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Criteria for Outpatient Use Guidelines

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Fentanyl Oral Transmucosal Lozenges (Actiq®) and Buccal Tablets (Fentora®)

[Developed, February 2003; Revised, January 2006, July 2007, July 2010]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults1-12
Fentanyl citrate oral transmucosal lozenges, buccal tablets, and buccal films are FDA-approved for the management of breakthrough cancer pain in patients 18 and older that are already receiving and are tolerant to opioid therapy for persistent cancer pain. Patients are considered opioid tolerant if they are taking around-the-clock opioids consisting of at least 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl/hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer. Fentanyl citrate transmucosal lozenges (Actiq®) are available as 200, 400, 600, 800, 1200, 1400, and 1600 mcg transmucosal lozenges. Fentanyl citrate buccal tablets (Fentora®) are available as 100, 200, 300, 400, 600, and 800 mcg buccal tablets. Fentanyl buccal soluble films (Onsolis®) are available as 200, 400, 600, 800, and 1200 mcg buccal films, but are obtained only through a restricted distribution program, the FOCUS program, in which only physicians, pharmacists and patients who have registered for the program can prescribe, dispense, and obtain fentanyl buccal films.

Due to pharmacokinetic differences between oral transmucosal and buccal fentanyl citrate formulations, these products are not interchangeable on a mcg per mcg basis and should not be substituted on a mcg for mcg basis as enhanced or attenuated pharmacologic effects could occur. Dosage conversions between fentanyl oral transmucosal lozenges and buccal tablets are summarized in Table 1.

Table 1
Dosage Conversions for Fentanyl Oral Transmucosal Lozenges and Fentanyl Buccal Tablets
Current Fentanyl Oral Transmucosal Lozenge Dose (mcg) Initial Fentanyl Buccal Tablet Dose (mcg)
200 100
400 100
600 200
800 200
1200 400
1600 400

Patients receiving fentanyl oral transmucosal lozenges for breakthrough pain are prescribed an initial dose of 200 mcg with instructions to allow the lozenge to dissolve over 15 minutes as the product is not designed to be chewed. Until the appropriate dose is reached, patients may find it necessary to use an additional oral transmucosal unit during a single episode. Redosing may start 30 minutes after the start of the previous unit. During the titration phase, no more than two units should be administered for each individual cancer breakthrough pain episode. To limit the number of units during the titration period, patients should be prescribed a maximum supply of six 200 mcg fentanyl oral transmucosal lozenges. At each new dose of oral transmucosal lozenge required by a patient, it is recommended that no more than six units of the titration dose be prescribed. Once a successful dose is identified for a patient, the quantity of lozenges utilized by a patient should be limited to 4 or fewer units per day. If consumption increases to greater than 4 units per day, the dose of the lozenge should be re-evaluated. To discontinue use of fentanyl oral transmucosal lozenges, a downward titration is recommended as the opioid level at which signs and symptoms of abrupt withdrawal will occur is not known.

Patients prescribed fentanyl buccal tablets for breakthrough pain should begin therapy with an initial dose of 100 mcg. The tablet is placed in the buccal cavity (the space between the upper cheek and rear molar) and allowed to dissolve completely over a period of 30 minutes. If there are any tablet pieces remaining after 30 minutes, the patient may swallow them with a glass of water. The same dosage strength may be repeated once during a breakthrough pain episode, administered no sooner than 30 minutes after initiating buccal fentanyl tablet therapy, if pain is not relieved by the first buccal tablet dose. The fentanyl buccal tablet dose should be increased in patients requiring greater than one breakthrough dose for several consecutive episodes. Patients requiring fentanyl buccal tablet doses higher than 100 mcg should be titrated in multiples of 100 mcg. Patients may receive up to four 100 mcg tablets at one time placed on each side of the mouth in each buccal cavity (2 tablets per side). Fentanyl buccal tablet dosages greater than 400 mcg should be titrated in 200 mcg increments. Doses should be titrated to achieve adequate analgesia with acceptable side effects. Patients should receive only one buccal tablet dosage strength at a time to minimize confusion and the possibility of overdose. If more than four breakthrough pain episodes happen per day, the maintenance fentanyl buccal tablet dosage scheme should be re-evaluated.

Therapy with fentanyl buccal films for breakthrough pain should be initiated with one 200 mcg buccal film placed on a wetted area inside the cheek. If pain relief does not occur with one 200 mcg buccal film, the dose may be titrate upward in multiples of 200 mcg until a dose is reached that provides the patient with adequate analgesia. When multiple 200 mcg films are used concurrently, they should not be placed on top of one another and may be applied to both sides of the mouth. No more than four 200 mcg buccal films should be administered simultaneously. If the patient tolerates the 800 mcg dose but pain relief is not achieved with this dose (4 x 200 mcg films), the next breakthrough episode can be treated with one 1200 mcg buccal film. Fentanyl buccal film doses should not exceed 1200 mcg per dose or four doses per day. Fentanyl buccal films should only be utilized once during a breakthrough pain episode; single doses should be separated by at least 2 hours. When an adequate fentanyl buccal film dose has been determined, the patient should receive a prescription for the effective dosage strength and use or dispose of the remaining unused 200 mcg films. Fentanyl buccal films should not be torn or cut prior to use and will dissolve within 15 to 30 minutes following application.

