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Fentanyl (Systemic)

Primary: CN 101

Note: Controlled substance classification—

Note: Controlled substance classification

U.S.—Schedule II
Commonly used brand name(s): Actiq.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).




General considerations
Transmucosal fentanyl should be used in opioid-tolerant patients only {01}. Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine per day, 50 mcg of transdermal fentanyl per hour, or an equivalent dose of another opioid analgesic for a week or longer {01}.

Transmucosal fentanyl is intended to be used only in the care of cancer patients and only by oncologists and pain specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain {01}.


Pain, chronic cancer (treatment)—Transmucosal fentanyl is indicated for the management of breakthrough cancer pain in adults with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain {01}.

Transmucosal fentanyl is contraindicated in treatment of acute or postoperative pain {01}. Use of this formulation for patients not taking chronic opiates may cause severe hypoventilation {01}.


Physicochemical characteristics:
    Synthetic {01}.

Chemical group—
    Phenylpiperidine derivative {01}.
Molecular weight—
    336.51 {01}

    7.41 {01}.

    7.3 and 8.41 {01}

Partition coefficient
    816:1100 {01}.

Mechanism of action/Effect:

Fentanyl produces its effects predominantly via agonist actions at the mu receptor {01}.

Other actions/effects:

Fentanyl, like other opioid analgesics, may cause respiratory depression {01}. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects {01}.

Fentanyl, like other opioid analgesics, increases the tone and decrease contractions of the smooth muscle of the gastrointestinal tract {01}. While opioids generally increase the tone of urinary tract smooth muscle, the overall effect tends to vary {01}.


The absorption of the transmucosal dosage form is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the gastrointestinal tract {01}. Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed {01}. Approximately 25% of the total dose of transmucosal fentanyl is rapidly absorbed from the buccal mucosa and becomes systemically available {01}. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the gastrointestinal tract {01}. About one-third of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available {01}. Lower peak concentrations and lower bioavailability may result if a unit dose is chewed and swallowed than when consumed as directed {01}.


Fentanyl is highly lipophilic {01}. Fentanyl is distributed to the brain, heart, lungs, kidneys, and spleen followed by a slower redistribution to muscle and fat {01}.

Protein binding:

High (80 to 85%), primarily by alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute {01}.


Primarily hepatic, via dealkylation and hydroxylation into inactive metabolites {01}.


Approximately 7 hours {01}.

Time to peak concentration:

Following administration of 200 mcg, 400 mcg, 800 mcg, 1600 mcg doses (based on consumption time of 15 minutes)—Within 20-40 (range, 20-480 minutes) minutes {01}.

    Primarily hepatic; less than 7% and 1% of the dose is excreted as unchanged fentanyl in the urine and feces, respectively {01}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to fentanyl or its components may be hypersensitive to transmucosal fentanyl also {01}.


No carcinogenic studies have been conducted with fentanyl citrate {01}.


No evidence of mutagenicity was demonstrated in the Ames test, the in-vitro mouse lymphoma mutagenesis assay, and the in-vivo micronucleus cytogenetic assay in the mouse {01}.

Reproduction studies in rats revealed a significant decrease in the pregnancy rate of all experimental groups {01}. This decrease was most pronounced in the high-dose group (1.25 mg per kg of body weight [mg/kg] subcutaneously) in which one of twenty animals became pregnant {01}.

Fentanyl has been shown to impair fertility and to have embryocidal effects with an increase in resorptions in rats when given for a period of 12 to 21 days in doses of 30 mcg per kg of body weight (mcg/kg) intravenously or 160 mcg/kg subcutaneously {01}.

Adequate and well-controlled studies in humans with fentanyl have not been done {01}.

No evidence of teratogenic effects has been observed after administration of fentanyl citrate to rats {01}.

FDA Pregnancy Category C {01}.

Labor and delivery—

Use of transmucosal fentanyl to provide analgesia during labor and delivery is not recommended {01}.


Fentanyl is distributed into human milk {01}. Use of transmucosal fentanyl by nursing women is not recommended because of the possibility of sedation and/or respiratory depression in infants {01}.


Appropriate studies on the relationship of age to the effects of transmucosal fentanyl have not been performed in the pediatric population {01}. Safety and efficacy have not been established {01}. Patients and their caregivers must be instructed that transmucosal fentanyl contains a medicine in an amount that can be fatal to a child {01}. Patients and their caregivers must be instructed to keep transmucosal fentanyl out of the reach of children and to discard open units properly in a secured container {01}.


