Criteria for Outpatient Use Guidelines
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[Developed, February 2003; Revised, January 2006, July 2007]
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].
Fentanyl citrate intranasal spray as well as oral transmucosal lozenges, buccal tablets, buccal films, sublingual tablets, and sublingual spray are FDA-approved for managing 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 equi-analgesic dose of another opioid daily for a week or longer.
|Fentanyl Dosage Form||Dosage Strengths||Maximum Dose|
|transmucosal lozenge (Actiq®)||200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1400 mcg, or 1600 mcg per lozenge||no more than 4 units/lozenges per 24 hours|
|buccal tablet (Fentora®)||100 mcg, 200 mcg, 300 mcg, 400 mcg, 600 mcg, or 800 mcg per tablet||800 mcg/dose; no more than 4 treated episodes per 24 hours|
|buccal soluble film (Onsolis®)||200 mcg, 400 mcg, 600 mcg, 800 mcg, or 1200 mcg per film||1200 mcg/dose; no more than 4 treated episodes per 24 hours|
|sublingual tablet (Abstral®)||100 mcg, 200 mcg, 300 mcg, 400 mcg, 600 mcg, or 800 mcg per tablet||800 mcg/dose; no more than 4 treated episodes per 24 hours|
|sublingual spray (Subsys®)||100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, or 1600 mcg per spray||1600 mcg/dose; no more than 4 treated episodes per 24 hours|
|intranasal spray (Lazanda®)||100 mcg or 400 mcg per actuation||800 mcg/dose; no more than 4 doses per 24 hours|
Because of the risk of abuse, addiction, misuse and overdose, all intranasal and oral fentanyl dosage forms are obtained solely through a restricted distribution program, the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Management Strategy (REMS) Access program, in which only outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors who have registered for the program can prescribe, dispense, and/or obtain intranasal and oral fentanyl.
Due to pharmacokinetic differences between intranasal, oral transmucosal, buccal, and sublingual 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 2.
|Current Fentanyl Oral Transmucosal Lozenge Dose (mcg)||Initial Fentanyl Buccal Tablet Dose (mcg)|
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. Patients must wait at least 4 hours before administering fentanyl oral transmucosal lozenges for another episode of breakthrough pain. 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 to minimize potential withdrawal adverse effects.
Patients prescribed fentanyl buccal tablets for breakthrough pain should begin therapy with an initial
dose of 100 mcg, with the exception of those previously treated with fentanyl oral transmucosal lozenges (see Table 2). 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. Patients must wait at least 4 hours before administering a fentanyl buccal tablet dose for another episode of breakthrough pain. 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. To discontinue fentanyl buccal tablet use, a downward titration is recommended to minimize potential withdrawal adverse effects.
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. If adequate pain relief is not provided by fentanyl buccal film after 30 minutes during a breakthrough pain episode, an alternative rescue medication may be utilized as directed by the patient’s healthcare provider. 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.
All patients receiving fentanyl sublingual tablets, including those patients previously treated with other fentanyl dosage forms, should initially receive a 100 mcg dose. If patients do not achieve adequate analgesia within 30 minutes, a second fentanyl sublingual tablet dose may be administered as directed. No more than two doses should be administered for any breakthrough pain episode. If pain relief for the breakthrough episode is not relieved with the 100 mcg dose, titrate using multiples of 100 mcg or 200 mcg tablets until adequate analgesia is achieved. Doses may be titrated upward to 300 mcg, 400 mcg, 600 mcg, or 800 mcg per dose. Doses higher than 800 mcg have not been evaluated in clinical trials. If adequate pain relief is not achieved within 30 minutes of the first dose, a second dose of the same strength may be administered. Patients should not use more than 4 tablets at one time. Patients must wait at least 2 hours before administering fentanyl sublingual tablets for another episode of breakthrough pain. Once an effective fentanyl sublingual tablet dose has been determined, patients should be maintained on this dose. If pain is not effectively managed with this dose of fentanyl sublingual tablet, a patient may use a second dose as directed by their health care provider, with no more than two doses being used to treat any breakthrough pain episode. Again, patients must wait at least two hours before treating subsequent breakthrough pain episodes. Fentanyl sublingual tablets should be used for no more than four breakthrough pain episodes per day.
Treatment with fentanyl sublingual spray should be initiated with a 100 mcg dose. If patients do not achieve adequate analgesia within 30 minutes, a second fentanyl sublingual spray dose of the same strength may be administered. No more than two doses should be administered for any breakthrough pain episode. Patients should be prescribed only a titration supply of 100 mcg dose units during titration to minimize the number of available units during titration. If pain relief for the breakthrough episode is not relieved with the 100 mcg dose, titrate doses upward to 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, or 1600 mcg per dose. If adequate pain relief is not achieved within 30 minutes of the first dose, a second dose of the same strength may be administered. Patients must wait at least 4 hours before administering fentanyl sublingual tablets for another episode of breakthrough pain. Once an effective fentanyl sublingual spray dose has been determined, patients should be maintained on this dose. If pain is not effectively managed with this dose of fentanyl sublingual tablet, a patient may use a second dose as directed by their health care provider, with no more than two doses being used to treat any breakthrough pain episode. Again, patients must wait at least four hours before treating subsequent breakthrough pain episodes. Increase the fentanyl sublingual spray dose only when treatment at the current dose fails to provide pain relief for several episodes. To reduce the risk of overdose, patients should have only one fentanyl sublingual spray dosage strength available at any time. Fentanyl sublingual spray should be used for no more than four breakthrough pain episodes per day.
