fentanyl (transdermal)

Absorption: Well absorbed (92% of dose) through skin surface under transdermal patch, creating a depot in the upper skin layers. Release from transdermal system into systemic circulation ↑ gradually to a constant rate, providing continuous delivery for 72 hr.

Distribution: Crosses the placenta; enters breast milk.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP3A4 isoenzyme; 10–25% excreted unchanged by the kidneys.

Half-Life: 17 hr after removal of a single application patch, ↑ to 21 hr after removal of multiple patches (because of continued release from deposition of drug in skin layers).

Time/Action Profile ⬆ ⬇

(↓ pain)

ROUTE	ONSET	PEAK	DURATION
Transdermal	6 hr‡	12–24 hr	72 hr‡

‡Achievement of blood levels associated with analgesia. Maximal response and dose titration may take up to 6 days.

‡While patch is worn.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity to fentanyl or adhesives;
Patients who are not opioid tolerant
Acute, mild, intermittent, or postoperative pain;
Significant respiratory depression;
Acute or severe bronchial asthma;
Paralytic ileus;
Severe hepatic or renal impairment
Alcohol intolerance (small amounts of alcohol released into skin);
OB: Not recommended during labor and delivery;
Lactation: Lactation.

Use Cautiously in:

Diabetes;
Patients with severe pulmonary disease;
Mild or moderate hepatic or renal impairment
CNS tumors;
↑intracranial pressure;
Head trauma;
Adrenal insufficiency;
Undiagnosed abdominal pain;
Hypothyroidism;
Alcoholism;
Cardiac disease (particularly bradyarrhythmias);
Fever or situations that ↑ body temperature (↑ release of fentanyl from delivery system);
Cachectic or debilitated patients (dose ↓ suggested because of altered drug disposition);
OB: Use during pregnancy only if the potential maternal benefit justifies the potential fetal risk;
Pedi: Children <2 yr (safety not established); pediatric patients initiating therapy at 25 mcg/hr should be opioid tolerant and receiving at least 60 mg oral morphine equivalents per day;
Geri: ↑risk of respiratory depression in older adults (dose ↓ suggested).

Adv. Reactions/Side Effects ⬆ ⬇

CV: bradycardia, hypotension

Derm: sweating, erythema

Endo: adrenal insufficiency

GI: anorexia, constipation, dry mouth, nausea, vomiting

Local: application site reactions

MS: skeletal and thoracic muscle rigidity

Neuro: confusion, sedation, weakness, dizziness, restlessness

Resp: APNEA, bronchoconstriction, laryngospasm, RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA)

Misc: physical dependence, psychological dependence

Interactions ⬆ ⬇

Drug-drug:

Avoid use in patients who have received MAO inhibitors within the previous 14 days (may produce unpredictable, potentially fatal reactions).
Concomitant use of CYP3A4 inhibitors including ritonavir, ketoconazole, itraconazole, clarithromycin, nelfinavir, nefazodone, amiodarone, diltiazem, aprepitant, fluconazole, fosamprenavir, verapamil, and erythromycin may result in ↑ plasma levels and ↑ risk of CNS and respiratory depression.
Levels and effectiveness may be ↓ by CYP3A4 inducers including rifampin, carbamazepine, and phenytoin.
Use with benzodiazepines or other CNS depressants including other opioids, non-benzodiazepine sedative/hypnotics, anxiolytics, general anesthetics, muscle relaxants, antipsychotics, and alcohol may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
Mixed agonist/antagonist analgesics, including nalbuphine or butorphanol and partial agonist analgesics, including buprenorphine, may ↓ fentanyl's analgesic effects and/or precipitate opioid withdrawal in physically dependent patients.
Drugs that affect serotonergic neurotransmitter systems, including tricyclic antidepressants, SSRIs, SNRIs, MAO inhibitors, TCAs, tramadol, trazodone, mirtazapine, 5–HT3 receptor antagonists, linezolid, methylene blue, and triptans↑ risk of serotonin syndrome.