No difference was noted in the safety profile of the patient group over 65 years of age as compared to younger patients in clinical trials, although the older population did titrate to a slightly lower dose {01}. However, greater sensitivity to fentanyl in older individuals cannot be ruled out {01}. Therefore, exercise caution in elderly patients to provide adequate efficacy while minimizing the risks {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» CNS (central nervous system) depression-producing medications, other (see Appendix II) or    (concurrent use with transmucosal fentanyl may result in increased CNS depressant, respiratory depressant, and hypotensive effects; careful monitoring is recommended and dosage adjustment may be required {01})

Enzyme inhibitors, hepatic, cytochrome P450, such as:
» Erythromycin
» Itraconazole
» Ketoconazole
» Ritonavir     (inhibitors of potent hepatic cytochrome P450 enzymes may increase the bioavailability and decrease the clearance of transmucosal fentanyl, thereby resulting in increased or prolonged opioid effects; patients should be monitored carefully and a dosage adjustment may be required {01})

» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (caution is recommended when any opioid analgesic is given to patients who have received an MAO inhibitor within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics {01})

Naloxone or
Nalmefene    (may precipitate withdrawal symptoms in physically dependent patients {01})

Opioid, other    (in addition to their potential for causing additive effects when used concurrently with fentanyl, opioids having partial mu-receptor activity [e.g., buprenorphine and dezocine] and some opioids having mixed agonist/antagonist activity [e.g., nalbuphine and pentazocine] have the potential to antagonize transmucosal fentanyl's therapeutic and adverse effects {01})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:
» Respiratory depression, acute    (opioids may decrease respiratory drive in patients with this condition; transmucosal fentanyl should be titrated with caution in these patients {01})

Risk-benefit should be considered when the following medical problems exist
» Respiratory impairment or disease, chronic    (opioids may decrease respiratory drive in patients with these conditions; transmucosal fentanyl should be titrated with caution in these patients {01})

» Bradyarrhythmias    (may be exacerbated {01})

Drug abuse or dependence, current or history of, including alcoholism     (patient predisposition to drug abuse {01})

Head injury or
Intracranial lesions    (risk of respiratory depression and further elevation of cerebrospinal fluid pressure, which may lead to complications such as impaired consciousness, is increased; also, transmucosal fentanyl may cause sedation and pupillary changes that may obscure the clinical course of patients with head injury {01})

Hepatic function impairment or
Renal function impairment    (potential for reduced clearance of fentanyl, leading to higher plasma concentrations {01})

Caution is also recommended in administration to elderly or very ill or debilitated patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of opioid analgesics {01}
Sensitivity to fentanyl

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Heart rate
» Respiratory rate
» Sedation, degree of    (should be monitored at periodic intervals, especially at the beginning of therapy and after increases in dosage {01})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
Central nervous system (CNS)-depression {01} (dizziness, lightheadedness, feeling faint, unusual tiredness, or weakness)
dyspnea {01} (shortness of breath)

Incidence less frequent
CNS effects {01} ( abnormal thinking; anxiety; confusion; dizziness; drowsiness; false sense of well-being; nervousness; problems with coordination ; weakness)
hallucinations {01} (seeing, hearing, or feeling things that are not there)
urinary retention {01} ( decrease in urine volume; decrease in frequency of urination)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
dry mouth {01}
nausea and/or vomiting {01}

Those indicating possible need for medical attention if they occur after medication is discontinued
Diarrhea {01}
nausea and/or vomiting {01}
restlessness or irritability {01}
speech disorder {01}
stomach cramps {01}
trouble in sleeping {01}
weakness {01}

For specific information on the agents used in the management of fentanyl overdose, see:    • Charcoal, Activated (Oral-Local) monograph; and/or
   • Naloxone (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
Cold, clammy skin {01}
convulsions {01}
dizziness (severe), drowsiness, nervousness, restlessness, or weakness {01}
hypotension {01} (dizziness, lightheadedness, or feeling faint)
miosis {01} (pinpoint pupils of the eyes )
slow or troubled breathing {01}

Treatment of overdose
General measures—Removing medicine, if still in mouth {01}.

To decrease absorption—Emptying the stomach via gastric lavage {01}.

To enhance elimination—Administering activated charcoal {01}.

Specific treatment— For hypotension: Use of intravenous fluids and/or vasopressors and using other supportive measures as needed {01}.

For hypoventilation: Verbal stimulation or waking the patient may be sufficient to increase the respiratory rate and provide adequate ventilation. Use of the opioid antagonist naloxone if necessary {01}.

