General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

**REMS Drug**

Pronunciation:
fen-ta-nil

fentaNYL (buccal tablet)

Trade Name(s)

• Fentora

fentaNYL (oral transmucosal lozenge)

Trade Name(s)

• Actiq

fentaNYL (sublingual spray)

Trade Name(s)

• Subsys

Ther. Class.

opioid analgesics

Pharm. Class.

opioid agonists

Controlled Substance Schedule: II

Indications

Management of breakthrough pain in cancer patients >18 yr old already receiving opioids and tolerant to around-the-clock opioids for persistent cancer pain (60 mg/day of oral morphine or equivalent).

Action

Binds to opioid receptors in the CNS, altering the response to and perception of pain.

Therapeutic Effect(s):

Decrease in severity of breakthrough pain.

Pharmacokinetics

Absorption: Buccal tablet– 65% absorbed from buccal mucosa; 50% is absorbed transmucosally, remainder is swallowed and is absorbed slowly from the GI tract. Buccal absorption is enhanced by an effervescent reaction in the dose form;  Sublingual spray– 76% absorbed through sublingual mucosa;  Transmucosal lozenge– Initial rapid absorption (25%) from buccal mucosa is followed by more prolonged absorption (25%) from GI tract (combined bioavailability 50%).

Distribution: Readily crosses the placenta and enters breast milk.

Metabolism and Excretion: Mostly metabolized in the liver and intestinal mucosa via the CYP3A4 isoenzyme; inactive metabolites are excreted in urine; <7% excreted unchanged in urine.

Half-life: Buccal tablet– 2.6–11.7 hr (↑ with dose);  Sublingual spray– 5–12 hr;  Transmucosal lozenge– 7 hr.

TIME/ACTION PROFILE (↓ pain)

Contraindication/Precautions

Contraindicated in:

• Known intolerance or hypersensitivity;
• Acute/postoperative pain including headache/migraine, dental pain, or emergency room use;
• Opioid–naive (nontolerant) patients;
• Concurrent use of MAO inhibitors;
• OB:  Labor and delivery;
•  Lactation: Avoid use during breast feeding; may cause infant sedation and/or respiratory depression.

Use Cautiously in:

• Chronic obstructive pulmonary disease or pre-existing medical conditions predisposing to hypoventilation;
• Concurrent use of CNS active drugs;
• History of substance abuse;
• Severe renal/hepatic impairment (use lowest effective starting dose);
• Concurrent use of CYP3A4 inhibitors (use lowest effective dose);
• Bradyarrhythmias;
• OB:  Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic maternal treatment with opioids during pregnancy may result in neonatal abstinence syndrome;
• Pedi:  Safety and effectiveness not established in children;
• Geri:  Older adults may be more sensitive to effects and may have an ↑ risk of adverse reactions; titrate dosage carefully.

Exercise Extreme Caution in:

Patients susceptible to intracranial effects of CO₂  retention including those with ↑ intracranial pressure, head injuries, or impaired consciousness.

Adverse Reactions/Side Effects

CV: hypotension

Endo: adrenal insufficiency

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

Neuro: dizziness, drowsiness, headache, confusion, depression, fatigue, hallucinations, headache, insomnia, weakness

Resp: RESPIRATORY DEPRESSION (including central sleep apnea and sleep-related hypoxemia), dyspnea

Misc: allergic reaction including ANAPHYLAXIS, physical dependence, psychological dependence

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Should not be used within 14 days of  MAO inhibitors  because of possible severe and unpredictable reactions.
• Concurrent use of  CYP3A4 inhibitors  including  ritonavir,  ketoconazole,  itraconazole,  fluconazole,  clarithromycin,  erythromycin,  nefazodone,  diltiazem,  verapamil,  nelfinavir, and  fosamprenavir  ↑ levels and risk of opioid toxicity; careful monitoring during initiation, dose changes, or discontinuation of the inhibitor is recommended.
• Concurrent use with  CYP3A4 inducers  including  barbiturates,  carbamazepine,  efavirenz,  corticosteroids,  modafinil,  nevirapine,  oxcarbazepine,  phenobarbital,  phenytoin,  rifabutin, or  rifampin  may ↓ fentanyl levels and analgesia; if inducers are discontinued or dosage ↓, patients should be monitored for signs of opioid toxicity and necessary dose adjustments should be made.
• Use with  benzodiazepines  or other  CNS depressants  including other  opioids,  non-benzodiazepine sedative/hypnotics,  anxiolytics,  general anesthetics,  muscle relaxants,  antipsychotics, and  alcohol  may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
• Drugs that affect serotonergic neurotransmitter systems, including  tricyclic antidepressants,  SSRIs,  SNRIs,  MAO inhibitors,  TCAs,  tramadol,  trazodone,  mirtazapine,  5–HT₃  receptor antagonists,  linezolid,  methylene blue, and  triptans  ↑ risk of serotonin syndrome.

