FENTANYL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Other Oral Formulations
-Fentanyl products are not bioequivalent and are not interchangeable.
-The use of transmucosal fentanyl products are generally not recommended for use in pediatric patients. Actiq oral lozenges are FDA-approved for use in patients 16 years of age and older; other transmucosal formulations are approved for adult use only. The use of these products should only be under the direct supervision of a clinician highly experienced in pediatric pain management.
-Transmucosal formulations should only be used in opioid-tolerant patients. These products are not for use in the management of acute or postoperative pain.

Actiq Oral Lozenge
-Open the child-resistant blister package with scissors immediately prior to use.
-Place between the cheek and lower gum, occasionally moving from 1 side of the mouth to the other using the handle. Patients should be instructed to suck but not chew or crush the lozenges.
-Consume over 15 minutes. Longer or shorter consumption times may reduce efficacy.
-Using the handle, remove the unit after it has been consumed or after the patient has achieved the desired level of sedation or is experiencing respiratory depression. If overdose is suspected, remove any remaining dosage from the mouth and seek immediate medical attention.
-Storage: Keep in a secure location out of the reach of children, pets, and others for whom the drug was not prescribed. Protect from freezing and moisture. Do not use if the blister pack has been opened.
-Disposal: During the disposal process, avoid contact with skin, eyes, or mucous membranes. Wash hands thoroughly when finished. All handles, even those that have been fully consumed and/or the drug has been properly removed, must be disposed of in a place that is out of the reach of children and pets.-Disposal of consumed units: Remove any drug matrix that is remaining on the handle by placing it under running hot tap water until matrix is completely dissolved. Dispose of the handle in a trash container that is out of the reach of children and pets.
-Disposal of partially consumed units: A temporary storage bottle is provided as part of the child safety kit; use this kit in the event that a partially consumed unit cannot be disposed of promptly. Dispose of handles stored in this container at least once daily.
-Disposal of unopened units: Remove unit from blister package using scissors. Hold unit by its handle over the toilet bowl and use a wire-cutting plier to cut the drug matrix off into the toilet. Flush the toilet twice after 5 units have been cut and deposited in the toilet. Dispose of the handle in a trash container that is out of the reach of children and pets.




Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Only individuals trained in the administration of general anesthetics and the management of the respiratory effects of potent opioids should give the drug. Pulse oximetry or some other means for measuring respiratory function is recommended.
-Resuscitative medications, including naloxone, and size-appropriate equipment for bag/valve/mask ventilation and intubation must be readily available.
Intravenous Administration
IV Push
-Inject directly into a vein or into the tubing of a freely flowing IV solution slowly over 1 to 3 minutes. Rapid IV injection of fentanyl may result in apnea.

Continuous IV Infusion
-May dilute in 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 10 mcg/mL or 50 mcg/mL.
-Administer using a controlled-infusion device.
-Adjust dose and rate based on patient response.

Intramuscular Administration
-Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [deltoid for children and adolescents only]).

Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.
-Fentanyl has been given as a subcutaneous continuous infusion in children weaning from prolonged sedation.

Other Injectable Administration
Epidural Administration
-Epidural administration should only be used by specially trained healthcare professionals.
-May be given as intermittent bolus, continuous infusion, or patient controlled epidural analgesia.
-Prior to administration, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available. The patient should be in a setting where adequate monitoring is possible.
-Placement of epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. Fentanyl only produces segmental analgesic effects and should only be used when the catheter tip is close to the incisional dermatome.

Intermittent Epidural Injection
-After ensuring proper placement of the needle or catheter, inject appropriate dose into the epidural space.
-Monitor patient in a fully equipped and staffed environment for at least 24 hours after each dose.

Continuous Epidural Infusion
-A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored in a fully equipped and staffed environment for several days after implantation of the device.
-If dilution of the injection is necessary, 0.9% Sodium Chloride Injection is recommended.
-Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5 micron (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdose.
-To avoid exacerbation of severe pain and/or reflux of cerebrospinal fluid into the reservoir, depletion of the reservoir should be avoided.
-Monitor patient in a fully equipped and staffed environment.



Topical Administration
Transdermal Patch Formulations
-Apply the patch immediately upon removal from the package. Do not use if the pouch seal is broken or the patch is damaged.
-Prior to application, the skin may be cleansed with clear water and excessive hair should be clipped. Do not shave. Do not use soaps, oils, lotions, alcohol, or any other agents that may irritate the skin. Pat skin dry completely before applying patch.
-Apply patch to a flat, intact, non-irritated, and non-irradiated area on the upper torso (e.g., chest, back, flank, or upper arm). Avoid cuts and sores.
-In young children or those with cognitive impairment, place the patch on the upper back to minimize the potential of inappropriate patch removal. Adhesion of the patch should be closely monitored; patients or caregivers should frequently check that the patch has not fallen off, particularly after exercising, bathing, and sleeping. -Small children have removed patches on sleeping adults or found patches that have fallen off and ingested them or applied them to themselves (e.g., like a bandage); such cases have resulted in fatality. To limit curiosity and/or poor adhesion, patients should not apply patches in the company of young children, to an area of the body where young children can see it, or on areas of frequent movement.

-Do not cut the patch to deliver partial doses. If it is necessary to use a smaller and commercially unavailable dosage, placing impermeable material (e.g., adhesive bandage) on the skin under the patch may block a proportional delivery of the drug.
-Firmly press the patch onto the application site with the palm of the hand for 30 seconds. Make sure contact is complete and edges adhere to the skin. If there is difficulty with adhesion, the patch edges may be taped down with first aid tape or overlaid with a transparent adhesive film dressing (e.g., Tegaderm). Avoid other tight coverings over the patch.
-When applying the patch touch the adhesive side as little as possible. Exposure to the adhesive matrix may lead to serious adverse events such as respiratory depression and fatal overdose. If unintended skin contact occurs, thoroughly rinse exposed skin with large amounts of water; do not use soap, alcohol, or other solvents as this may enhance the drug's ability to penetrate the skin.
-Wash hands with soap and water immediately after patch application.
-Change patch every 3 days (72 hours); remove any patches in use prior to application of a new patch. Rotate patch application site.
-If the patch falls off before 72 hours of use (including immediately after application) dispose of patch by folding in half so that adhesive side is inward and immediately flushing down the toilet. Use a new patch at a different skin site.
-Avoid contact with unwashed or unclothed application sites; this contact may result in secondary accidental exposure. Accidental exposure may occur during activities such as hugging, bed-sharing, or accidental caregiver skin contact during patch application and removal.
-Avoid exposing the patch application site and surrounding areas to external heat sources (e.g., heating pads, electric blankets, heated water beds, tanning beds, hot baths or saunas, excessive sun exposure, or hot climate). Patients should also be counseled to avoid strenuous exercise, which can heat the body.
-Storage: Instruct patients and caregivers to keep patches in a secure location out of the reach of children, pets, and others for whom the drug was not prescribed.
-Disposal: Instruct patients and caregivers to dispose of damaged, used, or unused patches remaining from a prescription when they are no longer needed. Improperly disposed of patches can cause serious illness or death, particularly to children or pets who might be inadvertently exposed.-Disposal of used patches: Upon removal, used patches should be folded in half so that the adhesive side of the patch adheres to itself and immediately flushed down the toilet.
-Disposal of unused patches: Unused patches should first be removed from their pouches and the protective liners removed before they are folded in half so that the adhesive side of the patch adheres to itself and immediately flushed down the toilet.




Other Administration Route(s)
Intranasal Administration
NOTE: There is currently no commercially available product that is FDA-approved for pediatric intranasal administration. The Lazanda nasal spray is for opioid-tolerant adults only and has not been studied in pediatric patients.
-Pediatric studies have utilized the injectable solution off-label for intranasal administration at a concentration of 50 to 300 mcg/mL; however, only the 50 mcg/mL concentration is commercially available in the US.

-In clinical practice, the parenteral solution is administered intranasally via drop installation with a needleless syringe or using a mucosal atomizer device. Use of the mucosal atomizer device improves absorption.-Clear the nasal passages prior to administration (e.g., suction or have the patient blow their nose).
-Place the patient's head at 45 degrees.
-Administer half of the dose to each nare. Do not use more than 0.5 to 1 mL of medication per nostril. If a higher dose is required, apply it in 2 separate doses a few minutes apart to allow for adequate absorption of the first dose.
-The patient should remain in a semi-reclined position for several minutes after administration.

Pharmacologic tolerance to the analgesic effects of opiate agonists including fentanyl has been reported. Tolerance is the need for increasing opioid doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and is managed by increasing the opioid dose or frequency. There is no limit to tolerance; thus, some patients may require very large doses of opiate analgesics to control their pain. When increasing doses of analgesia are required causes may be multifactorial including tolerance, progression of disease, or psychological distress.