Drug-Natural Products:

Concomitant use of kava-kava, valerian, or chamomile can ↑ CNS depression.

Drug-Food:

Grapefruit juice is a moderate inhibitor of the CYP3A4 enzyme system; concurrent use may ↑ blood levels and the risk of respiratory and CNS depression. Careful monitoring and dose adjustment is recommended.

Route/Dosage ⬆ ⬇

Transdermal (Adults ): 25 mcg/hr is the initial dose; patients who have not been receiving opioids should receive not more than 25 mcg/hr. To calculate the dose of transdermal fentanyl required in patients who are already receiving opioid analgesics, assess the 24-hr requirement of currently used opioid. Using the equianalgesic table in Equianalgesic Dosing Guidelines, convert this to an equivalent amount of morphine/24 hr. Conversion to fentanyl transdermal may be accomplished by using the fentanyl conversion table (Equianalgesic Dosing Guidelines). During dose titration, additional short-acting opioids should be available for breakthrough pain. Morphine 10 mg IM or 60 mg PO every 4 hr (60 mg/24 hr IM or 360 mg/24 hr PO) is considered to be approximately equivalent to transdermal fentanyl 100 mcg/hr. Transdermal patch lasts 72 hr in most patients. Some patients require a new patch every 48 hr.
Transdermal (Adults >60 yr, Debilitated, or Cachectic Patients): Initial dose should be 25 mcg/hr unless previous opioid use was >135 mg morphine PO/day (or other opioid equivalent).

Hepatic Impairment

Transdermal (Adults ): Mild-to-moderate hepatic impairment: 12 mcg/hr is the initial dose.

Renal Impairment

Transdermal (Adults ): Mild-to-moderate renal impairment: 12 mcg/hr is the initial dose.

Availability ⬆ ⬇

(Generic available)

Transdermal systems: 12.5 mcg/hr; 25 mcg/hr; 37.5 mcg/hr; 50 mcg/hr; 62.5 mcg/hr; 75 mcg/hr; 87.5 mcg/hr; 100 mcg/hr

Assessment ⬆ ⬇

Assess type, location, and intensity of pain before and 24 hr after application and periodically during therapy. Monitor pain frequently during initiation of therapy and dose changes to assess need for supplementary analgesics for breakthrough pain.
Assess BP, pulse, and respirations before and periodically during administration. If respiratory rate is <10/min, assess level of sedation. Physical stimulation may be sufficient to prevent significant hypoventilation. Dose may need to be decreased by 25–50%. Initial drowsiness will diminish with continued use. Monitor for respiratory depression, especially during initiation or following dose increase; serious, life-threatening, or fatal respiratory depression may occur. May cause sleep-related breathing disorders (central sleep apnea, sleep-related hypoxemia).
Prolonged use may lead to physical and psychological dependence and tolerance. This should not prevent patient from receiving adequate analgesia. Most patients who receive opioid analgesics for pain rarely develop psychological dependence.
Progressively higher doses may be required to relieve pain with long-term therapy. It may take up to 6 days after increasing doses to reach equilibrium, so patients should wear higher dose through 2 applications before increasing dose again. Increased doses and prolonged use may increase risk of overdose. Prolonged use of opioids should be reserved for patients whose pain remains severe enough to require them and alternative treatment options continue to be inadequate. Many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
Assess bowel function routinely. Prevent constipation with increased intake of fluids and bulk, and laxatives to minimize constipating effects. Administer stimulant laxatives routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid induced constipation.
Assess risk for opioid addiction, abuse, or misuse prior to administration. Misuse or abuse of transdermal fentanyl by chewing, swallowing, snorting or injecting fentanyl extracted from transdermal system will result in the uncontrolled delivery of fentanyl and risk of overdose and death.

Lab Test Considerations:

May ↑ plasma amylase and lipase levels.

