dose, if needed, may be started 30 minutes after the start of the first dose. Note: For patients previously using the transmucosal lozenge (Actiq®), the initial dose should be selected using the conversions listed below (maximum: 2 doses per breakthrough pain episode every 4 hours).

Dose titration, if required, should be done using multiples of the 100 mcg tablets. Patient can take two 100 mcg tablets (one on each side of mouth). If that dose is not successful, can use four 100 mcg tablets (two on each side of mouth). If titration requires >400 mcg/dose, then use 200 mcg tablets.

Conversion from lozenge to buccal tablet (Fentora®):

Lozenge dose 200-400 mcg, then buccal tablet 100 mcg

Lozenge dose 600-800 mcg, then buccal tablet 200 mcg

Lozenge dose 1200-1600 mcg, then buccal tablet 400 mcg

Note: Four 100 mcg buccal tablets deliver approximately 12% and 13% higher values of C_max and AUC, respectively, compared to one 400 mcg buccal tablet. To prevent confusion, patient should only have one strength available at a time. Using more than four buccal tablets at a time has not been studied.

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

Chronic pain management: Children ?2 years and Adults (opioid-tolerant patients): Transdermal patch (eg, Duragesic®):

Initial: To convert patients from oral or parenteral opioids to transdermal patch, a 24-hour analgesic requirement should be calculated (based on prior opiate use). Using the tables, the appropriate initial dose can be determined. The initial fentanyl dosage may be approximated from the 24-hour morphine dosage equivalent and titrated to minimize adverse effects and provide analgesia. With the initial application, the absorption of transdermal fentanyl requires several hours to reach plateau; therefore transdermal fentanyl is inappropriate for management of acute pain. Change patch every 72 hours.

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

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

Frequency of adjustment: The dosage should not be titrated more frequently than every 3 days after the initial dose or every 6 days thereafter. Patients should wear a consistent fentanyl dosage through two applications (6 days) before dosage increase based on supplemental opiate dosages can be estimated. Note: Upon discontinuation, ~17 hours are required for a 50% decrease in fentanyl levels.

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

Dose conversion guidelines for transdermal fentanyl1 (see tables).

Dosing adjustment in hepatic impairment: Actiq®: Although fentanyl kinetics may be altered in hepatic disease, Actiq® can be used successfully in the management of breakthrough cancer pain. Doses should be titrated to reach clinical effect with careful monitoring of patients with severe hepatic disease.

Dental Usual Dosing

Surgery: Adults:

Premedication: I.M., slow I.V.: 25-100 mcg/dose 30-60 minutes prior to surgery

Adjunct to regional anesthesia: Slow I.V.: 25-100 mcg/dose over 1-2 minutes. Note: An I.V. should be in place with regional anesthesia so the I.M. route is rarely used but still maintained as an option in the package labeling.

Administration: Oral

Lozenge: Foil overwrap should be removed just prior to administration. Place the unit in mouth and allow it to dissolve. Do not chew. Lozenge may be moved from one side of the mouth to the other. The unit should be consumed over a period of 15 minutes. Handle should be removed after it is consumed or if patient has achieved an adequate response and/or shows signs of respiratory depression.

Buccal tablet: Patient should not open blister until ready to administer. The blister backing should be peeled back to expose the tablet; tablet should not be pushed out through the blister. Immediately use tablet once removed from blister. Place entire tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Tablet should not be broken, sucked, chewed, or swallowed. Should dissolve in about 14-25 minutes when left between the cheek and the gum. If remnants remain they may be swallowed with water.

Administration: I.V.

Administer as slow I.V. infusion over 1-2 minutes. May also be administered as continuous infusion or PCA (unlabeled use) routes. Muscular rigidity may occur with rapid I.V. administration.

Administration: Topical

Transdermal patch (eg, Duragesic®): Apply to nonirritated and nonirradiated skin, such as chest, back, flank, or upper arm. Do not shave skin; hair at application site should be clipped. Prior to application, clean site with clear water and allow to dry completely. Do not use damaged, cut or leaking patches; patch may be less effective. Skin exposure from fentanyl gel leaking from patch may lead to serious adverse effects; thoroughly wash affected skin surfaces with water (do not use soap). Firmly press in place and hold for 30 seconds. Change patch every 72 hours. Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin; use copious amounts of water. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub).