The most significant adverse reactions associated with opiate agonist use are respiratory depression, respiratory arrest, and apnea. This results from a decreased sensitivity to both carbon dioxide and electrical stimulation in the brainstem respiratory centers. Fentanyl can potentially cause hypoventilation or respiratory depression (1% or less), apnea, or dyspnea regardless of administration route. If untreated these may result in respiratory arrest. Respiratory depression is more common in debilitated or cachectic patients, chronic pulmonary disease, after large initial doses in non-opioid tolerant patients, or when opioids are given with other CNS depressants. Concurrent use of a CYP3A4 inhibitor or discontinuation of a concurrently used 3A4 inducer may increase plasma fentanyl concentrations. In addition, patients with mucositis receiving transmucosal fentanyl are at risk for increased drug exposure. Increased fentanyl concentrations put these patients at increased risk for life-threatening respiratory depression. When fentanyl is appropriately titrated, the risk of respiratory depression is generally small as tolerance rapidly develops to this effect. Caution needs to be employed in patients with chronic lung disease, decreased pulmonary reserve, cardiovascular disease, or those who are taking other CNS depressants. Other respiratory adverse reactions reported with various forms of fentanyl in adults include pleural effusion, decreased breathing sounds, wheezing, cough, laryngospasm, pulmonary embolism (nasal spray), hemoptysis, oropharyngeal pain, pharyngolaryngeal pain, hypoxia, exertional dyspnea, hiccups, and increased sputum/pulmonary secretions. Stertorous breathing, asthma, respiratory insufficiency, bradypnea, respiratory distress, hyperventilation, pneumothorax, atelectasis, and pneumonia have also been reported. Transmucosal and transdermal forms of fentanyl should be removed at the first sign of respiratory depression. Symptomatic respiratory depression should be treated cautiously with an opiate antagonist such as naloxone. With fentanyl transdermal patch therapy, hypoventilation may occur up 1 to 3 days after the initial application or after a dose increase. Peak fentanyl concentrations occur 20 to 72 hours after the first patch is applied. After removal of a transdermal patch, significant amounts of fentanyl may be absorbed from the skin for 17 hours or more. Therefore, respiratory depression may be prolonged in these patients. Respiratory depression after epidural administration of fentanyl is rare due to the rapid clearance from the CSF; a delayed effect, as seen after epidural morphine, has not been reported with fentanyl.

In addition to centrally-mediated effects on ventilation, adverse respiratory effects of fentanyl may be related to chest wall rigidity. Chest wall rigidity is an uncommon but severe adverse reaction and may be more prominent in neonates and infants. In general, reactions occur with large doses given by rapid intravenous (IV) administration. However, fentanyl doses as low as 1 mcg/kg have been implicated. One report describes chest wall rigidity in a neonate after administration of fentanyl 20 mcg/kg/hour to the mother prior to cesarean delivery. Common clinical manifestations include laryngospasm, decreased pulmonary compliance, hypoventilation, and hypercarbia. Effects may be noted immediately after fentanyl administration. While some events may be self-limited, treatment with an opiate antagonist (e.g., naloxone), neuromuscular blockade, and/or mechanical ventilation may be necessary.

One of fentanyl's most noticeable adverse reactions is sedation. Warn patients and their caregivers that activity requiring mental alertness can be affected because drowsiness/somnolence (5%), fatigue (2%), confusion (2%), disorientation (less than 1%), impaired cognition, asthenia (1%), and dizziness (2%) can occur. Patients with mucositis receiving transmucosal fentanyl have increased fentanyl exposure; this may put them at risk for central nervous system (CNS) adverse reactions. Tolerance to an opioid's depressive CNS effects develops within a few days. Sedation after intravenous or epidural fentanyl is mild to moderate and usually short-lived. CNS-related adverse reactions reported with transdermal fentanyl therapy in pediatric patients include insomnia (6%), depression (2%), tremor (2% to 3%), paresthesias (2%), anxiety (3% to 4%), hallucinations (1% to 2%), euphoria (less than 1%), hypoesthesia (1% or less), and disorientation (less than 1%). Adverse reactions reported in adult trials with various formulations of fentanyl include dysphoria, lightheadedness, feeling cold, malaise, abnormal gait and/or coordination (ataxia), lethargy, dysphonia or speech disorder, restlessness, irritability, aphasia, paranoia, nervousness, abnormal thinking, abnormal dreams, emotional lability, incoordination, myoclonus/myoclonia, vertigo, hypokinesia, peripheral neuropathy, acute brain syndrome, cerebral ischemia, facial paralysis, foot drop, hemiplegia, and subdural hematoma. Postmarketing reports have included seizures, amnesia, agitation, depressed level of consciousness, and loss of consciousness. Carbon dioxide retention seen with opioid therapy may cause increased intracranial pressure. Use fentanyl with caution in patients with head injuries, brain tumors, or pre-existing seizure disorders. Additionally, certain patients may be at risk for headache (12% to 16%) and migraine, both of which have been reported during fentanyl clinical trials. Overuse of fentanyl by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of the overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement.

Fentanyl may cause a variety of effects on the gastrointestinal (GI) system, most commonly nausea (24%) and vomiting (34%). Nausea and vomiting is most commonly seen at the initiation of therapy or when switching agents. Opiate agonists affect the vestibular system and may cause more nausea/vomiting in ambulatory patients than bedridden patients. Scheduled treatment with an antiemetic during the first 1-2 days, then as needed during opiate therapy may control these symptoms until tolerance develops. Constipation (13%) due to decreased GI motility and secretions is common during fentanyl therapy. In some cases patients may develop fecal impaction, ileus (< 1%), or GI obstruction. Tolerance rarely develops to the constipating effect of fentanyl; therefore, patients require a bowel regimen consisting of a stool softener and mild stimulant throughout opioid therapy. Other GI effects reported during pediatric clinical trials include diarrhea (10-13%), abdominal pain (3-9%), and anorexia (4%). GI effects reported during clinical trials in adults include abdominal distension, decreased appetite, cachexia, weight loss, dysgeusia, dyspepsia, flatulence, dysphagia, esophagitis, esophageal stenosis, impaired gastric emptying, gastritis, eructation (belching), stomatitis, gastroesophageal reflux, GI bleeding, rectal hemorrhage, and fecal incontinence.

Fentanyl can cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients as a result of peripheral vasodilation. Patients at increased risk include those whose ability to maintain blood pressure is already compromised by reduced blood volume or concurrent administration of certain central nervous system depressants (e.g., phenothiazines, general anesthetics); monitor these patients carefully. Cardiovascular effects reported in pediatric patients during fentanyl transdermal patch clinical trials include peripheral edema (5%) and cyanosis (< 1%). Other effects reported with fentanyl use in adults include bradycardia, sinus tachycardia, hypertension, hypotension, chest pain (unspecified), angina pectoris, palpitations, peripheral vascular disorder, phlebitis or deep thrombophlebitis, deep vein thrombosis, pallor, edema, diaphoresis, and syncope. Cases of respiratory depression, apnea, and/or chest wall rigidity left untreated may lead to circulatory depression, shock, and cardiac arrest.

Fentanyl and other opiate agonists are known to cause pruritus. A high incidence of this reaction is associated with epidural fentanyl. In pediatric clinical trials of the fentanyl transdermal system, 13% of patients reported pruritus. Opiate agonist-induced pruritus is thought to be mediated through stimulation of central opiate receptors since opiate antagonists (i.e., nalmefene or naloxone) have been shown to ameliorate pruritus associated with cholestasis. Use of H1-blockers or changing to a different opioid may lessen the pruritus.

Some patients may experience anticholinergic adverse reactions with fentanyl therapy. Pediatric patients have reported xerostomia (2%) and urinary retention (1% to 3%) during clinical trials. Xerophthalmia and blurred vision have been reported in adult patients. Xerostomia and the use of fentanyl transmucosal lozenge (Actiq), which has 2 grams of sugar per unit, may contribute to the development of dental caries, tooth loss, gum line erosion, or gum hemorrhage. Gingivitis and periodontal abscess have also been reported. As some cases of dental decay occurred despite reported oral hygiene, counsel patients to consult their dentist to ensure appropriate oral hygiene.

Application site reactions (1%) have been reported with specific fentanyl formulations. Reported application site reactions of the fentanyl transdermal patch include skin irritation, dermatitis (1%), allergic dermatitis (< 1%), contact dermatitis (< 1%), eczema or atopic dermatitis (< 1%), or localized erythema (1-3%), papules, itching, and edema. Localized adverse effects reported by patients using transmucosal fentanyl lozenges (Actiq) include oral ulceration, oral irritation and pain, glossitis, oral moniliasis, and cheilitis (lip inflammation). In addition, each unit of Actiq contains approximately 2 grams of sugar per unit and may predispose patients to dental decay. Patients using intranasal fentanyl have reported nasal discomfort, rhinorrhea, nasal congestion, nasal irritation, postnasal drip, and epistaxis. Intranasal administration of the 50 mcg/ml intravenous solution is generally well-tolerated; local irritation is not commonly reported. Localized effects may not be exclusive to the route of administration, but rather related to the drug itself or the underlying medical condition. For example, oral ulceration has been reported with fentanyl nasal spray use and epistaxis has been reported transmucosal lozenges. Patients with a predisposition to skin diseases should be treated with caution when using transdermal fentanyl.