Toxicity and Overdose:

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For patients weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg/kg every 2 min. Titrate dose to avoid withdrawal, seizures, and severe pain. Monitor patient closely; dose may need to be repeated or may need to be administered as an infusion because of long duration of action despite removal of patch.

Implementation ⬆ ⬇

Do not confuse fentanyl with sufentanil.
High Alert: Accidental overdose of opioid analgesics has resulted in fatalities. Before administering, confirm patient is opioid tolerant and clarify ambiguous orders.
12-mcg patch delivers 12.5 mcg/hr of fentanyl. Use supplemental doses of short-acting opioid analgesics to manage pain until relief is obtained with the transdermal system. Patients may continue to require supplemental opioids for breakthrough pain. If >100 mcg/hr is required, use multiple transdermal systems.
- Titrate dose based on patient’s report of pain until adequate analgesia (50% reduction in patient’s pain rating on numerical or visual analogue scale or patient reports satisfactory relief) is attained. Determine dose by calculating the previous 24-hr analgesic requirement and converting to the equianalgesic morphine dose using Equianalgesic Dosing Guidelines. The conversion ratio from morphine to transdermal fentanyl is conservative; 50% of patients may require a dose increase after initial application. Increase after 3 days based on required daily doses of supplemental analgesics. Base increases on ratio of 45 mg/24 hr of oral morphine to 12.5 mcg/hr increase in transdermal fentanyl dose.
- Coadministration with nonopioid analgesics may have additive analgesic effects and permit lower opioid doses.
- To convert to another opioid analgesic, remove transdermal fentanyl system and begin treatment with half the equianalgesic dose of the new analgesic in 12–18 hr.
- Discontinue medication gradually after long-term use to prevent withdrawal symptoms. May be necessary to provide patient with a lower dose strength for a successful taper. Monitor frequently to manage pain and withdrawal symptoms (restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate). If withdrawal symptoms occur, pause the taper for a period of time or raise the dose of opioid analgesic to the previous dose, and then proceed with a slower taper. Also, monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.
REMS: FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain, available at www.fda.gov/OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or www.opioidanalgesicrems.com.
Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.
Apply system to flat, nonirritated, and nonirradiated site such as chest, back, flank, or upper arm. If skin preparation is necessary, use clear water and clip, do not shave, hair. Allow skin to dry completely before application. Apply immediately after removing from package. Do not alter the system (cut) in any way before application. Remove liner from adhesive layer and press firmly in place with palm of hand for 30 sec, especially around the edges, to make sure contact is complete. Remove used system and fold so that adhesive edges are together. Flush system down toilet immediately on removal or follow the institutional disposal policy. Apply new system to a different site.

Patient/Family Teaching ⬆ ⬇

REMS: Instruct patient in how and when to ask for and take pain medication. Do not increase doses without discussing with health care professional, may lead to overdose. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide (PCG) is available at www.fda.gov/OpioidAnalgesicREMSPCG. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
Instruct patient in correct method for application and disposal of transdermal system. Fatalities have occurred from children having access to improperly discarded patches. May be worn while bathing, showering, or swimming.
Advise patient to avoid grapefruit juice during therapy.
Advise patient that fentanyl is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (by prescription, directly from a pharmacist, or as part of a community-based program).
May cause drowsiness or dizziness. Caution patient to call for assistance when ambulating or smoking and to avoid driving or other activities requiring alertness until response to medication is known.
Advise patient to change positions slowly to minimize dizziness.
Caution patient to avoid concurrent use of alcohol or other CNS depressants with this medication.
Caution patient that fever, electric blankets, heating pads, saunas, hot tubs, and heated water beds increase the release of fentanyl from the patch.
Advise patient that good oral hygiene, frequent mouth rinses, and sugarless gum or candy may decrease dry mouth.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Advise patient referred for MRI test to discuss patch with referring health care professional and MRI facility to determine if removal of patch is necessary prior to test and for directions for replacing patch.
Rep: Instruct females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Chronic use may reduce fertility in females and males.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