Drug-Natural Products:

 St. John's wort  is an inducer of CYP3A4; concurrent use may ↓ levels and analgesia; if inducers are discontinued or dosage decreased, patients should be monitored for signs of opioid toxicity and necessary dosage adjustments made.

Drug-Food:

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

Route/Dosage

Transmucosal products are not equivalent on a mcg-to-mcg basis.

Buccal:  (Adults): Tablets– 100 mcg, then titrate to dose that provides adequate analgesia without undue side effects.

 Oral transmucosal: (Adults): One 200-mcg unit dissolved in mouth (see Implementation section) over 15 min; additional unit may be used 15 min after first unit is completed. If more than 1 unit is required per episode (as evaluated over several episodes), dose may be ↑ as required to control pain. Optimal usage/titration should result in using no more than 4 units/day.

SL (Adults): Spray– 100 mcg initially; if pain not relieved within 30 min, repeat 100-mcg dose (do not take more than 2 doses per breakthrough pain episode); patients must wait ≥4 hr before treating another episode of breakthrough pain. Dose may be titrated during subsequent pain episodes to 200 mcg, then 400 mcg, then 600 mcg, then 800 mcg, then 1200 mcg, and then 1600 mcg to provide adequate analgesia and undue side effects.

Availability (generic available)

Buccal tablets: 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg

Cost: 200 mcg $1,006.04/28

Oral transmucosal lozenge on a stick (berry flavor-sugar free): 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg

Cost:

Generic: 400 mcg $599.93/30, 1200 mcg $799.93/30, 1600 mcg $1,155.89/30

Sublingual spray: 100 mcg/spray, 200 mcg/spray, 400 mcg/spray, 600 mcg/spray, 800 mcg/spray

Assessment

• Monitor type, location, and intensity of pain before and 1 hr after administration of transmucosal fentanyl.
• Assess BP, pulse, and respirations before and periodically during administration, especially when starting therapy or when given with other drugs that depress respiration. May cause sleep-related breathing disorders (central sleep apnea, sleep-related hypoxemia). If respiratory rate is <10 min, assess level of sedation. Physical stimulation may be sufficient to prevent hypoventilation. Subsequent doses may need to be decreased. Patients tolerant to opioid analgesics are usually tolerant to the respiratory depressant effects also. Monitor for respiratory depression; serious, life-threatening, or fatal respiratory depression may occur.
• Monitor for application site reactions (paresthesia, ulceration, bleeding, pain, ulcer, irritation). Reactions are usually self-limited and rarely require discontinuation.
• Assess risk for opioid addiction, abuse, or misuse prior to administration.

Lab Test Considerations:

May cause anemia, neutropenia, thrombocytopenia, and leukopenia.

• May cause hypokalemia, hypoalbuminemia, hypercalcemia, hypomagnesemia, and hyponatremia.

Toxicity and Overdose:

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For patients weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg every 2 min. Use extreme caution when titrating dose in patients physically dependent on opioid analgesics to avoid withdrawal, seizures, and severe pain. Duration of respiratory depression may be longer than duration of opioid antagonist, requiring repeated doses.

Implementation

• High Alert: Accidental overdose of opioid analgesics has resulted in fatalities. Before administering, clarify all ambiguous orders.
• Do not confuse fentanyl with sufentanil.

• Patients considered opioid-tolerant are those who are taking ≥60 mg of oral morphine/day, at least 25 mcg transdermal fentanyl/hr, 30 mg of oxycodone/day, 8 mg of hydromorphone/day or an equianalgesic dose of another opioid for ≥1 wk.