Hematologic abnormalities reported with fentanyl therapy in adults include anemia, leukopenia, neutropenia, thrombocytopenia, and pancytopenia. Prolonged bleeding time has also been reported. It is important to note that many fentanyl clinical trials exclusively enroll patients with an underlying malignancy.

Opioid agonists can interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH), and by stimulating secretion of prolactin, growth hormone (GH), insulin, and glucagon. Chronic opioid use may influence hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression). Adolescent females may experience amenorrhea. Other various medical, physical, lifestyle, and psychological stressors may influence gonadal hormone concentrations; these stressors have not been adequately controlled for in clinical studies with opioids. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation. Opioid agonists can inhibit the release of thyrotropin, leading to a decrease in thyroid hormone. Morphine and related compounds can stimulate the release of vasopressin (ADH). Hyponatremia can occur as a result of SIADH. Opioid agonists can inhibit the release of thyrotropin, leading to a decrease in thyroid hormone. Morphine and related compounds can stimulate the release of vasopressin (ADH). Hyponatremia can occur as a result of SIADH.

Muscle cramps or spasms (2%), muscle-twitching (< 1%), and influenza-like symptoms (< 1%) have been reported during pediatric clinical trials of fentanyl. Though causality is unclear, various complaints of pain were reported during fentanyl clinical trials in adult patients including generalized pain, cancer pain, back pain, bone pain, chest pain (unspecified), extremity pain, flank pain, neck pain and neck rigidity, pelvic pain, and shoulder pain. Other general disorders reported in adult patients include fever, chills, rigors, myalgia, myasthenia, muscular weakness, arthralgia, joint swelling, hypertonia, myopathy, muscle atrophy, synovitis, and joint, tendon, or bone disorder. In addition, cysts and granulomas were reported. In pre-marketing clinical trials of various fentanyl products, accidental injury, falls, contusions, ecchymosis, and bone fractures (e.g., spinal compression fractures, pathological fractures) have occurred in adult patients, perhaps in relation to the sedative effects of the drug.

Opioids may interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH) and cortisol. Rarely, adrenocortical insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency.

Fentanyl, like other opioids, causes miosis (< 1%) infrequently at typical therapeutic doses; miosis may even occur in total darkness. Adverse effects on special senses have been reported during fentanyl therapy in adults. These include blurred or abnormal vision, eye dryness (xerophthalmia), eye swelling, ptosis, strabismus, parosmia, amblyopia, ocular hemorrhage, and lacrimation disorder. In addition, tinnitus, ear disorder, ear pain, and hearing loss (partial permanent deafness and partial transitory deafness) have been reported.

Routine use of opiate agonists, such as fentanyl, by an expectant mother can lead to depressed respiration in the newborn and a neonatal opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome is estimated to occur in up to 50% of neonates born to opioid-dependent mothers. Withdrawal symptoms in a newborn generally occur 1 to 4 days after birth and include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. Monitor exposed neonates closely; neonatal opioid withdrawal can be life-threatening if not recognized and treated. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. As with other opioid agonists, use of fentanyl presents the potential for abuse. Physiological dependence will occur during chronic opioid agonist therapy as evidenced by a withdrawal syndrome occurring after abrupt discontinuation of the drug in these patients. While physiological and psychological dependence as a result of abuse is a concern with opioids, dependence in pediatric patients is more likely to occur in the setting of prolonged infusions in critically ill patients or as a result of chronic pain management. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur. Most symptoms resolve within 10 to 14 days; however, there appears to be a secondary or chronic abstinence syndrome which may last 2 to 6 months, characterized by insomnia, irritability, and muscle aches. It is important to differentiate physiological dependence, the onset of a withdrawal syndrome upon abrupt discontinuation of the drug, from psychological dependence. Psychological dependence is a behavioral syndrome characterized by drug craving, overwhelming concern with acquisition of the drug, and other drug-related behaviors such as drug selling and seeking the drug from multiple sources.

Jaundice, elevated hepatic enzymes (alkaline phosphatase), liver tenderness, and ascites have been reported during clinical trials of adult patients receiving fentanyl. In addition, hepatorenal syndrome has been reported in clinical trials of transmucosal fentanyl.

Dehydration and thirst have been reported in adults during clinical trials of various fentanyl products. Results of laboratory analysis demonstrated metabolic abnormalities such as hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hypercalcemia, hypoglycemia, hyperglycemia, hypoalbuminemia, and hypoproteinemia. Elevated serum lactate and acidosis were also observed. Hypoglycemia has been reported during opioid therapy. Most reports occurred in persons with at least 1 predisposing risk factor, such as diabetes.

The following adverse reactions have been reported after concurrent administration of a tranquilizer (e.g., droperidol) with parenteral fentanyl: chills and/or shivering, restlessness, and postoperative hallucinatory episodes, which are sometimes associated with transient periods of mental depression; extrapyramidal symptoms (dystonic reaction, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. According to the manufacturer, extrapyramidal symptoms can usually be controlled with anti-Parkinson agents in age-appropriate patients. The incidence of these effects is unknown.

Infection (viral, bacterial, and fungal) has been reported during adult clinical trial experience with fentanyl, including reports of rhinitis, sinusitis, pharyngitis, laryngitis, bronchitis, upper respiratory tract infection, pneumonia, influenza, gastroenteritis, urinary tract infection, and sepsis. Abscess, cellulitis, conjunctivitis, oral herpes, and oral candidiasis have also been reported. Although not attributed to any particular cause, lymphadenopathy and lymphedema have also been noted in adult patients during long-term use.

Although no cause-relationship has been established, renal failure (unspecified) and hepatorenal syndrome have been reported in adult patients receiving fentanyl lozenges. Other genitourinary effects reported during adult clinical trial experience with fentanyl include micturition disorder, urinary urgency, impaired urination, kidney pain, dysuria, nocturia, polyuria, hematuria, urinary incontinence, urinary tract infection, pyelonephritis, bladder discomfort or pain, oliguria, hydronephrosis, and increased urinary frequency. In addition, vaginitis, vaginal bleeding, breast pain, breast neoplasm, scrotal edema, and proctalgia have been reported.

Opiate analgesics, such as fentanyl, can cause spasm of the sphincter of Oddi. Hyperamylasemia, secondary to drug-induced spasm of the sphincter of Oddi, has been associated with various opiate agonists. While serum amylase and lipase concentrations can rise as a result of biliary obstruction or spasm, overt pancreatitis is rare with opiate analgesics. Gastritis and hepatotoxicity are also relatively rare with these agents.

Although rare, anaphylactoid reactions including cases of anaphylactic shock been reported with fentanyl use. Hypersensitivity (unspecified) (1-3%), rash (unspecified) (2-6%), and hyperhidrosis (3%) were reported during pediatric clinical trials of the fentanyl transdermal patch. Urticaria, alopecia, exfoliative dermatitis, maculopapular rash, vesiculobullous rash (bullous rash), skin ulcer, and facial edema were reported in clinical trials of the transmucosal lozenge. Other dermal effects reported with fentanyl include erythematous rash, pustules, hot flashes, cold sweat, night sweats, skin lesions, skin discoloration, and decubitus ulcers.

Serotonin syndrome has been reported in patients taking opioids at recommended doses. Patients taking an opioid concomitantly with a serotonergic medication should seek immediate medical attention if they develop symptoms such as agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Symptoms generally present within hours to days of taking an opioid with another serotonergic agent, but may also occur later, particularly after a dosage increase. If serotonin syndrome is suspected, either the opioid and/or the other agent should be discontinued.

Cases of opioid-induced hyperalgesia (OIH) have been reported, both with short-term and longer-term use of opioids. OIH occurs when an opioid paradoxically causes an increase in pain or an increase in sensitivity to pain. Symptoms of OIH include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Data suggests a strong biologic plausibility between opioids and OIH and allodynia. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching to a different opioid).

Fentanyl use is contraindicated in patients with a history of hypersensitivity reactions to fentanyl or any component of the specific dosage form. The fentanyl iontophoretic transdermal system is specifically contraindicated in patients with cetylpyridinium chloride hypersensitivity (e.g., Cepacol), an inactive ingredient in the hydrogel. Further, do not use other opioid agonists of the phenylpiperidine subclass including meperidine and sufentanil. If fentanyl hypersensitivity occurs, it may be possible to treat the patient with an opioid agonist from another subclass (e.g., phenanthrene, diphenylheptane, phenylpropylamine).

