Buy the Book PDA Download

Update Me E-mail alerts The Merck Manual Minute

Print This Topic

This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or standards of non-Merck sources.

Special Alerts

Product Safety and Fentora™ (Transmucosal Buccal Tablet) ? September, 2007

Cephalon, Inc, in conjunction with the Food and Drug Administration (FDA), has notified healthcare providers of fatal adverse events that have occurred in patients treated with Fentora™, a transmucosal buccal tablet formulation of fentanyl. The fatalities have been attributed to several factors, including improper patient selection, improper dosing, and/or improper product substitution. The FDA emphasized that Fentora™ only be used for labeled indications and only in patients who are opioid-tolerant. When using Fentora™ for breakthrough pain (BTP), it is recommended that patients not exceed 2 tablets per BTP episode and that patients allow ?4 hours to elapse between doses. Additionally, Fentora™ should not be used in patients with acute pain, postoperative pain, headache/migraine, or sports injuries. The FDA also stressed that Fentora™ and Actiq® (transmucosal lozenge) are not equivalent and that these products should not be used interchangeably on a mcg-per-mcg basis.

For more information, refer to the following FDA website: http://www.fda.gov/medwatch/safety/2007/safety07.htm#Fentora

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.

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 drugs which have a heightened risk of causing significant patient harm when used in error.

New 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.

Iontophoretic transdermal system (Ionsys™) may contain conducting metal (eg, aluminum); remove patch prior to MRI. Transdermal patch (eg, Duragesic®) does not contain any metal-based compounds; however, the printed ink used to indicate strength on the outer surface of the patch does contain titanium dioxide, but the amount is minimal.

Pronunciation

(FEN ta nil)

U.S. Brand Names

• Actiq®
• Duragesic®
• Fentora™
• Ionsys™
• Sublimaze®

Index Terms

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

Generic Available

Yes: Excludes buccal tablet and iontophoretic transdermal system

Canadian Brand Names

• Actiq®
• Duragesic®
• Fentanyl Citrate Injection, USP

Pharmacologic Category

• Analgesic, Opioid
• General Anesthetic

Pharmacologic Category Synonyms

• Narcotic Analgesic
• Opiate Analgesic
• Anesthetic, General

Use: Labeled Indications

Injection: Sedation, 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 moderate-to-severe chronic pain

Transmucosal lozenge (eg, Actiq®), buccal tablet (Fentora™): Management of breakthrough cancer pain

Use: Dental

Adjunct in preoperative intravenous conscious sedation in patients undergoing dental surgery

Restrictions

C-II

An FDA-approved medication guide for buccal tablet (Fentora™) and transmucosal lozenge (eg, Actiq®) must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.

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: Iontophoretic transdermal system (Ionsys™), 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; increased intracranial pressure; severe respiratory disease or depression including acute asthma (unless patient is mechanically ventilated); paralytic ileus; severe liver or renal insufficiency; pregnancy (prolonged use or high doses near term)

Iontophoretic transdermal system (Ionsys™): Hypersensitivity to fentanyl, cetylpyridinium chloride (eg, Cepacol®) or any component of Ionsys™ system

Transmucosal buccal tablets (Fentora™), lozenges (eg, Actiq®), and/or transdermal patches (eg, Duragesic®) are recommended for use only in patients who are opioid-tolerant. Patients are considered opioid-tolerant if they are taking at least 60 mg morphine/day, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mcg transdermal fentanyl/hour, or an equivalent dose of another opioid for ?1 week. Transmucosal buccal tablets (Fentora™), lozenges (eg, Actiq®), and transdermal patches (eg, Duragesic®) are not for use in acute pain, mild pain, intermittent pain, or postoperative pain management.

Warnings/Precautions

Box warnings:

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

• Iontophoretic transdermal system: See “Dosage form specific issues” 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.

Disease-related concerns:

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

• 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.

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

• Obesity: Use with caution in patients who are morbidly obese.

• 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 and iontophoretic transdermal system. [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:

•Iontophoretic transdermal system (Ionsys™): To avoid overdose, the patient should be the only one to activate the system. Unintended exposure to fentanyl hydrogel could lead to absorption of fatal dose; hydrogel should not come in contact with fingers or mouth. Should be used only in patients who are able to understand and follow instructions to operate the system. The error detection circuit uses a series of audible signals to alert the patient when a dose is not being delivered; use caution in patients who have high frequency hearing impairment. Ionsys™ contains metal parts; remove prior to MRI procedure, cardioversion, or defibrillation. May interfere with radiographic image or CAT scan as system contains radiopaque components. Patients on chronic opioids or with a history of opioid abuse may require higher analgesic doses than Ionsys™ is able to provide. Prior to patient's hospital discharge, the system must be removed and disposed of in accordance with State and Federal regulations for a C-II substance. [U.S. Boxed Warning]: Even if all 80 doses are used, a significant amount of fentanyl remains in the iontophoretic transdermal system and requires proper removal and disposal to avoid misuse, abuse, or diversion.

