Fentanyl

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

Serious, life-threatening, or fatal respiratory depression may occur, including following use in opioid non-tolerant patients and improper dosing. Monitor closely for respiratory depression, especially during initiation or dose escalation. Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis, or Subsys should only be prescribed for opioid-tolerant patients. Risk of respiratory depression usually occurs after administration of initial dose in nontolerant patients or when given with other drugs that depress respiratory function. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

May occur with concomitant use of serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs), lithium, St John’s wort, agents that impair metabolism of serotonin (eg, MAO inhibitors), or agents that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors). Monitor patients for symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma); autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia); neuromuscular changes (eg, hyperreflexia, incoordination); and/or GI symptoms (eg, nausea, vomiting, diarrhea). Disease-related concerns:

May obscure diagnosis or clinical course of patients with acute abdominal conditions.

Use with caution in patients with adrenal insufficiency, including Addison's disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan, 2013).

Intranasal: Allergic rhinitis is not expected to alter fentanyl absorption following nasal administration; however, use of nasal decongestants (eg, oxymetazoline) during episodes of rhinitis may result in lower peak concentrations and delayed Tmax, therefore, titration of intranasal fentanyl is not recommended during use of nasal decongestants.

Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

Use with caution in patients with bradycardia or bradyarrhythmias (may produce further bradycardia).

Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

Use with caution in patients with delirium tremens.

Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.

Use with caution in patients with hepatic impairment. Avoid transdermal (patch) in patients with severe hepatic impairment.

Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

Use with caution in patients who are morbidly obese.

Sublingual spray (Subsys): Cancer patients with oral mucositis experienced increased fentanyl exposure following sublingual spray administration; avoid use in patients with grade 2 or higher mucositis; use with caution in patients with grade 1 mucositis, and closely monitor for respiratory and CNS depression.

Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

Use with caution in patients with toxic psychosis.

Use with caution in patients with renal impairment. Avoid transdermal (patch) in patients with severe renal impairment.

Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

Use with caution in patients with a history of seizure disorders; may cause or exacerbate seizures.

Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

Use with caution in patients with thyroid dysfunction. Concurrent drug therapy issues:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of oxycodone/acetaminophen and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

The concomitant use of fentanyl with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl and any CYP3A4 inhibitor or inducer.

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Buccal film, buccal tablet, intranasal, sublingual tablet, sublingual spray, and lozenge: [US Boxed Warning]: Preparations contain an amount of medication that can be fatal to children. Keep all used and unused products out of the reach of children at all times and discard products properly. Patients and caregivers should be counseled on the dangers to children including the risk of exposure to partially-consumed products. Dosage form specific issues:

IV: Inject slowly over 1 to 2 minutes; rapid IV infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest; nondepolarizing skeletal muscle relaxant may be required.

- [US Boxed Warning]: Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Ionsys REMS Program. Healthcare facilities that dispense Ionsys must be certified in this program and comply with the REMS requirements. - [US Boxed Warning]: For use only in patients in the hospital. Discontinue treatment before patients leave the hospital. Only the patient should activate Ionsys dosing. Accidental exposure to an intact Ionsys device or to the hydrogel component, especially by children, can result in a fatal overdose of fentanyl. Following accidental contact with the device or its components, immediately rinse the affected area thoroughly with water. Do not use soap, alcohol, or other solvent because they may enhance the drug’s ability to penetrate the skin; monitor for signs of respiratory or CNS depression. If the device is not handled correctly using gloves, healthcare professionals are at risk of accidental exposure to a fatal overdose of fentanyl. - Ionsys device is considered magnetic resonance unsafe. The device contains metal parts and must be removed and properly disposed of before an MRI procedure to avoid injury to the patient and damage to device. It is unknown if exposure to an MRI procedure increases release of fentanyl from the device. Monitor any patients wearing the device with inadvertent exposure to an MRI for signs of CNS and respiratory depression. - Use of Ionsys device during cardioversion, defibrillation,

- [US Boxed Warning]: Transdermal patch is contraindicated for use as an as-needed analgesic, in acute or postoperative pain, or in patients who are opioid nontolerant. Monitor closely for respiratory depression during use, particularly during initiation of therapy or after dose increases. Should only be prescribed by health care professionals who are knowledgeable in the use of potent opioids in the management of chronic pain. - [US Boxed Warning]: Exposure of application site and surrounding area to direct external heat sources (eg, heating pads, electric blankets, heat or tanning lamps, sunbathing, hot baths, hot tubs, heated water beds, saunas) may increase fentanyl absorption and has resulted in fatalities. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources. Serum fentanyl concentrations may increase by approximately one-third for patients with a body temperature of 40°C (104°F) secondary to a temperature-dependent increase in fentanyl release from the patch and increased skin permeability. - [US Boxed Warning]: Deaths due to a fatal overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal patch. Strict adherence to recommended handling and disposal instructions is necessary to prevent accidental exposures. Avoid unclothed/unwashed application site exposure, inadvertent person-to-person patch transfer (eg, while hugging), incidental exposure (eg, sharing same bed,

Use exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing fentanyl and monitor all patients regularly for the development of these behaviors and conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

Accidental ingestion of even one dose, especially by children, can result in a fatal overdose of fentanyl. Fentanyl must be kept out of reach of children.

Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully just

An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms. Taper dose gradually when discontinuing.