  • High Alert: Dose may be lethal to a child; keep out of reach of children.
  • Do not substitute fentanyl products; doses are not equivalent.
• For patients no longer requiring opioid therapy, consider discontinuing, along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain, but no longer require treatment for breakthrough pain, therapy can usually be discontinued immediately.
• Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.
•  REMS: Health care professionals who prescribe transmucosal immediate-release fentanyl (TIRF) medicines for outpatient use are required to enroll in the TIRF REMS Access program. Health care professionals already enrolled in an individual Risk Evaluation and Mitigation Strategy (REMS) program for at least one TIRF medicine, will be automatically transitioned to the shared TIRF REMS Access program, and do not need to re-enroll. Enrollment renewal in TIRF REMS program is required every 2 yr from the date of enrollment. Information can be found at www.TIRFREMSaccess.com. A TIRF REMS Access Patient-Prescriber Agreement Form must be signed with each new patient before writing the patient's first TIRF prescription and health care professionals must also provide patients with a copy of the  Medication Guide  during counseling about the proper use of their TIRF medicine. Pharmacists who dispense TIRF medicines are also required to enroll in the TIRF REMS program and re-enroll every 2 yr. Patients are enrolled in the TIRF REMS Access program by the pharmacy at the time their first prescription is filled. Patients can locate a participating pharmacy by consulting their prescriber or calling the TIRF REMS Access program at 1-866-822-1483.
• Buccal:  

    Fentora : Do not attempt to push tablet through blister, may cause damage to tablet. Open by tearing along perforations to separate from blister card. Then bend blister unit on line where indicated. Blister backing should then be peeled to expose tablets. Use immediately; do not store, may damage integrity of tablet. Tablets are not to be sucked, chewed, or swallowed whole; this will reduce medication effectiveness. Place between cheek and gum above a molar or under tongue and allow medication to dissolve, usually 14–25 min. May cause bubbling sensation between teeth and gum while tablet dissolves. Do not attempt to split tablet. After 30 min, if remnants of tablet remain, swallow with glass of water.

  • For patients not previously using transmucosal fentanyl, initial dose should be 100 mcg. Titrate to provide adequate relief while minimizing side effects. For patients switching from oral transmucosal fentanyl to fentanyl buccal, if transmucosal dose is 200–400 mcg, switch to 100 mcg buccal; if transmucosal dose is 600–800 mcg, switch to 200 mcg buccal; if transmucosal dose is 1200–1600 mcg, switch to 400 mcg buccal fentanyl.
  • Dose may be repeated once during a single episode of breakthrough pain if not adequately relieved. Re-dose may occur 30 min after start of administration of fentanyl buccal and the same dose should be used.
  • If more than 1 dose is required per breakthrough pain episode for several consecutive episodes, dose of maintenance opioid and fentanyl buccal tablets should be adjusted. To increase dose, use multiples of 100 mcg tablet, use two 100-mcg tablets (1 on each side of mouth in buccal cavity). If unsuccessful in controlling breakthrough pain episode, two 100-mcg tablets may be placed on each side of mouth in buccal cavity (four 100-mcg tablets). Titrate above 400 mcg by 200 mcg increments. To reduce risk of overdose, patients should have only one strength available at any one time.
  • Once a successful dose has been established, instruct patient to use only one dose for each breakthrough episode; if pain is not relieved in 30 min after completion, only one additional use of the same strength can be used for that episode. Instruct patient to wait 4 hr before treating another episode of breakthrough pain. If more than 4 breakthrough pain episodes/day occur, re-evaluate opioid dose for persistent pain.
  • Inform patient if medication is no longer needed they should contact Teva Pharmaceuticals at 1-888-483-8279 or remove from blister pack and flush any remaining product down toilet.
• Transmucosal: Actiq:

  Open the foil package immediately before use. Instruct patient to place unit in the mouth between the cheek and lower gum, moving it from one side to the other using the handle. Patient should suck, not chew, the lozenge. If it is chewed and swallowed, lower peak concentrations and lower bioavailability may occur. Instruct patient to consume lozenge over 15-min period; longer or shorter periods may be less efficacious. If signs of excessive opioid effects occur, remove from patient's mouth immediately and decrease future doses.

