fentanyl transdermal (Rx)

Frequency Not Defined

Asthenia

Confusion

Constipation

Dry mouth

Nausea

Somnolence

Sweating

Vomiting

Abdominal pain

Anorexia

Anxiety

Apnea

Depression

Diarrhea

Dizziness

Dyspepsia

Dyspnea

Euphoria

Fatigue

Hallucinations

Headache

Hemoptysis

Hypoventilation

Influenzalike symptoms

Nervousness

Pharyngitis

Pruritus

Upper respiratory tract infection Urinary retention

Abnormal coordination, thinking, gait, dreams

Accidental injury

Agitation

Amnesia

Angina pectoris

Application-site reaction

Back pain

Bradycardia

Bronchitis

Cardiac arrest, ST-segment elevation

Coma

Dysphoria

Faintness

Fever

Flatulence

Flushing

Hiccups

Mental clouding

Micturition disorder

Myocardial infarction

Oliguria

Paranoid reaction

Paresthesia

Rash

Respiratory arrest

Respiratory/circulatory depression

Rhinitis

Sedation

Seizures

Severe cardiac arrhythmias

Shock

Sinusitis

Speech disorder

Syncope

Tremor

Urinary retention

Ventricular tachycardia

Visual disturbances

Warmness of face/neck/upper thorax, urticaria

Weakness

Contraindications

Hypersensitivity to drug or components of the formulation

Known or suspected gastrointestinal obstruction, including paralytic ileus

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Within 2 weeks of monoamine oxidase inhibitor (MAOI) therapy

Management of postoperative, mild, or intermittent pain

Opioid-naive or non-opioid-tolerant patients

Cautions

Use caution in acute pancreatitis, Addison disease, benign prostatic hyperplasia, cardiac arrhythmias, central nervous system (CNS) depression, drug abuse or dependence, emotional lability, gallbladder disease, gastrointestinal (GI) disorder, pseudomembranous colitis, GI surgery, head injury, hypothyroidism or untreated myxedema, intracranial hypertension, brain tumor, toxic psychosis, urethral stricture, urinary tract surgery, seizures, acute alcoholism, delirium tremens, shock, cor pulmonale, chronic pulmonary disease, emphysema, hypercapnia, kyphoscoliosis, severe obesity, renal or hepatic impairment, elderly or debilitated patients

Increased risk of potentially fatal respiratory depression, pruritus (despite little histamine release), and abuse or addiction

May impair physical or mental abilities; use caution when operating machinery or driving

Schedule II opioid analgesics expose users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids due to the larger amount of active opioid present (see Black Box Warnings); addiction can occur at recommended dosages and if drug is misused or abused

Severe hypotension may occur including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

In patients who may be susceptible to intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

Addiction, abuse, and misuse risks are increased in patients with a personal or family history of substance abuse or mental illness (eg, major depression); the potential for these risks should not, however, prevent the prescribing of proper pain management in any given patient; intensive monitoring is necessary (see Black Box Warnings)

Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Serious, life-threatening, or fatal respiratory depression reported (see Black Box Warnings)

Accidental exposure reported, including fatalities (see Black Box Warnings)

Bradycardia may occur; monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy

Therapy may increase frequency of seizures in patients with seizure disorders and in other clinical settings associated with seizures; monitor patients for worsened seizure control during therapy

Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black Box Warnings)

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24-72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of opioid

Deaths have occurred in nursing infants exposed to high levels of opioid in breast milk because mothers were ultra-rapid metabolizers of opioid (see Lactation)

Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

Opioid pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

Opioid analgesic risk evaluation and mitigation strategy (REMS)

• To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
• To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

Drug interactions overview

• Also see Black Box Warnings
• Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (eg, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
• Coadministration with anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus
• Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone
• Monoamine oxidase inhibitors (MAOIs) may potentiate effects of opioid, opioid’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of initiating or stopping MAOIs
• Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected
• Avoid use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients
• Concomitant use with a CYP3A4 inhibitor, such as macrolide antibiotics (eg, erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (eg, ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of fentanyl injection is achieved; similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl-injection treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions; when using fentanyl Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl-Injection treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl injection until stable drug effects are achieved
• Concomitant use of fentanyl injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl; when using fentanyl injection with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur
• Interactions with CNS depressants (eg, alcohol, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids) can cause additive effects and increase risk for respiratory depression, profound sedation, and hypotension

Pregnancy

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly; opioids cross placenta and may produce respiratory depression and psychophysiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; opioid sulfate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions

Fertility

• Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether effects on fertility are reversible

Lactation

Opioid is secreted into human milk; in women with normal opioid metabolism (normal CYP2D6 activity), the amount of opioid secreted into human milk is low and dose-dependent; some women are ultra-rapid metabolizers of opioid; these women achieve higher-than-expected serum levels of opioid's active metabolite, opioid, leading to higher-than-expected levels of opioid in breast milk and potentially dangerously high serum opioid levels in their breastfed infants that can potentially lead to serious adverse reactions, including death, in nursing infants

Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Narcotic agonist-analgesic of opiate receptors; inhibits ascending pain pathways; alters pain perception, thus altering response to pain; produces analgesia, respiratory depression, and sedation

Absorption

After patch removal, continued systemic absorption occurs from residual fentanyl in skin, so that serum concentrations fall by average of 50% in ~20-27 hr

Onset: 6 hr

Duration: 72-96 hr

Peak plasma time: 28.8-35.8 hr (dose dependent; following first application)

Peak plasma concentration: 0.38-3.36 ng/mL (dose dependent; following first application)

Distribution

Vd: 4-6 L/kg

Protein binding: 80-85%

Metabolism

Metabolized in liver by CYP3A4

Elimination

Half-life: 20-27 hr

Excretion: Urine (75% mostly as metabolites), feces (9% as metabolites)

Transdermal Preparation

Hair at application site may be clipped (not shaved) prior to system application

If application site must be cleaned prior to application of the patch, do so with clear water; do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics

Allow skin to dry completely prior to patch application

Patch must not be altered (eg, cut) in any way prior to application

Do not use if the pouch seal is broken or if the patch is cut or damaged

Transdermal Administration

Transdermal use only

Apply to intact, non-irritated, and non-irradiated skin on a flat surface (eg, chest, back, flank, or upper arm)

In young children and persons with cognitive impairment, monitor adhesion an upper back is the preferred location to minimize the potential of inappropriate patch removal

Avoid exposing application site and surrounding area to direct external heat sources (see Black Box Warnings)

Apply immediately upon removal from sealed package

Firmly press in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges

Each patch may be worn continuously for 72 hr; rotate application sites to a different skin site after removal of the previous transdermal system

Patients or caregivers who apply the patch should wash their hands immediately with soap and water after applying; contact with unwashed or unclothed application sites can result in secondary exposure to drug and should be avoided

Instruct patients, family members, and caregivers to keep patches in a secure location out of the reach of children and of others

Resolutions to adhesion issues

• If problems with adhesion of the patch occur, edges of the patch may be taped with first aid tape
• If problems with adhesion persist, patch may be overlaid with a transparent adhesive film dressing
• If patch falls off before 72 hr, dispose of it by folding in half and flushing down the toilet

Disposal

• Dispose of used patches immediately upon removal by folding the adhesive side of the patch to itself, then flushing down the toilet
• Remove unused patches from their pouches, remove the release liners, fold patches so that the adhesive side of the patch adheres to itself, and to immediately flush the patches down the toilet
• Dispose of any patches remaining from a prescription as soon as they are no longer needed

Storage

Unopened pouches: Store up to 25°C (77°F); excursions permitted to 15-30°C (59-86°F)