•Transmucosal: Lozenge (eg, Actiq®), 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. [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.

•Transdermal patch: [U.S. Boxed Warning]: Serious or life-threatening hypoventilation may occur, even in opioid-tolerant patients. 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. Avoid exposure of application site to direct external heat sources. Patients who experience adverse reactions should be monitored for at least 24 hours after removal of the patch. Transdermal patch does not contain any metal-based compounds; the printed ink used to indicate strength on the outer surface of the patch does contain titanium dioxide, but the amount is minimal; adverse events have not been reported while wearing during an MRI.

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: Hypotension, bradycardia

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

Gastrointestinal: Nausea, vomiting, constipation, xerostomia

Local: Application-site reaction (iontophoretic system 14%)

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

Ocular: Miosis

Respiratory: Respiratory depression

Miscellaneous: Diaphoresis

1% to 10%:

Cardiovascular: Cardiac arrhythmia, edema, orthostatic hypotension, hypertension, syncope, tachycardia

Central nervous system: Abnormal dreams, abnormal thinking, agitation, amnesia, anxiety, dizziness, euphoria, fatigue, fever, hallucinations, headache, insomnia, nervousness, paranoid reaction

Dermatologic: Erythema, papules, pruritus (iontophoretic system 6%), rash

Gastrointestinal: Abdominal pain, anorexia, biliary tract spasm, diarrhea, dyspepsia, flatulence, ileus

Genitourinary: Urinary retention (iontophoretic transdermal system 3%)

Hematologic: Anemia

Local: Application site reactions (buccal tablet)

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

Respiratory: Apnea, bronchitis, dyspnea, hemoptysis, hypoxia, pharyngitis, rhinitis, sinusitis, upper respiratory infection

Miscellaneous: Hiccups, flu-like syndrome, speech disorder

<1%: Abdominal distention, ADH release, amblyopia, aphasia, bladder pain, bradycardia, bronchospasm, circulatory depression, CNS excitation or delirium, cold/clammy skin, convulsions, depersonalization, dysesthesia, exfoliative dermatitis, hostility, hyperpigmentation (application site of iontophoretic system), hyper-/hypotonia, laryngospasm, oliguria, paradoxical dizziness, physical and psychological dependence with prolonged use, polyuria, pustules, stertorous breathing, stupor, urinary tract spasm, urticaria, vertigo

Postmarketing and/or case reports: Anorgasmia, blurred vision, dental caries (Actiq®), ejaculatory difficulty, gum line erosion (Actiq®), libido decreased, tachycardia, tooth loss (Actiq®), weight loss

Metabolism/Transport Effects

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

Drug Interactions

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

Ammonium chloride: May increase the excretion of analgesics (opioid).

Antipsychotic agents (phenothiazines): May enhance the hypotensive effect of analgesics (opioid).

CNS depressants: Increased sedation with fentanyl; monitor closely.

CYP3A4 inhibitors: May increase the levels/effects of fentanyl. Potentially fatal respiratory depression may occur when a potent inhibitor is used in a patient receiving chronic fentanyl (eg, transdermal patch). Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.

MAO inhibitors: Not recommended to use Actiq® within 14 days. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Pegvisomant: Analgesics (opioid) may diminish the therapeutic effect of pegvisomant.

Protease inhibitors: May decrease the metabolism, via CYP isoenzymes, of fentanyl.

Rifamycin derivatives: May decrease the serum concentration of fentanyl.

Selective serotonin reuptake inhibitors (SSRIs): Analgesics (opioid) may enhance the serotonergic effect of SSRIs. This may cause serotonin syndrome.

Sibutramine: Fentanyl may enhance the serotonergic effect of sibutramine.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Glucose may cause hyperglycemia.

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 15°C to 25°C (59°F to 86°F). Protect from light.

Iontophoretic transdermal system: Store at 15°C to 30°C (59°F to 86°F).

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

Transmucosal (buccal tablets, lozenges): Store at controlled room temperature of 15°C to 30°C (59°F to 86°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.: 7-15 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:

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

Iontophoretic transdermal system (Ionsys™): Fentanyl levels continue to rise for 5 minutes after the completion of each 10-minute dose

Distribution: 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

Iontophoretic transdermal system (Ionsys™): 11 hours

Transdermal patch: 17 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: 46 minutes; Lozenge: ~91 minutes; Transdermal patch: 24-72 hours

Excretion: Urine (primarily as metabolites, <7% to 10% as unchanged drug)

Dosage

Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses 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.