Life-threatening hypoventilation resulting in apnea or respiratory arrest may occur at any dose of available non-parenteral fentanyl products in patients not taking chronic opioids and not tolerant to opioids. As such, fentanyl transdermal patches and oral transmucosal lozenges (Actiq) are contraindicated in opioid-naive patients and in the management of acute and postoperative pain. Persons considered opioid tolerant are those who are using at least 60 mg/day oral morphine, 30 mg/day oral oxycodone, 8 mg/day oral hydromorphone, 25 mg/day oral oxymorphone, 60 mg/day oral hydrocodone, 25 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer. Use of the transdermal patches is specifically contraindicated in mild pain. Use of Actiq is specifically contraindicated in headache, migraine, and dental pain. Parenteral fentanyl use requires a clinician trained in the use of anesthetic drugs, airway management, and assisted ventilation. Parenteral fentanyl use also requires a specialized care setting. Adequate facilities for the management of postoperative respiratory depression must be available when using injectable fentanyl.

Fentanyl causes decreased gastrointestinal (GI) motility and delayed digestion; patients with pre-existing GI disease may be at increased risk for adverse events. In critically ill newborns and pediatric patients receiving fentanyl, monitor for abdominal distention and loss of bowel sounds. Fentanyl transdermal patches are contraindicated for use in patients with known or suspected paralytic ileus; however, all fentanyl products should be used with extreme caution in this setting. Due to the effects of opiate agonists on the GI tract, use fentanyl cautiously in patients with GI obstruction, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Patients with acute ulcerative colitis (UC) or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdomen.

Opioid use requires an experienced clinician who is knowledgeable about the use of opioids, including the use of extended-release/long-acting opioids, and how to mitigate the associated risks. Opioids expose users to the risks of addiction, abuse, and misuse, which can occur at any dosage or duration. Although the risk of addiction in any individual is unknown, it can occur in persons appropriately prescribed an opioid. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each individual's risk for opioid addiction, abuse, or misuse before prescribing an opioid, and monitor for the development of these behaviors or conditions. Risks are increased in persons with a personal or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression). The potential for these risks should not prevent the proper management of pain in any given individual. Persons at increased risk may be prescribed opioids but use in such persons necessitates intensive counseling about the risks and proper use of the opioid along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse and addiction are separate and distinct from physical dependence and tolerance; persons with addiction may not exhibit tolerance and symptoms of physical dependence. Opioids are sought by drug abusers and persons with addiction disorders and are subject to criminal diversion. Abuse of opioids has the potential for overdose or poisoning and death. Consider these risks when prescribing or dispensing opioids. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Keep opioids out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure or improper use may cause respiratory failure and a fatal overdose. Accidental exposure of even a single dose of an opioid, especially by younger persons, can result in a fatal overdose. Advise patients and caregivers to wash hands after handling any fentanyl product or packaging and to seek immediate medical help if an accidental exposure occurs. Cases of pediatric accidental exposure to the patch have resulted in hospitalization and death; more than half of the cases evaluated by the FDA have involved children under the age of 2 years, indicating the mobility and curiosity of toddlers provides ample opportunity for finding improperly stored or discarded patches. Contact with unwashed or unclothed application sites from the transdermal patch can result in secondary exposure and should be avoided; examples include transfer of the drug to a child's body while hugging, sharing the same bed as the patient, or accidentally sitting on a patch. Used patches still may contain enough fentanyl to cause a fatal overdose in a child, adult, or pet. After 3 days of continuous use, a patch may contain approximately 30% to 85% of the original drug content. Placing a patch in the mouth, chewing it, or swallowing it may cause choking or overdose that may be fatal. Buccal absorption of fentanyl is increased more than 30-fold compared to transdermal absorption and allows large amounts of drug to rapidly enter the circulation. Swallowing an intact patch results in less rapid drug release, however, systemic absorption is still significant. To limit curiosity and/or poor adhesion, patches should not be applied in the company of children, to an area of the body where children can see it, or on areas of frequent movement. In addition, persons should frequently check that transdermal systems have not fallen off, particularly after exercising, bathing, and sleeping. Advise patients and caregivers to wash hands after handling any fentanyl product or packaging and properly dispose of all delivery systems, used and unused, per the manufacturers' recommendations. If gel from the transdermal patch accidentally contacts unintended skin, thoroughly rinse the exposed skin with large amounts of water; do not use soap, alcohol, or other solvents as they may enhance the drug's ability to penetrate the skin. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of an opioid for persons in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Do not use immediate-release opioids for an extended period unless the pain remains severe enough to require an opioid and for which alternative treatment options continue to be inadequate. Many acute pain conditions (e.g., pain occurring with surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid. Clinical guidelines on opioid prescribing for some acute pain conditions are available. Extended-release opioids are not intended for use in the management of acute pain or on an as-needed basis but rather only for the management of severe and persistent pain that requires an extended treatment period with a daily opioid and for which alternative treatment options are inadequate. Discuss the availability of naloxone with all patients and consider prescribing it in persons who are at increased risk of opioid overdose, such as those who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental exposure or opioid overdose.

Nonparenteral fentanyl products are contraindicated for use in patients with acute or severe bronchial asthma (e.g., status asthmaticus) in an unmonitored setting or in the absence of resuscitative equipment. Fentanyl transdermal patches, lozenges, buccal tablets, and the iontophoretic transdermal system are contraindicated for use in patients with significant respiratory depression. Receipt of moderate doses in these patients may significantly decrease pulmonary ventilation. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant use of these drugs for patients in whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations possible and monitor patients closely for signs and symptoms of respiratory depression and sedation. In patients with pulmonary disease such as chronic lung disease (CLD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to fentanyl as even usual therapeutic doses of fentanyl may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with debilitation or sleep apnea are at an increased risk for the development of respiratory depression associated with fentanyl. Use with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in patients with CSA. Fentanyl should not be used during impaired consciousness or coma, as significant decreases in respiratory drive may lead to adverse intracranial effects from carbon dioxide retention. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Management of respiratory depression should include observation, necessary supportive measures, and opioid antagonist use when indicated. Much like the transdermal patch, patients experiencing adverse reactions with the iontophoretic transdermal fentanyl system require continued monitoring even after system removal due to gradually declining systemic drug concentrations. To avoid the potential for overdose, only the patient should activate iontophoretic transdermal fentanyl system dosing, and no more than 1 system should be applied at the same time. Although the use of transmucosal and transdermal fentanyl products is not common in the general pediatric population, these products are used off-label for certain patients with chronic pain and carry a serious risk of respiratory depression. Only healthcare professionals who are knowledgeable of the use of opioids for the management of chronic pain in children should prescribe transdermal or transmucosal fentanyl. Proper dosing and titration are essential. Monitor patients for respiratory depression, particularly during the first 24 to 72 hours after therapy initiation or a dose increase. Careful monitoring is required, particularly when CYP450 3A4 inhibitors or inducers are used concomitantly; concurrent use of a 3A4 inhibitor or discontinuation of a concurrently used 3A4 inducer may increase plasma fentanyl concentrations and potentiate the risk of fatal respiratory depression.

Most fentanyl products, with the exception of parenteral fentanyl and the iontophoretic transdermal system, are contraindicated in opioid-naive patients; as such, do not use these products in patients who require only short-term analgesia for postoperative or dental pain. However, patients who are taking fentanyl as part of ongoing analgesia therapy may be safely continued on the drug after surgery or dental work, if appropriate dosage adjustments are made considering the procedure, other drugs given, and temporary changes in physiology caused by the surgical intervention. Parenteral fentanyl is indicated for peri-operative use. The iontophoretic transdermal system (Ionsys) is specifically indicated for acute postoperative pain during hospitalization in adult patients. Monitor for decreased bowel motility in postoperative patients receiving opiate agonists.

Fentanyl and other opiate agonists can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with bladder obstruction, urethral stricture, pelvic malignancy, or renal disease. Drug accumulation or prolonged duration of action can occur in patients with renal impairment or renal failure and in those patients with hepatic disease. Although fentanyl kinetics are known to be altered as a result due to alterations in metabolic clearance and plasma protein binding, the duration of effect for the initial dose of fentanyl is largely determined by the rate of distribution of the drug. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver disease or renal impairment may require less frequent dosing intervals; titrate doses carefully and more slowly in patients with renal or hepatic impairment. Diminished metabolic clearance may become significant, especially with repeated dosing or with very high single doses. Avoid the use of fentanyl transdermal patches in patients with severe hepatic or renal impairment.

Use fentanyl with caution in patients with CNS depression, toxic psychosis, head trauma, intracranial mass, or increased intracranial pressure. Monitor for signs of drowsiness and depressed respirations, particularly when initiating fentanyl. Opioids may aggravate such conditions and alter neurologic parameters (e.g., level of consciousness, pupillary responses). Fentanyl-induced hypoventilation can produce cerebral hypoxia, carbon dioxide retention, and raise CSF pressure. Avoid the use of fentanyl in patients with impaired consciousness. Seizures can be precipitated by opioid agonists in patients with a preexisting seizure disorder, and fentanyl may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during fentanyl therapy.