Administration: I.V. Detail

pH: 4.0-7.5

Monitoring Parameters

Respiratory and cardiovascular status, blood pressure, heart rate; signs of misuse, abuse, or addiction

Transdermal patch: Monitor for 24 hours after application of first dose

Dietary Considerations

Transmucosal lozenge contains 2 g sugar per unit.

Patient Education

Take exactly as prescribed. Do not use more often or increase dosage, and do not use alcohol and other prescription or OTC medications (especially sedatives, tranquilizers, antihistamines, or pain medications) without consulting prescriber. If using oral transmucosal lozenge, you may be at risk for dental carries due to the sugar content. Maintain good oral hygiene. If using patch, avoid exposing application site to external heat sources (eg, heating pad, electric blanket, hot tub, heat lamp). Maintain adequate hydration unless instructed to restrict fluid intake. May cause hypotension, dizziness, drowsiness, impaired coordination, or blurred vision (use caution when driving, climbing stairs, or changing position - rising from sitting or lying to standing, or when engaging in tasks requiring alertness until response to drug is known); nausea or vomiting (frequent mouth care, small frequent meals, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help; if unresolved, consult prescriber about use of stool softeners). Report acute dizziness, chest pain, slow or rapid heartbeat, acute headache; confusion or changes in mentation; changes in voiding frequency or amount; swelling of extremities or unusual weight gain; temperature >102°F; shortness of breath or respiratory difficulty; or vision changes. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Transdermal patch: Apply to clean, dry skin, immediately after removing from package. Firmly press in place and hold for 30 seconds. Do not use damaged, cut, or leaking patches. If fentanyl gel should leak, wash affected skin surfaces with water; do not use soap. Remove patch while having MRI scan; can cause burns.

Transmucosal lozenge (eg, Actiq®): Contains an amount of medication that can be fatal to children. Keep all units out of the reach of children and discard any open units properly. Actiq® Welcome Kits are available which contain educational materials, safe storage, and disposal instructions.

Geriatric Considerations

The elderly may be particularly susceptible to the CNS depressant and constipating effects of narcotics; therefore, use with caution. The effect of age on the pharmacokinetics of Fentora® (oral transmucosal buccal tablets) has not been studied.

Additional Information

Fentanyl is 50-100 times as potent as morphine; morphine 10 mg I.M. is equivalent to fentanyl 0.1-0.2 mg I.M.; fentanyl has less hypotensive effects than morphine due to lack of histamine release. However, fentanyl may cause rigidity with high doses. If the patient has required high-dose analgesia or has used for a prolonged period (~7 days), taper dose to prevent withdrawal; monitor for signs and symptoms of withdrawal.

Transmucosal (oral lozenge): Disposal of lozenge units: After consumption of a complete unit, the handle may be disposed of in a trash container that is out of the reach of children. For a partially-consumed unit, or a unit that still has any drug matrix remaining on the handle, the handle should be placed under hot running tap water until the drug matrix has dissolved. Special child-resistant containers are available to temporarily store partially consumed units that cannot be disposed of immediately.

Transdermal patch (Duragesic®): Upon removal of the patch, ~17 hours are required before serum concentrations fall to 50% of their original values. Opioid withdrawal symptoms are possible. Gradual downward titration (potentially by the sequential use of lower-dose patches) is recommended. Keep transdermal patch (both used and unused) out of the reach of children. Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin as they may increase transdermal absorption, use copious amounts of water. Avoid exposure of direct external heat sources (eg, heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds) to application site.

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: Fentanyl or hydromorphone is preferred in patients who are hypotensive or have renal dysfunction. Morphine or hydromorphone is recommended for intermittent, scheduled therapy. Both have a longer duration of action requiring less frequent administration. Fentanyl is useful in preventing pain during a procedure and can be dosed intermittently for such an application. Prolonged analgesia requires an infusion.