Fentanyl intranasal spray should be initiated in all patients with a dose of 100 mcg (one spray in one nostril). If adequate analgesia is achieved, this dose will be used to manage future breakthrough pain episodes. If adequate pain relief is not achieved with the 100 mcg dose, titrate the dose upward in a stepwise manner to 200 mcg (2 x 100 mcg – one spray in each nostril), 400 mcg (1 x 400 mcg – one spray in one nostril), or 800 mcg (2 x 400 mcg – one spray in each nostril) per dose until adequate analgesia is achieved with minimal adverse effects. Patients must wait at least 2 hours before administering subsequent fentanyl intranasal spray doses. Safety and efficacy of doses greater than 800 mcg have not yet been determined in clinical trials. Once an effective dose has been established, fentanyl intranasal spray should be used to manage no more than four breakthrough episodes per day. If adequate analgesia is not achieved within 30 minutes of a fentanyl intranasal spray dose or a breakthrough pain episode occurs before the next fentanyl intranasal spray dose (i.e., within 2 hours of a fentanyl intranasal spray dose), a rescue medication may be utilized as dictated by the patient’s health care provider.
The lowest effective fentanyl oral transmucosal, buccal, intranasal, or sublingual 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 buccal, nasal, sublingual, or transmucosal fentanyl concurrently for greater than two months will be reviewed. Patient profiles containing prescriptions for greater than four doses per day of fentanyl intranasal spray will be reviewed. Patient profiles documenting treatment of more than 4 breakthrough episodes daily with fentanyl buccal, transmucosal, or sublingual dosage forms 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.16, 17
Fentanyl citrate transmucosal lozenges are FDA-approved for use in adolescents 16 years and older. Fentanyl nasal spray as well as oral fentanyl buccal tablet, buccal film, sublingual spray, and sublingual tablet safety and efficacy have not been established in patients below 18 years of age. Although not FDA-approved, oral fentanyl citrate has been studied in non-opioid tolerant patients as young as 2 years of age for various indications including surgical procedure pain, wound dressing changes in burn patients, and sedation in single doses ranging from 10-20 μg/kg given prior to procedures with mixed efficacy rates. Similarly, intranasal fentanyl has been effectively utilized in pediatric patients as young as 6 months of age for non-FDA approved uses (e.g., analgesia, burns, postoperatively) at doses of 1-2 mcg/kg with success.
2. Duration of Therapy
Therapy duration for fentanyl oral transmucosal lozenges, fentanyl buccal tablets, fentanyl buccal films, fentanyl sublingual tablets, fentanyl sublingual spray, and fentanyl nasal spray 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, buccal films, sublingual tablets, sublingual spray, or nasal spray 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 3. 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:
|Interacting Drug(s)||Interaction||Recommendation||Clinical Significance#^|
|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)
|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)
|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)
|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, 3-moderate (CP)
|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)
|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)
|nasal decongestants (e.g., oxymetazoline) and intranasal fentanyl||combined administration of intranasal fentanyl with vasoconstrictive nasal decongestants results in reduced fentanyl absorption through the nasal mucosa, reduced Cmax and delayed Tmax, and the potential for reduced effectiveness in pain management||use combination cautiously; avoid intranasal fentanyl dose titration in patients using vasoconstrictive decongestants as inappropriate maintenance dose may be calculated; interaction does not occur with other fentanyl dosage forms||2-major (CP)|
|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)
|selective serotonin reuptake inhibitors (SSRIs)||concurrent use increases risk for serotonin syndrome or neuroleptic malignant syndrome-like reactions as both agents have serotonergic properties||administer cautiously together; observe for signs/symptoms of serotonin syndrome (e.g., agitation, confusion, hyperthermia, shivering)||major (DrugReax)
|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; if combined therapy necessary, observe for signs/symptoms of serotonin syndrome (e.g., agitation, confusion, hyperthermia, shivering)||major (DrugReax)
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- Binstock W, Rubin R, Bachman C, et al. The effect of premedication with OTFC, with or without ondansetron, on postoperative agitation and nausea and vomiting in pediatric ambulatory patients. Paediatr Anaesth. 2004;14:759-67.
- Dsida RM, Wheeler M, Birmingham PK, et al. Premedication of pediatric tonsillectomy patients with oral transmucosal fentanyl citrate. Anesth Analg. 1998;86:66-70.
- Epstein RH, Mendel HG, Witkowski TA, et al. The safety and efficacy of oral transmucosal fentanyl citrate for preoperative sedation in young children. Anesth Analg. 1996;83:1200-5.
- Howell, TK, Smith S, Rushman SC, et al. A comparison of oral transmucosal fentanyl and oral midazolam for premedication in children. Anaesthesia. 2002 ;57:798-805.
- Mahar PJ, Rana JA, Kennedy CS, et al. A randomized clinical trial of oral transmucosal fentanyl citrate versus intravenous morphine sulfate for initial control of pain in children with extremity injuries. Pediatr Emerg Care. 2007 ;23:544-8.
- Robert R, Brack A, Blakeney P, et al. A double-blind study of the analgesic efficacy of oral transmucosal fentanyl citrate and oral morphine in pediatric patients undergoing burn dressing change and tubbing. J Burn Care Rehabil. 2003;24:351-355.
- Schechter NL, Weisman SJ, Rosenblum M, et al. The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics. 1995;95:335-9.
- Sharar SR, Bratton SL, Carrougher GJ, et al. A comparison of transmucosal fentanyl citrate and oral hydromorphone for inpatient pediatric burn wound care analgesia. J Burn Care Rehabil. 1998; 19:516-21.
- Sharar SR, Carrougher GJ, Selzer K, et al. A comparison of oral transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care Rehabil. 2002;23:27-31.
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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.