In anesthesia and critical care, fentanyl is often preferred to morphine due to its ability to attenuate hemodynamic responses and maintain cardiac stability. Fentanyl causes minimal histamine release and therefore has a reduced incidence of hypotension when compared to morphine. However, fentanyl can cause bradycardia, peripheral vasodilation, and hypotension. As such, fentanyl should be used with caution in patients whose ability to maintain blood pressure has already been compromised by hypovolemia, or in those receiving phenothiazines or general anesthetics, which may alter the capacity to sustain adequate pressures. In addition, use fentanyl with caution in patients with circulatory shock as drug-induced vasodilation may further reduce cardiac output and blood pressure. Opiate agonists, including fentanyl, can stimulate a vasovagal response that may produce sinus bradycardia, which could be problematic in patients with angina, pre-existing hypotension, cardiac arrhythmias, cardiac disease, or heart failure. Use fentanyl with caution in patients with pre-existing orthostatic hypotension.

Neonates and infants younger than 6 months of age have highly variable clearance of opiate agonists. Therefore, infants younger than 6 months of age may be given opiate agonists but must be closely monitored for apnea until 24 hours after their last dose. Clinical practice guidelines suggest close monitoring of infants up to 1 year of age. Fentanyl clearance may correlate with gestational age and birth weight; premature neonates and neonates younger than 1 week of age may have significantly slower clearance than other populations. Careful monitoring and titration in small dosage increments is warranted.

The opiate agonist morphine is well recognized to increase the tone of the biliary tract causing spasms (especially in the sphincter of Oddi) and increasing biliary tract pressure. Biliary effects due to opiate agonists have resulted in plasma amylase and lipase concentrations up to 2 to 15 times the normal values. Fentanyl and meperidine, members of a different chemical group of opiates, are less likely to produce this effect. Nevertheless, fentanyl should be used with caution in patients with biliary tract disease, acute pancreatitis, or in those who are undergoing biliary tract surgery.

Do not abruptly discontinue fentanyl in patients who may be physically dependent on opioids. Abrupt discontinuation of fentanyl in physically opioid-dependent patients has resulted in serious withdrawal symptoms, uncontrolled pain, suicide, and drug-seeking behavior. Consider the opioid dose, duration of therapy, type of pain being treated, and physical and psychological attributes of the patient when decreasing the opioid dose or discontinuing therapy. Ensure ongoing care of the physically opioid-dependent patient, including a multimodal approach to pain management, and devise an appropriate tapering schedule and follow-up plan so that patient and provider goals are clear and realistic. When discontinuing therapy due to suspected substance abuse, evaluate and treat the patient or refer for evaluation and treatment of the substance abuse disorder. For physically opioid-dependent patients, decrease the fentanyl dose by no more than 25% of the total daily dose every 2 to 4 weeks. Patients who have been taking opioids for shorter periods of time may tolerate a more rapid taper. Reassess patients frequently to manage pain and withdrawal symptoms, if they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur. If withdrawal symptoms arise, pause the taper or increase the opioid dose to the previous dose, then proceed with a slower taper. Monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. Avoid use of partial agonists (e.g., buprenorphine), mixed agonists/antagonists (e.g., nalbuphine), or pure antagonists (e.g., naloxone) in patients physically dependent on opioids, as an acute withdrawal syndrome may precipitate. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the opioid antagonist. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, the use of partial agonists or mixed agonist/antagonists in patients who have received or are receiving opioid agonist analgesia may reduce the analgesic effects of fentanyl.

Advise any patient (or their caregiver) receiving an opiate agonist, such as fentanyl, about the possibility of sedation. Use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle or operating a vehicle or machinery).

Application of transdermal systems to areas of preexisting skin abrasion can subject the patient to an additional risk of local adverse effects and increased fentanyl exposure; transdermal systems are only for application to intact skin and should not be placed on abnormal skin sites (e.g., scars, burns, tattoos). Patients and caregivers should be advised to avoid exposing the fentanyl patch application site to direct external heat sources and conditions of ambient temperature increase (e.g., a heating pad, electric blanket, heated waterbed, heat or tanning lamp, sunbathing, hot baths, hot tubs, saunas). Application of heat over fentanyl transdermal patches worn by healthy adults increased fentanyl mean serum concentration (Cmax) by 61% and mean systemic exposure (AUC) by 120%. Fatal overdose attributable to heat exposure has occurred. Based on pharmacokinetic models, serum concentrations of fentanyl may increase by approximately one-third in patients with fever more than 104 degrees F (40 degrees C) due to both increased skin permeability and an increase in fentanyl release from the transdermal system. Patients with fever who are wearing fentanyl transdermal patches should be carefully monitored for increased side effects; dosage adjustments may be necessary. In addition, patients wearing transdermal patches should avoid strenuous exercise that may increase core body temperature.

In order to minimize risk of ocular exposure and/or unintended topical or mucous membrane exposure during the use or disposal of fentanyl transdermal patches, nasal spray, and transmucosal dosage forms advise patients and caregivers in correct administration technique and to wash hands after handling. Thoroughly rinse exposed area (e.g., skin, eyes) with water after any accidental exposure to avoid absorption and possibility of side effects; obtain medical attention should any adverse events develop.

Transmucosal (and/or sublingual) fentanyl products may be inappropriate for certain patients with mouth inflammation (mucous membrane stomatitis). Such products may worsen mucous membrane pain and oral inflammation. Although stomatitis has been reported among patients receiving fentanyl oral lozenges (Actiq), use was not specifically studied in patients with pre-existing mucositis or stomatitis. Compromised mucosal integrity may also increase fentanyl exposure; increased monitoring is warranted. The Actiq brand fentanyl oral lozenge contains approximately 2 grams of sugar per unit; frequent consumption of sugar-containing products may increase the risk of dental disease, especially dental caries. The occurrence of dry mouth associated with the use of opiate agonists, such as fentanyl, may add to the risk. Therefore, patients using these fentanyl oral lozenges should consult their dentist to ensure appropriate oral hygiene; patients with diabetes mellitus should be advised of the sugar content in each lozenge unit.

Because some fentanyl transdermal systems (i.e. patches) contain aluminum or other metal components, patients and caregivers should be instructed to remove the patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered.

Prolonged in utero exposure to fentanyl may lead to signs and symptoms of drug withdrawal in the newborn. Neonatal opioid withdrawal syndrome can be life-threatening if not recognized and treated; severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the exposed neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, excessive or high-pitched crying, tremor, vomiting, diarrhea, poor feeding, weight loss, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

Use fentanyl with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenocortical insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids and, if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

Description: Fentanyl is a potent synthetic opioid analgesic used for the relief of moderate to severe acute and chronic pain due to various etiologies. Intravenous fentanyl is used to aid induction and maintenance anesthesia and is commonly used as a component of sedation/analgesia regimens in critically ill pediatric patients. A 100 mcg intravenous dose is approximately equipotent to 10 mg of intravenous morphine. As compared with morphine or meperidine, fentanyl has a shorter duration of action and half-life. In pediatric anesthesia, fentanyl is preferred over morphine due to its lack of histamine release and therefore its ability to attenuate hemodynamic responses and maintain cardiac stability. Fentanyl is available in a variety of formulations that are not interchangeable on a mcg-to-mcg basis, even those administered via the same route, due to significant pharmacokinetic differences. Accidental exposure to fentanyl has resulted in fatality. More than half of the cases evaluated by the FDA have involved fentanyl transdermal patches and children under the age of 2 years, indicating the mobility and curiosity of a toddler may provide ample opportunity to find improperly stored or discarded patches. It is imperative that patients and caregivers are counseled appropriately about the risks, proper use, storage, and disposal of fentanyl dosage forms, particularly those that may contain high quantities and/or residual drug after use (e.g., patches, lozenges). While many fentanyl products are not FDA-approved for use in pediatric patients, both the solution for injection and transdermal patch carry indications for patients as young as 2 years of age.

