fentanyl (transmucosal)

FEN-ta-nil

Therapeutic Classification: opioid analgesics

Pharmacologic Classification: opioid agonists

High Alert

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

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

Therapeutic effects:

Decrease in severity of breakthrough pain.

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; Transmucosal lozenge: Initial rapid absorption (25%) from buccal mucosa is followed by more prolonged absorption (25%) from GI tract (combined bioavailability 50%).

Distribution: Widely distributed to tissues.

Metabolism/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); Transmucosal lozenge: 7 hr.

(analgesia)

ROUTE	ONSET	PEAK	DURATION
Buccal tablet	15 min	40–60 min	60 min
Transmucosal lozenge	rapid	15–30 min	several hr

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: Lactation.

Use Cautiously in:

Personal or family history of substance use disorder or mental illness;
Chronic obstructive pulmonary disease or pre-existing medical conditions predisposing to hypoventilation;
Concurrent use of CNS active drugs;
Severe renal/hepatic impairment (use lowest effective starting dose);
Bradyarrhythmias;
OB: Use during pregnancy only if the potential maternal benefit justifies the potential fetal risk;
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.

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

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: dyspnea, RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA)

Misc: allodynia, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), opioid-induced hyperalgesia, physical dependence, psychological dependence

Drug-drug:

Should not be used within 14 days of MAO inhibitors because of possible severe and unpredictable reactions.
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.
CYP3A4 inducers, including barbiturates, carbamazepine, efavirenz, corticosteroids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, or rifampin, may ↓ 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, nonbenzodiazepine 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 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.

Grapefuit juice may ↑ levels and the risk of CNS and respiratory depression. Careful monitoring and dose adjustment may be necessary.

Transmucosal products are not equivalent on a mcg-to-mcg basis.
(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 1st 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.

(Generic available)

Buccal tablets: 100 mcg; 200 mcg; 400 mcg; 600 mcg; 800 mcg
Oral transmucosal lozenge on a stickberry flavor, sugar-free: 200 mcg; 400 mcg; 600 mcg; 800 mcg; 1200 mcg; 1600 mcg

Monitor type, location, and intensity of pain before and 1 hr after administration of transmucosal fentanyl.
Assess for opioid-induced hyperalgesia, which can appear as ↑ levels of pain upon increasing the dose of the opioid, ↓ levels of pain upon decreasing the dose of the opioid, or pain from ordinarily nonpainful stimuli (allodynia). This condition is different from tolerance. If a patient is suspected to be experiencing opioid-induced hyperalgesia, consider ↓ the dose of the current opioid or switching to a different opioid analgesic.
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 <10 min, assess level of sedation. Physical stimulation may be sufficient to prevent hypoventilation. Subsequent doses may need to be ↓. 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.

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.
- 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.
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.
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. Redose 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 ↑ 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 ↓ 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 four 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 ↓ 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 1 unit is ineffective, a 2nd unit may be started 15 min after the completion of the 1st 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 ↓ 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.
  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.

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 in case of changes. 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.
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.
Advise patient that transmucosal fentanyl is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children and in a location not accessible by others.
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 breastfeeding during therapy. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Chronic use may 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 and regular dental exams.

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

fentaNYL (buccal tablet): Fentora,

fentaNYL (oral transmucosal lozenge): Actiq

Schedule II (C-II)

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆ ⬇

Contr. Subst. Schedule ⬆