Sedation for minor procedures/analgesia:

Children 1-12 years:

Sedation for minor procedures/analgesia: I.M., I.V.: 1-2 mcg/kg/dose; may repeat at 30- to 60-minute intervals. Note: Children 18-36 months of age may require 2-3 mcg/kg/dose

Continuous sedation/analgesia: Initial I.V. bolus: 1-2 mcg/kg; then 1-3 mcg/kg/hour to a maximum dose of 5 mcg/kg/hour

Children >12 years and Adults: I.V.: 25-50 mcg; may repeat every 3-5 minutes to desired effect or adverse event; maximum dose of 500 mcg/4 hours; higher doses are used for major procedures

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.

Adjunct to general anesthesia: Slow I.V.:

Low dose: 0.5-2 mcg/kg/dose depending on the indication. For example, 0.5 mcg/kg will provide analgesia or reduce the amount of propofol needed for laryngeal mask airway insertion with minimal respiratory depression. However, to blunt the hemodynamic response to intubation 2 mcg/kg is often necessary.

Moderate dose: Initial: 2-15 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: Note: High-dose (20-50 mcg/kg/dose) fentanyl is rarely used, but is still maintained in the package labeling.

Acute pain management: Adults:

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

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

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

Lockout interval: 5-8 minutes

Mechanically-ventilated patients (based on 70 kg patient): Slow I.V.: 0.35-1.5 mcg/kg every 30-60 minutes as needed; infusion: 0.7-10 mcg/kg/hour

Iontophoretic transdermal system: 40 mcg per activation on-demand (maximum: 6 doses/hour). Note: Patient's pain should be controlled prior to initiating system. Instruct patient how to operate system. Only the patient should initiate system. Each system operates for 24 hours or until 80 doses have been administered, whichever comes first.

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.

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®): Dose should be reduced to 2.5-5 mcg/kg

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 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.

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 fentanyl 1 (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.

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 or cut patches; a rapid release of fentanyl and increased systemic absorption may occur. 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).

Iontophoretic transdermal system: System should be tested and applied by healthcare professional. The sticker on the back of the pouch is intended for use by the registered nurse. The sticker should be removed and applied to the Ionsys™ system with a date and time of application so that subsequent healthcare providers will know when the system expires (24 hours after application). Apply to intact, nonirritated, nonirradiated skin on chest or upper outer arm. Do not apply to scarred, burned, or tattooed areas. Any excessive hair at application site should be clipped; do not shave. Remove clear, plastic release liner before placement on skin. Avoid pulling on red tab. To administer a dose, the patient must press the button twice firmly within 3 seconds. An audible tone (beep) indicates the start of the delivery of the dose; red light remains on throughout the 10-minute dosing period. Each system operates for 24 hours or until 80 doses have been used (whichever comes first). Rotate skin site if another system is required after the first one is finished. Do not touch sticky side of system or the gels. If the hydrogel (where fentanyl is housed) becomes separated from the delivery system during removal, use gloves or tweezers to remove the hydrogel from skin. Do not use soap, alcohol, or other solvents to remove the hydrogel as they can increase absorption of fentanyl. Once a system has been removed, the same system can not be reapplied. Contains metal; remove prior to MRi procedure, cardioversion, or defibrillation.

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

While using this medication, 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 (2-3 L/day of fluids) 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; 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.

Transdermal iontophoretic system (Ionsys™): This medication is rapidly absorbed. Avoid handling the hydrogel compartments or the adhesive. Handle carefully and notify healthcare provider if accidental exposure occurs.

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. For Ionsys™, age does not significantly affect the extent of drug absorption. Before using Ionsys™ in elderly patients, assess cognitive function and ability to operate the dosage system. 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.

Iontophoretic transdermal system: Pharmacist should test before dispensing for patient. Without opening pouch, pharmacist should locate button side, find button and firmly press and release button twice within 3 seconds. Listen for a single audible tone (beep) confirming that the system is functional. The pharmacist should sign the front of the pouch after performing the functionality test.

Four minutes after the functional test, the system will beep for 15 seconds indicating that it is not in contact with skin. Open by cutting on dotted line of pouch, remove and discard plastic liner covering adhesive. Do not pull on red tab while removing. Press system firmly in place with sticky side down, on skin for at least 15 seconds. Make sure all sides of outer edge stick to skin. May tape sides down if they loosen; don't tape over button or red light. To determine the number of doses delivered, the red light will flash between doses in one second pulses to indicate the approximate number of doses that have been administered up to the present time. Each flash indicates up to 5 doses have been administered: One flash 1-5 doses; two flashes 6-10 doses; three flashes 11-15 doses; four flashes 16-20 doses, continuing up to 16 flashes (76-80 doses).

To dispose of system, wear gloves and pull the red tab to separate the bottom from the top. Fold the bottom in half with the sticky side facing in and flush down the toilet (needs to be witnessed by second healthcare provider). Dispose of top section according to hospital procedures for batteries.