General dosing information
-Individualize dosing for each patient; consider severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse. Use the lowest effective dose for the shortest duration consistent with individual treatment goals.
-Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours after initiation and dose escalation, and adjust the dosage accordingly. Continually reevaluate patients to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to monitor for the development of addiction, abuse, or misuse. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the opioid dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
-There is substantial interpatient variability in the relative potency of different opioid drugs and products. When adjusting fentanyl dosages or converting from another opioid agonist, it is better to underestimate the patient's daily dose requirements and give rescue doses than to risk an adverse event. If an adverse event occurs, the next dose may be reduced. Refer to the Opioid Agonists Drug Class Overview for approximate equianalgesic doses.
-When discontinuing fentanyl therapy in patients who are opioid-dependent, taper the dose gradually by 10% to 25% every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

Recommended initial Duragesic dose based on daily oral morphine dose:
NOTE: Do NOT use this table to convert from the fentanyl transdermal system to other opioid agonist therapy because this conversion to the transdermal system is conservative. Use of this table for conversion to other opioid agonists can overestimate the needed dose, leading to toxicity.
NOTE: An additional 37.5 mcg/hour transdermal system is available for use during conversion from prior opioids or dose titration.
-Morphine 60 to 134 mg/day PO: Initial transdermal dose 25 mcg/hour.
-Morphine 135 to 224 mg/day PO: Initial transdermal dose 50 mcg/hour.
-Morphine 225 to 314 mg/day PO: Initial transdermal dose 75 mcg/hour.
-Morphine 315 to 404 mg/day PO: Initial transdermal dose 100 mcg/hour.
-Morphine 405 to 494 mg/day PO: Initial transdermal dose 125 mcg/hour.
-Morphine 495 to 584 mg/day PO: Initial transdermal dose 150 mcg/hour.
-Morphine 585 to 674 mg/day PO: Initial transdermal dose 175 mcg/hour.
-Morphine 675 to 764 mg/day PO: Initial transdermal dose 200 mcg/hour.
-Morphine 765 to 854 mg/day PO: Initial transdermal dose 225 mcg/hour.
-Morphine 855 to 944 mg/day PO: Initial transdermal dose 250 mcg/hour.
-Morphine 945 to 1,034 mg/day PO: Initial transdermal dose 275 mcg/hour.
-Morphine 1,035 to 1,124 mg/day PO: Initial transdermal dose 300 mcg/hour.

For the treatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequate:
Intravenous or Intramuscular dosage:
Neonates*: 0.5 to 3 mcg/kg/dose IV every 2 to 4 hours as needed. Titrate dosage as needed to achieve adequate pain relief.
Infants* and Children 1 year*: 0.5 to 2 mcg/kg/dose IV or IM every 1 to 2 hours as needed. Procedural doses are generally given every 30 to 60 minutes as needed; doses up to 25 mcg may be repeated every 3 to 5 minutes as needed for up to 4 to 5 doses. In general, young children require higher doses (e.g., 2 to 3 mcg/kg/dose) than infants and older children. Titrate dosage as needed to achieve adequate pain relief.
Children and Adolescents 2 to 17 years*: 0.5 to 2 mcg/kg/dose (Max initial dose: 50 mcg/dose) IV or IM every 1 to 2 hours as needed. Procedural doses are generally given every 30 to 60 minutes as needed; doses up to 25 mcg may be repeated every 3 to 5 minutes as needed for up to 4 to 5 doses. In general, young children require higher doses (e.g., 2 to 3 mcg/kg/dose) than older children and adolescents. Titrate dosage as needed to achieve adequate pain relief.
Intranasal dosage*:
NOTE: The Lazanda nasal spray formulation has not been studied in pediatrics, and is indicated ONLY for opioid-tolerant adults. Pediatric studies have utilized the injectable solution for intranasal administration.
Children* and Adolescents*: 1.5 to 2 mcg/kg/dose (Max: 100 mcg/dose) intranasally; administer half of dose into each nare.
-for the treatment of persistent, severe pain that requires an extended treatment period with a daily opioid and for which alternative treatments are inadequate:
Transdermal dosage (e.g., Duragesic 72-hour transdermal patch):
Children and Adolescents 2 to 17 years: TO CONVERT OPIOID-TOLERANT PEDIATRIC PATIENTS FROM OTHER OPIATE AGONISTS TO FENTANYL TRANSDERMAL 72-HOUR SYSTEM: 1) Calculate the previous 24-hour opioid analgesic requirement; 2) Convert this amount to the equianalgesic oral morphine dose; 3) Consult the table in the FDA-approved product labeling for the recommended conversion to the corresponding transdermal fentanyl system dose. Initially, apply at minimum a 25 mcg/hour transdermal patch for patients receiving at least 60 mg/day oral morphine equivalents. Discontinue all other around-the-clock opioid drugs upon transdermal fentanyl initiation. Some experts suggest opioid-tolerant pediatric patients receiving 30 mg/day or more of oral morphine equivalents can be safely initiated on the 12.5 mcg/hour transdermal system. Open-label trials have started opioid-tolerant pediatric patients receiving 45 mg/day of oral morphine equivalents on a fentanyl transdermal system of 25 mcg/hour with a low incidence of adverse respiratory events. 4) Change patch system every 72 hours. DOSE TITRATION: If adequate analgesia is not achieved, may titrate the initial dosage upward after 3 days (72 hours); subsequent titrations should be made no more frequently than every 6 days. Breakthrough pain may require transdermal fentanyl dosage adjustment or rescue medication with an appropriately dosed immediate-release analgesic. Attempt to identify the source of increased pain before increasing the transdermal fentanyl dose. Appropriate transdermal system dosage adjustments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/day of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage. Change patch system every 72 hours; dosing intervals less than this are not recommended in children and adolescents. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. DISCONTINUATION: To convert to another opioid, remove the fentanyl transdermal system and titrate the dose of the new analgesic to adequate pain relief. Once the patch is removed, 17 hours or more are required for a 50% decrease in fentanyl concentrations. To discontinue the transdermal system when not converting to another opioid, gradually decrease the system dose by 50% every 6 days. Monitor patients for signs and symptoms of withdrawal. If signs and symptoms develop, resume the previous dose and taper more slowly. Do not discontinue abruptly.
-for the treatment of severe breakthrough pain in opioid-tolerant patients:
Transmucosal dosage (Actiq ONLY):
Adolescents 16 to 17 years: Initially, a single 200-mcg lozenge placed between the cheek and lower gum as needed for breakthrough pain. The unit should be sucked, not chewed, over a period of 15 minutes. If pain is not relieved within 15 minutes after complete consumption, may repeat dose once. Max: 2 lozenge units/breakthrough pain episode. Do not repeat additional dosing for at least 4 hours. Max: 4 lozenge units/day. An initial titration supply of only six 200-mcg lozenge units should be prescribed to limit the number of units in the home and decrease the potential for confusion and overdose. Patients/caregivers should only have 1 strength of lozenge available. If several consecutive breakthrough pain episodes require more than 1 unit for treatment, practitioners should increase the dose to the next available strength. Evaluate the new dose over 1 to 2 days to determine if adequate pain relief and acceptable side effects occur. Re-evaluate maintenance opioid therapy if the patient experiences more than 4 episodes/day of breakthrough pain once an appropriate breakthrough dose is determined. If respiratory depression or signs of excessive sedation occur before unit is completely consumed, immediately remove unit from the patient's mouth; subsequent doses should be decreased.

For analgesia and/or sedation maintenance* in mechanically-ventilated intensive care patients:
Intravenous dosage:
Neonates: 0.5 to 3 mcg/kg/dose IV every 30 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
Infants, Children, and Adolescents weighing less than 60 kg: 1 to 2 mcg/kg/dose IV every 30 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
Children and Adolescents weighing 60 kg or more: 50 to 100 mcg/dose IV every 30 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
Continuous Intravenous Infusion dosage:
Neonates: 0.5 to 2 mcg/kg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
Infants, Children, and Adolescents weighing less than 60 kg: 1 to 10 mcg/kg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
Children and Adolescents weighing 60 kg or more: 25 to 100 mcg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.

For general anesthesia induction and general anesthesia maintenance:
NOTE: The fentanyl dosage required to produce anesthesia varies considerably based on the surgical procedure, the use of adjuvant anesthesia, and the child's age. High-dose opioid anesthesia should be titrated slowly, balancing surgical stimulation, to prevent hypotension.
-for adjuvant management of general anesthesia induction and maintenance:
Intravenous or Intramuscular dosage:
Neonates*: Limited data available; 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient based on dosing data in children 2 to 12 years of age. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.
Infants* and Children younger than 2 years*: Limited data available; 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient based on dosing data in children 2 to 12 years of age. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. In general, young children require higher doses than infants. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.
Children 2 to 12 years: 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient per the manufacturer. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. In general, young children require higher doses than older children and adolescents. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.
Adolescentswho require a "low dose" for minor surgical procedures: 2 mcg/kg IV or IM as a total dose.
Adolescents who require a "moderate dose" for more major surgical procedures: 2 to 20 mcg/kg IV or IM as a total dose. Respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.
Adolescents who require a "high dose" for prolonged, complicated surgeries to limit stress response: 20 to 50 mcg/kg IV or IM as a total dose. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this dosing is to produce "stress free" anesthesia.
-for general anesthesia induction and maintenance when attenuation of the responses to surgical stress is especially important such as during major surgery like open heart surgery or complicated neurological or orthopedic procedures:
Intravenous or Intermuscular dosage:
Neonates*: Limited data available. Some experts describe fentanyl doses of 30 to 100 mcg/kg IV for cardiac surgery. Total doses of 50 to 100 mcg/kg IV or IM, administered with oxygen and a muscle relaxant but without the use of additional anesthetic agents may be sufficient based on dosing data in children 2 to 12 years of age. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.
Infants* and Children younger than 2 years*: Limited data available. Some experts describe fentanyl doses of 30 to 100 mcg/kg IV for cardiac surgery. Total doses of 50 to 100 mcg/kg IV or IM, administered with oxygen and a muscle relaxant but without the use of additional anesthetic agents may be sufficient based on dosing data in children 2 to 12 years of age. In general, young children require higher doses than infants. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.
Children and Adolescents 2 to 17 years: 50 to 100 mcg/kg IV or IM as a total dose may be administered with oxygen and muscle relaxant, without the use of additional anesthetic agents. In certain cases, total doses up to 150 mcg/kg may be necessary to produce adequate anesthetic effect. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression. In general, young children require higher doses than older children and adolescents.