Supportive care—May include establishing adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled respiration {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Fentanyl— (Systemic) .
In providing consultation, consider emphasizing the following selected information; (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to fentanyl or its derivatives

Pregnancy—Use of transmucosal fentanyl is not recommended during labor and delivery

Breast-feeding—Opioid effects including sedation, respiratory depression, and physical dependence may occur in the nursing infant

Use in the elderly—May be more sensitive to the effects of transmucosal fentanyl
Other medications, especially alcohol, CNS depression producing medications, hepatic enzyme inhibitors, or MAO inhibitors
Other medical problems, especially acute or chronic pulmonary diseases, or bradyarrhythmias

Proper use of this medication
» Reading patient instructions carefully before using

» Keep medication in sealed pouch until ready to use. The foil package should be opened with scissors immediately prior to product use. Place the medicine in mouth between the cheek and lower gum, occasionally moving the medicine from one side to the other using the handle. The medicine should be sucked not chewed. Consume each dose of the medicine over a 15-minute period.

» Proper dosing
Missed dose (if on scheduled dosing): Using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Transmucosal fentanyl contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep transmucosal fentanyl out of the reach of children and to discard open units

Regular consultations with health care professional during long-term therapy

» Avoiding use of alcoholic beverages or other CNS depressants during therapy, unless prescribed or otherwise approved by physician

» Caution if dizziness, drowsiness, lightheadedness, or false sense of well-being occurs; checking with health care professional if severe drowsiness persists for more than a few days

Getting up slowly from a lying or sitting position; lying down for a while may provide relief if patient becomes dizzy, lightheaded, or faint

Compliance with regimen for preventing severe constipation, if prescribed

» Informing physician or dentist of use of medication if any kind of surgery (including dental surgery) or emergency treatment is required

Not discontinuing medication abruptly after prolonged use; checking with physician instead, since gradual withdrawal may be needed to minimize risk of precipitating abstinence syndrome

» Suspected overdose: Getting emergency help at once

Side/adverse effects
Signs of potential side effects, especially CNS depression, dyspnea, CNS effects, hallucinations, or urinary retention

General Dosing Information
Transmucosal fentanyl should be used in opioid-tolerant patients only {01}. Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine per day, 50 mcg of transdermal fentanyl per hour, or an equivalent dose of another opioid analgesic for a week or longer {01}.

Transmucosal fentanyl may cause respiratory depression, especially in elderly, very ill, or debilitated patients and patients with preexisting respiratory problems {01}. Lower doses may be required for these patients, at least initially {01}.

Safety considerations for handling this medication
Patients must be advised to dispose of any units remaining from a prescription as soon as they are no longer needed {01}. While all units should be disposed of immediately after use, partially consumed units represent a special risk because they are no longer protected by the child-resistant pouch, yet may contain enough medicine to be fatal to a child {01}.

A temporary storage bottle is provided as part of the Actiq ® Welcome Kit {01}. This container is to be used by patients or their caregivers in the event that a partially consumed unit cannot be disposed of promptly {01} (see manufacturer"s patient leaflet for proper disposal information). If additional assistance is required, call 1-800-615-0187 {01}.

Oral Dosage Forms


Note: Transmucosal fentanyl contains fentanyl citrate. However, dosage and strength are expressed in terms of fentanyl base {01}.

Usual adult dose
Analgesic (opioid tolerant patients only)
Transmucosal, 200 mcg (base), initially, with dosage then being adjusted according to the requirements of the individual patient {01}. See manufacturer"s prescribing information for recommended dose titration schedule {01}.

Note: Each dose of transmucosal fentanyl should be consumed over a 15-minute period (30 minutes after start of the previous dose) {01}. Patients should not use any more than 2 units per episode of breakthrough pain. If signs of excessive opioid effects appear before the dose is consumed, the medicine should be removed from the patient"s mouth immediately and future doses should be decreased {01}.

Usual pediatric dose
Safety and efficacy in children younger than 16 years of age have not been established {01}.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available

200 mcg (base) (Rx) [Actiq{01} ( sucrose) (liquid glucose) ( artificial raspberry flavor) (white dispersion G.B. dye)]

400 mcg (base) (Rx) [Actiq{01} ( sucrose) (liquid glucose) ( artificial raspberry flavor) (white dispersion G.B. dye)]

600 mcg (base) (Rx) [Actiq{01} ( sucrose) (liquid glucose) ( artificial raspberry flavor) (white dispersion G.B. dye)]

800 mcg (base) (Rx) [Actiq{01} ( sucrose) (liquid glucose) ( artificial raspberry flavor) (white dispersion G.B. dye)]

1200 mcg (base) (Rx) [Actiq{01} ( sucrose) (liquid glucose) ( artificial raspberry flavor) (white dispersion G.B. dye)]

1600 mcg (base) (Rx) [Actiq{01} ( sucrose) (liquid glucose) ( artificial raspberry flavor) (white dispersion G.B. dye)]

Packaging and storage:
Store at 25º C (77 ºF), preferably between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer {01}.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • May be habit-forming.

Developed: 06/14/1999
Revised: 10/20/1999

  1. Product Information: Actiq®, oral transmucosal fentanyl citrate. Abbott Laboratories, North Chicago, IL, USA, 1998.

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