  • Initial dose for breakthrough pain should be 200 mcg. Six 200-mcg units should be prescribed and should be used before increasing to a higher dose. If one unit is ineffective, a 2nd unit may be started 15 min after the completion of the first unit. Do not use more than 2 units during a single episode of breakthrough pain during titration phase. With each new dose during titration, 6 units should be prescribed, allowing treatment of several episodes of breakthrough pain. Adequate dose is determined based on effective analgesia with acceptable side effects. Side effects during titration period are usually greater than after effective dose is determined.
  • Once an effective dose is determined, instruct patient to use only one  Actiq  unit for each breakthrough episode; if pain is not relieved in 15 min after completion, only one additional use of the same strength can be used for that episode. Instruct patient to wait 4 hr before treating another episode of breakthrough pain.
  • Discontinue with a gradual decrease in dose to prevent signs and symptoms of abrupt withdrawal.
  • To dispose of remaining unit, using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet. Flush remaining drug matrix down toilet. Drug remaining on handle may be removed by placing under running warm water until dissolved. Dispose of drug-free handle according to institutional protocol. High Alert: Partially consumed units are no longer protected by child-resistant pouch; dose may still be fatal. A temporary child-resistant storage bottle is provided for partially consumed units that cannot be disposed of properly.
• SL 

   Subsys: Assess for mucositis before administering  Subsys.  For patients with Grade 1 mucositis,  increased serum concentration and exposure may increase risk of respiratory depression. Monitor closely for respiratory depression and central nervous system depression.  For patients with ≥Grade 2 mucositis,  avoid use of  Subsys  unless the benefits outweigh the potential risk of respiratory depression from increased exposure.

  • Dose must start with 100 mcg initially, titrate to adequate pain relief; if initial dose is adequate, this will be the dose for subsequent breakthrough pain; if dose is inadequate within 30 min give supplemental 100-mcg dose and ↑ next breakthrough dose by 100 mcg; if inadequate continue to ↑ breakthrough dose to 400, then 600 mcg, then 800 mcg, then 1600 mcg.
  • If inadequate analgesia after first dose, a 2nd dose may be used after 30 min. No more than 2 doses may be used to treat an episode of breakthrough pain. Episodes should be separated by at least 4 hr. Other rescue medications may be used as directed.
  • Spray contents under tongue. Follow instructions in  Medication Guide.
  • Before you throw away the  Subsys  spray units, empty all of medicine (up to 10 spray units) into charcoal-lined disposal pouch provided with each dose. Put nozzle of spray unit upside-down into opening of charcoal-lined disposal pouch. Squeeze fingers and thumb together to spray into the charcoal lined disposal pouch. Place empty spray unit into pouch. To seal used charcoal-lined disposal pouch, remove backing from adhesive strip. Fold the flap down and press to seal charcoal-lined disposal pouch. Place sealed charcoal-lined disposal pouch into a disposal bag and seal. Discard sealed disposal bag in trash out of reach of children. This protects others, especially children from harm. Follow instructions for use of disposal pouch in  Medication Guide  and  Instructions for Use.

Patient/Family Teaching

• Instruct patient to take fentanyl transmucosal as directed. Instruct patient in correct technique for use and disposal. Do not take more often than prescribed, keep out of reach of children, protect it from being stolen, and do not share with others, even if they have the same symptoms. Open only when ready to administer. Advise patient to review  Medication Guide  before and with each Rx refill; new information may be available. Advise patient to notify health care professional if breakthrough pain is not alleviated, worsens, if >4 units/day are required to control pain, or if excessive opioid effects occur.
•  REMS: Explain TIRF REMS program to patient and caregiver. Patients must sign the Patient-Prescriber Agreement Form to confirm they understand the risks, appropriate use, and storage of fentanyl transmucosal.
• Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (by prescription, directly from a pharmacist, or as part of a community-based program).
• Advise patient to avoid grapefruit juice during therapy.
• Caution patient to make position changes slowly to minimize orthostatic hypotension.
• Medication causes dizziness and drowsiness. Advise patient to call for assistance during ambulation and transfer, and to avoid driving or other activities requiring alertness until response to medication is known.
• Instruct patient to avoid concurrent use of alcohol or other CNS depressants, such as sleep aids.
• Advise patient to notify health care professional if sores on gums or inside cheek become a problem.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
• Rep:  Instruct females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breast feeding during therapy. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Chronic use may reduce fertility in females and males.
• Actiq: Inform patient that this drug may contain sugar and may cause dry mouth. Advise patient to maintain good oral hygiene regular dental exams.

Evaluation/Desired Outcomes

Decrease in severity of pain during episodes of breakthrough pain in patients receiving and tolerant to long-acting opioids.