For sedation and analgesia prior to rapid-sequence intubation (RSI)*:
Intravenous dosage:
Neonates: 1 to 4 mcg/kg IV over at least 1 to 2 minutes has been recommended.
Infants, Children, and Adolescents: 2 to 3 mcg/kg IV over 1 to 2 minutes is a typical dose; however, a dose range of 1 to 5 mcg/kg has been recommended. Give dose 1 to 3 minutes prior to intubation. In general, infants, older children, and adolescents require lower doses than young children.

For procedural sedation* of non-intubated patients during surgical or other procedures:
Intravenous dosage:
Infants less than 6 months: Safety and efficacy have not been established. May cause apnea and oversedation; not considered an ideal agent for young infants in this setting.
Infants and Children 6 months and older: 0.5 to 2 mcg/kg/dose IV (Max: 50 mcg/dose). May repeat in small increments (e.g., one-half of original dose, no more than 1 mcg/kg/dose) every 3 to 5 minutes as needed; titrate slowly to desired effect. Onset of analgesia is approximately 2 to 5 minutes, and the duration is about 20 to 60 minutes. Respiratory depressive effects usually outlast the opioid effects; close monitoring of ventilation is essential, particularly in younger patients. NOTE: Fentanyl should be administered as an inducing agent only by those trained in anesthesia.
Adolescents: 0.5 to 2 mcg/kg/dose IV (Max: 50 mcg/dose). May repeat in small increments (e.g., one-half of original dose, no more than 1 mcg/kg/dose) every 3 to 5 minutes as needed; titrate slowly to desired effect. Alternatively, a single dose of 25 to 50 mcg IV may be used. If needed, may repeat the full dose (up to 50 mcg) after 5 minutes. For particularly invasive/painful procedures (e.g., bone marrow aspiration), an additional 25 mcg may be given every 5 minutes for up to 4 to 5 additional doses if needed. Onset of analgesia is approximately 2 to 5 minutes with a duration of 20 to 60 minutes. Respiratory depressive effects usually outlast the opioid effects; close monitoring of ventilation is essential.
Intranasal dosage*:
Infants, Children, and Adolescents weighing 10 kg or more: Limited data available; most reports have been in patients weighing 10 kg or more. The injection solution was used for intranasal application as no commercially appropriate product is available. A single dose of 1 to 2 mcg/kg intranasally has been recommended. The usual maximum is 100 mcg/dose intranasally ; however, some experts recommend a maximum of 200 mcg/dose. Studies utilizing an initial dose of 1.4 mcg/kg allowed for additional doses of 15 mcg (0.2 to 1.2 mcg/kg/dose) administered every 5 minutes to a maximum total dose of 3 mcg/kg intranasally. Onset of analgesia is approximately 5 to 10 minutes with a duration of 30 minutes.

Maximum Dosage Limits:
-Neonates
With appropriate dosage titration, there is no maximum dose of intravenous fentanyl; the safety and efficacy of other dosage forms have not been established.
-Infants
With appropriate dosage titration, there is no maximum dose of intravenous fentanyl; the safety and efficacy of other dosage forms have not been established.
-Children
1 year : With appropriate dosage titration, there is no maximum dose of intravenous fentanyl; the safety and efficacy of other dosage forms have not been established.
2 to 12 years: With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl; the safety and efficacy of other dosage forms have not been established.
-Adolescents
13 to 15 years: With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl; the safety and efficacy of other dosage forms have not been established.
16 to 17 years: 4 units/day of fentanyl transmucosal lozenge (i.e., Actiq). With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl; the safety and efficacy of other dosage forms have not been established.

Patients with Hepatic Impairment Dosing
Transdermal patches: Avoid use in severe hepatic impairment. Reduce the initial transdermal dose by 50% in patients with mild to moderate hepatic impairment and titrate to desired clinical effect. Monitor closely for signs of respiratory and CNS depression, including at each dosage increase.
Other dosage forms: Fentanyl dosage should be modified based on clinical response and degree of hepatic impairment. No quantitative recommendations are available.

Patients with Renal Impairment Dosing
Transdermal patches: Avoid use in severe renal impairment. Reduce the initial transdermal dose by 50% in patients with mild to moderate renal impairment and titrate to desired clinical effect. Monitor closely for signs of respiratory and CNS depression, including at each dosage increase.
Other dosage forms: Fentanyl dosage should be modified based on clinical response and degree of renal impairment. No quantitative recommendations are available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Similar to morphine, fentanyl is a strong agonist at mu- and kappa-opiate receptors, which have been reclassified by an International Union of Pharmacology subcommittee as OP2 (kappa) and OP3 (mu). These receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase3 C (PLC)-inositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2).

Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (mu2-, delta-, kappa-receptors) and higher levels in the CNS (mu1- and kappa3 receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opioids close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (mu and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opioids decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.

The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms including differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.

The actions of fentanyl are similar to those of morphine, although fentanyl is much more lipophilic as compared to morphine (580:1) and has a more rapid onset of action. Clinically, stimulation of mu-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Opiate-induced respiratory depression is caused by direct action on respiratory centers in the brain stem. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention. Fentanyl exhibits little hypnotic activity and rarely stimulates histamine release. Bradycardia is due to medullary vasomotor center depression and vagal nucleus stimulation and may lead to decreased cardiac output. Myocardial contractility is not affected by fentanyl. Muscle rigidity of the chest and abdominal muscles is often seen with opiate agonist anesthesia. This effect may be due to opiate stimulation of spinal reflexes or interference with basal ganglia integration. When used as part of anesthesia, opiate agonists provide analgesic protection against hemodynamic responses to surgical stress by attenuating the catecholamine response.

Pharmacokinetics: Fentanyl is administered via transmucosal, parenteral, transdermal, and intranasal routes. Analgesic effects are related to the fentanyl blood concentration.

Fentanyl is 80 to 85% protein bound mainly to alpha-1-acid glycoprotein, but free fractions of the drug increase with acidosis. Fentanyl is highly lipophilic. It is rapidly distributed to the brain, heart, lungs, kidneys and spleen, with slower redistribution to skeletal muscle and fat where it is released slowly into the blood. Slow release of unchanged fentanyl from peripheral compartments into the blood may cause a rebound in serum fentanyl concentrations ("secondary peaks") even after drug discontinuation. In addition, alterations in pH may affect the drug's distribution into the central nervous system (CNS). Volume of distribution varies with age and is larger in neonates and young infants; mean Vd in adults is 4 L/kg (range 3 to 8 L/kg). Fentanyl is metabolized in the liver and intestinal mucosa via cytochrome P450 3A4 by oxidative N-dealkylation to norfentanyl (inactive metabolite). Approximately 75% of the administered dose is excreted in the urine, primarily as metabolites with less than 10% as unchanged drug. Less than 10% of the administered dose is recovered in the feces as metabolites.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4 and P-glycoprotein (P-gp)
Fentanyl is primarily metabolized by the CYP3A4 isoenzyme system. Concurrent administration of drugs that induce CYP3A4 may reduce the efficacy of fentanyl, and concurrent administration of drugs that inhibit CYP3A4 may increase fentanyl plasma concentrations, resulting in increased or prolonged adverse drug effects and potentially fatal respiratory depression. Fentanyl is also a substrate for P-glycoprotein.