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

When developing a therapeutic plan for pain control, scheduled, intermittent opioid dosing or continuous infusion is preferred over the “as needed” regimen. 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. 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 great to prevent pain during a procedure and can be dosed intermittently for such an application. Prolonged analgesia requires an infusion.

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.

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 Comment.

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.

Infusion, as citrate [premixed in NS]: 0.05 mg (10 mL); 1 mg (100 mL); 1.25 mg (250 mL); 2 mg (100 mL); 2.5 mg (250 mL)

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

Sublimaze®: 0.05 mg/mL (2 mL, 5 mL, 10 mL, 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 [mounted on a plastic radiopaque handle; contains sugar 2 g/unit; raspberry flavor]

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]; 100 (5s) [delivers 100 mcg/hour; 25 cm²]; 100 (5s) [delivers 100 mcg/hour; 40 cm²]

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

Transdermal iontophoretic system, topical, as hydrochloride:

Ionsys™: Fentanyl 40 mcg/dose [80 doses/patch; contains 3-volt lithium battery]

References

Anwar M, Garrettson L, Huddleston K, et al, “Withdrawal Seizures in a Neonate Following Prolonged Fentanyl Use,” Clin Toxicol, 1995, 33(5):493.

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.

Bennett MR and Adams AP, “Postoperative Respiratory Complications of Opiates,” Clin Anaesthesiol, 1983, 1:41-56.

Billmire DA, Neale HW, and Gregory RO, “Use of I.V. Fentanyl in the Outpatient Treatment of Pediatric Facial Trauma,” J Trauma, 1985, 25(11):1079-80.

Chaturvedi AK, Rao NG, and Baird JR, “A Death Due to Self-Administered Fentanyl,” J Anal Toxicol, 1990, 14(6):385-7.

“Drugs for Pain,” Med Lett Drugs Ther, 2000, 42(1085):73-8.

Fine PG, “Fentanyl in the Treatment of Cancer Pain,” Semin Oncol, 1997, 24(5 Suppl 16):16-20-7.

Furuya H and Okumura F, “Hemolysis After Administration of High Dose Fentanyl,” Anesth Analg, 1986, 65(2):207-8.

Jacobi J, Fraser GL, Coursin DB, et al, “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult,” Crit Care Med, 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.

Jeal W and Benfield P, “Transdermal Fentanyl. A Review of Its Pharmacological Properties and Therapeutic Efficacy in Pain Control,” Drugs, 1997, 53(1):109-38.

Katz R, Kelly HW, and Hsi A, “Prospective Study on the Occurrence of Withdrawal in Critically Ill Children Who Receive Fentanyl by Continuous Infusion,” Crit Care Med, 1994, 22(5):763-7.

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.

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.

Poklis A, “Fentanyl: A Review for Clinical and Analytical Toxicologists,” J Toxicol Clin Toxicol, 1995, 33(5):439-47.

“Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain,” 5th ed, Glenview, IL: American Pain Society, 2003.

Roth B, Schlunder C, Houben F, et al, “Analgesia and Sedation in Neonatal Intensive Care Using Fentanyl by Continuous Infusion,” Dev Pharmacol Ther, 1991, 17(3-4):121-7.

Schechter NL, Weisman SJ, Rosenblum M, et al, “The Use of Oral Transmucosal Fentanyl Citrate for Painful Procedures in Children,” Pediatrics, 1995, 95(3):335-9.

Scholz J, Steinfath M, and Schulz M, “Clinical Pharmacokinetics of Alfentanil, Fentanyl, and Sufentanil. An Update,” Clin Pharmacokinet, 1996, 31(4):275-92.

Spigset O and Hagg S, “Analgesics and Breast-feeding: Safety Considerations,” Paediatr Drugs, 2000, 2(3):223-38.

Stoukides CA and Stegman M, “Diffuse Rash Associated With Transdermal Fentanyl,” Clin Pharm, 1992, 11(3):222.

Zeltzer LK, Altman A, Cohen D, et al, “Report of the Subcommittee on the Management of Pain Associated With Procedures in Children With Cancer,” Pediatrics, 1990, 86(5 Pt 2):826-31.

International Brand Names

• Actiq (CA)
• Duragesic (CA)
• Durogesic (PL)
• Fentabbott (BR)
• Fentanest (ES, IT, MX)
• Fentanyl (CR, DO, GT, HN, NI, PA, PL, SV)
• Fentanyl Citrate Injection, USP (CA)
• Fentanyl Janssen (PL)
• Ionsys (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HU, IE, IT, NL, NO, PT, RU, SE, TR)
• Leptanal (NO, SE)
• Sublimaze (AR, AU, GB, IE, NZ, PH, ZA)
• Tanyl (IL)
• Trofentyl (IN)

Lexi-Comp.com

Last full review/revision October 2007

Content last modified October 2007