Fentanyl has less hypotensive effects than morphine due to lack of histamine release; however, fentanyl may cause rigidity with high doses. If the patient has required high-dose analgesia or has used for a prolonged period (~7 days), taper dose to prevent withdrawal.

Pretreatment with fentanyl may reduce pain on injection from propofol (Pang, 1997). Fentanyl demonstrates synergistic respiratory depression when combined with benzodiazepines. In healthy volunteers, the combination of midazolam (0.05 mg/kg) with fentanyl (2 mcg/kg) produces synergistic respiratory deprsesion (92% incidence of hypoxemia [SaO₂ <90%] and 50% incidence of apnea) (Bailey, 1990).

Evidence-Based Information: The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) recommend fentanyl in patients who need immediate pain relief because of its rapid onset of action. Repeated doses or a continuous infusion of fentanyl may cause accumulation.

Cardiovascular Considerations

May precipitate bradycardia, hypotension, and peripheral vasodilation. These properties necessitate close hemodynamic monitoring.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia, changes in salivation (normal salivary flow resumes upon discontinuation), and orthostatic hypotension. Actiq® may contribute to dental carries due to sugar content of oral lozenge; advise patients to maintain good oral hygiene. See Dental Health Professional Considerations.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dental Comment

Transdermal fentanyl should not be used as a pain reliever in dentistry due to danger of hypoventilation

Mental Health: Effects on Mental Status

Drowsiness, sedation, and depression are common; may rarely cause paradoxical CNS excitement or delirium

Mental Health: Effects on Psychiatric Treatment

Concurrent use with low potency antipsychotics and TCAs may produce additive hypotension

Nursing: Physical Assessment/Monitoring

Assess other medications patient may be taking for additive or adverse interactions. Monitor therapeutic effectiveness and signs of adverse or overdose reactions. Monitor blood pressure, CNS and respiratory status, and degree of sedation at beginning of therapy and at regular intervals with long-term use. Monitor closely for 24 hours after transdermal product is removed. Order safety precautions for inpatient use. May cause physical and/or psychological dependence. Assess knowledge/teach patient appropriate use (if self-administered), adverse reactions to report, and appropriate interventions to reduce side effects.

Oncology: Vesicant

No

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Note: Strengths expressed as base.

Injection, solution, as citrate [preservative free]: 0.05 mg/mL (2 mL, 5 mL, 10 mL, 20 mL; 30 mL [DSC]; 50 mL)

Sublimaze®: 0.05 mg/mL (2 mL, 5 mL, 10 mL [DSC], 20 mL)

Lozenge, oral, as citrate [transmucosal]: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg

Actiq®: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg [contains sugar 2 g/lozenge; berry flavor]

Powder, for prescription compounding, as citrate: USP (1 g)

Tablet, for buccal application, as citrate:

Fentora®: 100 mcg, 200 mcg, 300 mcg, 400 mcg, 600 mcg, 800 mcg

Transdermal system, topical, as base: 12 (5s) [delivers 12.5 mcg/hour; 3.13 cm²]; 12 (5s) [delivers 12.5 mcg/hour; 5 cm²]; 25 (5s) [delivers 25 mcg/hour; 10 cm²]; 25 (5s) [delivers 25 mcg/hour; 6.25 cm²]; 50 (5s) [delivers 50 mcg/hour; 12.5 cm²]; 50 (5s) [delivers 50 mcg/hour; 20 cm²]; 75 (5s) [delivers 75 mcg/hour; 18.75 cm²]; 75 (5s) [delivers 75 mcg/hour; 30 cm²]; 75 (5s) [delivers 75 mcg/hour; 32.1 cm²]; 100 (5s) [delivers 100 mcg/hour; 25 cm²]; 100 (5s) [delivers 100 mcg/hour; 40 cm²]; 100 (5s) [delivers 100 mcg/hour; 42.8 cm²]