-Route-Specific Pharmacokinetics
Oral Route
Transmucosal Route (e.g., Actiq)
If administered as directed, approximately 25% of the fentanyl transmucosal lozenge dose is rapidly absorbed from the buccal mucosa. The remaining 75% is swallowed with the saliva and is slowly absorbed from the gastrointestinal tract. About one-third of this amount (25% of the total dose) avoids hepatic first-pass elimination and becomes systemically available. Thus, absolute bioavailability is approximately 50%. If the lozenge is improperly administered (i.e., chewed and swallowed), lower peak serum concentrations result and pain may not be adequately controlled. Onset of analgesia occurs as early as 4 minutes after administration. Dose proportionality exists for 4 available dosage strengths of Actiq: 200 mcg, 400 mcg, 800 mcg, and 1600 mcg. In adult pharmacokinetic studies, the mean Cmax was 0.39 ng/mL, 0.75 ng/mL, 1.55 ng/mL, and 2.51 ng/mL, respectively. The mean AUC was 102 ng x minute/mL, 243 ng x minute/mL, 573 ng x minute/mL, and 1026 ng x minute/mL for each dosage form, respectively. Administration of the 200 mcg unit appears to have a longer Tmax and a shorter half-life compared to other dosage strengths. The median Tmax for the 200 mcg lozenge was 40 minutes after the start of administration, versus a mean of 20 to 25 minutes (range 20 to 480 minutes) with the higher dosage strengths. Mean half-life for the 200 mcg lozenge was 193 minutes, compared to 358 to 386 minutes with the higher dosage strengths. Duration of analgesia was 145 minutes for the 200 mcg unit and 215 minutes for the 800 mcg unit. In separate comparative studies of the transmucosal lozenge versus the buccal tablet (Fentora) and buccal film (Onsolis), the rate and extent of fentanyl absorption was greater with the latter buccal dosage forms. In addition, Tmax was longer in the lozenge arm.

Intravenous Route
After IV administration of fentanyl, peak analgesia occurs within minutes and lasts for 30 to 60 minutes after a single dose. Respiratory depressant effects persist longer than analgesic actions, and residual fentanyl from 1 dose can potentiate the effect of subsequent doses.

Intramuscular Route
After IM administration of fentanyl, onset of analgesia is within 7 to 8 minutes and lasts for 1 to 2 hours. Respiratory depressant effects persist longer than analgesic actions, and residual fentanyl from 1 dose can potentiate the effect of subsequent doses.

Topical Route
Transdermal Route (e.g., Duragesic)
Fentanyl is released from the drug-in-adhesive matrix patch at a nearly constant rate into the skin, where a depot of fentanyl accumulates in the upper epidermis. From this depot the drug is systemically absorbed. Onset of analgesia is 12 to 24 hours after initial application. Serum fentanyl concentrations gradually increase over the first 12 to 24 hours after application; concentrations remain relatively constant for the remainder of the 72-hour application period. Peak concentrations occur 20 to 72 hours after initial application. With sequential use, serum fentanyl concentrations reach steady state by the end of the second 72-hour patch application. After removal, serum fentanyl concentrations decrease slowly due to absorption of residual drug concentrations in the skin. The average half-life of fentanyl transdermal patch is 17 hours after patch removal; analgesia may persist for up to 12 hours after patch removal. Fentanyl does not appear to be metabolized in the skin, as 92% of a transdermal dose can be found unchanged in systemic circulation. Exposure to external heat sources (e.g., heating pads, saunas, hot tubs, sunbathing) may increase fentanyl absorption from the transdermal system. In a study of healthy adult patients, direct heat application over the patch increased mean fentanyl exposure by 120% and average fentanyl concentrations by 61%.

Other Route(s)
Intranasal Route (e.g., Lazanda)
Fentanyl bioavailability is more than 50% after administration of the fentanyl nasal spray ; more precisely, systemic bioavailability after nasal application has been reported to be as high as 71 to 89%. In addition, the nasal spray has a 20% greater bioavailability than that of a compared (unspecified) oral transmucosal product. Onset of analgesia is within 10 minutes. Time to maximum plasma concentration occurs 15 to 21 minutes after administration. AUC and Cmax values are linear over a dosing range of 100 to 800 mcg (100 mcg, 200 mcg, 400 mcg, and 800 mcg). During adult pharmacokinetic studies, the mean Cmax after administration of each dosage was 0.35 ng/mL, 0.78 ng/mL, 1.55 ng/mL, and 2.84 ng/mL, respectively. The mean AUC was 2.46 ng x hour/mL, 4.36 ng x hour/mL, 7.51 ng x hour/mL, and 17.27 ng x hour/mL for each dosage, respectively. Repeat dosing in the same nostril results in increased Cmax. As compared to the first dose Cmax, the second dose Cmax was 30% greater with a 1-hour dosing interval, 25% greater with a 2-hour interval, and 10% greater with a 4-hour interval. The median Tmax ranged from 0.25 to 0.35 hours. Mean half-life ranges from 15 to 25 hours. Analgesic effects persist for 30 to 60 minutes. Allergic rhinitis does not appear to affect the rate or extent of absorption.


-Special Populations
Pediatrics
Neonates
Maturational effects such as differences in Vd, hepatic blood flow rates, and liver enzyme activity may contribute to decreased clearance values in younger neonates. Neonates have a larger Vd as compared to adults and older children. Multiple studies have suggested plasma clearance in neonates may significantly correlate with gestational age and birth weight. In a study of 14 neonates undergoing major surgical procedures, reported fentanyl pharmacokinetic values were generally larger than those of older children and adults. Mean Vd reported was 5.1 L/kg (range 1.3 to 13.5 L/kg); reported Vd is 4 L/kg in adults. This increase in Vd suggests larger weight-based dosing is needed in neonates to achieve similar plasma concentrations. In addition, elimination half-life was prolonged. In the same study, mean plasma clearance was 18 mL/kg/min and elimination half-life was 5.3 hours. After long-term fentanyl infusion, prolonged redistribution of unchanged fentanyl from peripheral compartments into the blood suggests a larger Vd and prolonged elimination half-life. In a pharmacokinetic study of 7 neonates (mean gestational age 32 +/- 4 weeks; mean postnatal age 16 +/- 9 days) administered a continuous fentanyl infusion for at least 48 hours, Vd ranged from 10 to 30 L/kg and mean elimination half-life was 9.5 +/- 2.6 hours. Mean plasma clearance was 19.2 mL/kg/minute. Perhaps relevant to all age groups but of particular interest in the neonatal population, the elimination of fentanyl is decreased in the presence of intra-abdominal pressure, such as that which occurs during abdominal surgery. This decrease in elimination time may occur for a variety of reasons, including retention of fentanyl in a poorly perfused compartment and diminished hepatic blood flow.

Infants, Children, and Adolescents
After intravenous administration, the Vd in infants ranges from 2 to 4.5 L/kg, while values for young children range from 1.5 to 3 L/kg. Adult values (4 L/kg) are reached during adolescence. After long-term fentanyl infusion, prolonged redistribution of unchanged fentanyl from peripheral compartments into the blood suggests a larger Vd and prolonged elimination half-life. In a study of patients 0.05 to 14 years of age, mean Vd was 15 L/kg (range 5 to 30 L/kg) after continuous infusion for more than 24 hours (mean rate of infusion 3.6 mcg/kg/hour). Plasma clearance is higher in infants (18 to 30 mL/kg/minute) and young children (12 mL/kg/minute) compared to adults (8 mL/kg/minute). The elimination half-life of fentanyl is comparable to that of adults within the first months of life, reported as 1 to 4 hours for infants and 2.5 to 4 hours for young children, respectively. Patients 6 months to 6 years had a mean clearance of 18.9 mL/kg/minute, while patients younger than 6 months and older than 6 years of age had similar mean clearance rates of 8 mL/kg/minute and 8.2 mL/kg/minute, respectively. Mean terminal half-life was 21 hours (range 11 to 36 hours).

After fentanyl patch application, fentanyl plasma concentrations are approximately twice as high as adult values in non-opioid tolerant pediatric patients aged 1.5 to 5 years. Pharmacokinetic parameters in older pediatric patients are similar to that of adults.

Hepatic Impairment
Pharmacokinetic data are limited regarding the use of fentanyl in patients with hepatic impairment. Fentanyl is metabolized primarily via the hepatic-dependent cytochrome P450 system and therefore hepatic impairment is expected to have clinically significant effects on the drug's pharmacokinetics. In adult surgical patients with cirrhosis, the Cmax and AUC of the fentanyl transdermal patch increased by 35% and 73%, respectively, when compared to control patients; use in severe hepatic disease is not recommended. Initial dosage adjustments are recommended for transdermal use in mild to moderate hepatic impairment. Dose selection for patients with hepatic impairment should be cautious with use of other dose forms.

Renal Impairment
Pharmacokinetic data are limited regarding the use of fentanyl in patients with renal impairment. Fentanyl is primarily eliminated in the urine and therefore renal impairment is expected to have clinically significant effects on the drug's pharmacokinetics. An inverse relationship between the degree of azotemia and fentanyl clearance was noted in 8 patients with end-stage renal failure undergoing kidney transplantation who got intravenous fentanyl 25 mcg/kg prior to skin incision. The 2 patients with the highest blood urea nitrogen concentrations (108 mg/dL and 111 mg/dL, compared to 35 to 80 mg/dL in the other patients) had the lowest rate of clearance and were also the only patients to require postoperative mechanical ventilation. In patients with severe renal impairment, avoid transdermal use of fentanyl; lower initial transdermal dosing is recommended for patients with mild to moderate renal impairment. Cautious dose selection is recommended with the use of other dosage forms in patients with renal impairment.