The lowest effective fentanyl oral transmucosal or buccal dose should be administered to patients with renal or hepatic dysfunction, as well as those patients receiving CYP3A4 inhibitor drugs concurrently.

Patient profiles containing prescriptions for greater than 4 units of fentanyl oral transmucosal lozenges per day during a maintenance phase or 6 units of fentanyl oral transmucosal lozenges during a transition phase will be reviewed. Patient profiles containing prescriptions for more than one strength of fentanyl buccal tablets concurrently for greater than two months will be reviewed. Patient profiles containing prescriptions for greater than four doses per day of fentanyl buccal films and/or more than one strength of fentanyl buccal films concurrently for greater than two months will be reviewed.

Although not FDA-approved, a few small studies have evaluated oral transmucosal fentanyl lozenge use for migraine headache pain management refractory to conventional treatment in patients with a history of parenteral opioid use in the Emergency Department (ED). These studies found the drug to be effective in reducing pain intensity scores and number of ED visits.13, 14

2. Duration of Therapy

Therapy duration for fentanyl oral transmucosal lozenges, fentanyl buccal tablets, and fentanyl buccal films is limited to the need for pain management in patients with cancer already receiving opioids and tolerant to opioid therapy.

3.* Duplicative Therapy

Concurrent therapy with fentanyl oral transmucosal lozenges, buccal tablets, or buccal films and other forms of fentanyl as well as other CNS depressants should be prescribed cautiously.  Patients should be monitored for signs of respiratory depression as well as excessive sedation.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

Drug-drug interactions considered clinically relevant for fentanyl are summarized in Table 2.  Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Table 2
Fentanyl Citrate Drug-Drug Interactions2, 3, 5-8, 24-28
Interacting Drug Interaction Recommendation Clinical Significance
Beta blockers (e.g., atenolol, metoprolol, propranolol) concomitant use may cause severe hypotension due to additive blood pressure-lowering effects cautiously administer concurrently; closely monitor blood pressure major (DrugReax)
2-major (Clinical Pharmacology)
Calcium channel blockers (e.g., amlodipine, nifedipine, verapamil) concomitant use may cause severe hypotension due to additive blood pressure-lowering effects cautiously administer concurrently; closely monitor blood pressure major (DrugReax)
2-major (Clinical Pharmacology)
Amiodarone concurrent use may result in cardiac toxicity (e.g., bradycardia, low cardiac output) and increased risk of fentanyl toxicity (e.g., respiratory and CNS depression) as amiodarone inhibits CYP3A4 if combination utilized, monitor patients closely for enhanced pharmacologic/toxic effects major (DrugReax)
3-moderate (Clinical Pharmacology)
1 (DIF)
CNS depressants (e.g., skeletal muscle relaxants,  haloperidol, other opioids) potential for additive CNS effects, including respiratory depression, excessive sedation or coma use cautiously together; modify fentanyl doses as necessary and observe patients for enhanced CNS adverse effects major (DrugReax)
2-major (Clinical Pharmacology)
CYP+ 3A4 inducers (e.g., rifampin, barbiturates, carbamazepine, phenytoin, aprepitant, efavirenz) may increase fentanyl clearance and reduce fentanyl systemic concentrations leading to decrease effectiveness as fentanyl is a CYP3A4 substrate monitor fentanyl efficacy in patients prescribed CYP3A4 inducers concurrently; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen moderate (DrugReax)
2-major (Clinical Pharmacology)
2 (DIF)
CYP+ 3A4 inhibitors (e.g., aprepitant, protease inhibitors, macrolides, azole antifungals, efavirenz) may decrease fentanyl clearance and increase fentanyl systemic concentrations leading to potential for enhanced pharmacologic/toxic effects as fentanyl is a CYP3A4 substrate monitor for enhanced fentanyl pharmacologic/toxic effects and adjust doses as necessary major (DrugReax)
2-major (Clinical Pharmacology)
1 (DIF)
MAOIs* (e.g., phenelzine, procarbazine, linezolid) concurrent administration may potentiate severe, unpredictable opioid effects including CNS depression and hypotension fentanyl should not be prescribed during or within 14 days of MAOI administration major (DrugReax)
2-major (Clinical Pharmacology)
Opioid antagonists (e.g., naloxone, naltrexone) may precipitate withdrawal symptoms and/or decrease fentanyl effectiveness use with caution only when necessary and monitor for signs of fentanyl withdrawal/loss of efficacy naltrexone: contraindicated (DrugReax)
2-major (Clinical Pharmacology)
Sibutramine (Meridia®) adjunctive administration with fentanyl may enhance serotonin output and increase risk for serotonin syndrome as both compounds may block serotonin reuptake avoid concurrent administration major (DrugReax)
3-moderate (Clinical Pharmacology)

References

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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.