Duragesic®: 12 (5s) [delivers 12.5 mcg/hour; 5 cm²; contains ethanol 0.1 mL/10 cm²]; 25 (5s) [delivers 25 mcg/hour; 10 cm²; contains ethanol 0.1 mL/10 cm²]; 50 (5s) [delivers 50 mcg/hour; 20 cm²; contains ethanol 0.1 mL/10 cm²]; 75 (5s) [delivers 75 mcg/hour; 30 cm²; contains ethanol 0.1 mL/10 cm²]; 100 (5s) [delivers 100 mcg/hour; 40 cm²; contains ethanol 0.1 mL/10 cm²]

Pricing: U.S. (www.drugstore.com)

Lozenge (Actiq)

200 mcg (20): $696.07

400 mcg (20): $888.28

600 mcg (20): $1076.77

800 mcg (20): $1255.99

1200 mcg (10): $708.23

1600 mcg (20): $1973.95

Lozenge (FentaNYL Citrate)

400 mcg (20): $399.95

1200 mcg (10): $299.95

1600 mcg (20): $770.59

Patch, 72-hour (Duragesic-100)

100 mcg/hr (20): $1646.31

Patch, 72-hour (Duragesic-12)

12 mcg/hr (20): $378.64

Patch, 72-hour (Duragesic-25)

25 mcg/hr (20): $457.64

Patch, 72-hour (Duragesic-50)

50 mcg/hr (20): $823.09

Patch, 72-hour (Duragesic-75)

75 mcg/hr (20): $1275.76

Patch, 72-hour (Fentanyl)

12 (12.5) mcg/hr (5): $67.99

25 mcg/hr (20): $266.65

50 mcg/hr (20): $526.62

75 mcg/hr (20): $633.31

100 mcg/hr (20): $839.99

Tablets (Fentora)

200 mcg (20): $445.63

References

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Bailey PL, Pace NL, Ashburn MA, et al, “Frequent Hypoxemia and Apnea After Sedation With Midazolam and Fentanyl,” Anesthesiology, 1990, 73(5):826-30.

Baraka A, “Fentanyl-Induced Laryngospasm Following Tracheal Extubation in a Child,” Anaesthesia, 1995, 50(4):375.

Bedforth NM and Lockey DJ, “Raynaud's Syndrome Following Intravenous Induction of Anaesthesia,” Anaesthesia, 1995, 50(3):248-9.

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Berde C, Ablin A, Glazer J, et al, “Report of the Subcommittee on Disease-Related Pain in Childhood Cancer,” Pediatrics, 1990, 86(5 Pt 2):818-85.

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Kornick CA, Santiago-Palma J, Khojainova N, et al, “A Safe and Effective Method for Converting Cancer Patients from Intravenous to Transdermal Fentanyl,” Cancer, 2001, 92(12):3056-61.

Leuschen MP, Willett LD, Hoie EB, et al, “Plasma Fentanyl Levels in Infants Undergoing Extracorporeal Membrane Oxygenation,” J Thorac Cardiovasc Surg, 1993, 105(5):885-91.

Liu LL and Gropper MA, “Postoperative Analgesia and Sedation in the Adult Intensive Care Unit,” Drugs, 2003, 63(8):755-67.

Maurer PM and Bartkowski RR, “Drug Interactions of Clinical Significance With Opiad Analgesics,” Drug Saf, 1993, 8(1):30-48.

Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.

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International Brand Names

• Actiq (AU, CH, DE, DK, ES, FI, FR, GB, IE, IL, NO, SE)
• Durogesic (CL, KP, MX, PL, SG)
• Durogesic D Trans (PE)
• Fenta (IL)
• Fentabbott (BR)
• Fentanest (IT, MX, UY)
• Fentanila (CN)
• Fentanilo (VE)
• Fentanyl (CR, DO, GT, HN, NI, PA, PL, SV)
• Fentanyl Janssen (PL)
• Fentas (KP)
• Fentax (PY)
• Ionsys (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
• Leptanal (NO, SE)
• Matrifen (DK, GB)
• Mezolar Matrix (GB)
• Sublimax (PH)
• Sublimaze (AR, AU, GB, IE, PH, ZA)
• Tanyl (IL)
• Trofentyl (IN)

Lexi-Comp.com

Last full review/revision September 2009

Content last modified September 2009