Transdermal Systems
• Indicated only for the management of persistent, moderate to severe pain that requires continuous, around the clock opiate administration for an extended period of time and that cannot be managed by other means (e.g., NSAIAs, opiate combination preparations, immediate-release opiates).
• Use only in opiate-tolerant patients who require a total daily opiate dosage equivalent to ≥25 mcg of transdermal fentanyl per hour. Opiate-tolerant patients are those who have been receiving ≥60 mg of oral morphine sulfate daily, ≥30 mg of oral oxycodone hydrochloride daily, ≥8 mg of oral hydromorphone hydrochloride daily, or equianalgesic dosage of another opiate for ≥1 week.
• Contraindicated because of potential for serious or life-threatening hypoventilation in patients not already opiate tolerant; in patients requiring opiate analgesia for only a short period of time; in the management of acute pain or postoperative pain, including in outpatient surgery or day surgeries (e.g., tonsillectomies); and in the management of mild or intermittent pain (e.g., use on an as-needed [“prn”] basis).
• Peak fentanyl concentrations occur 24–72 hours following application; serious or life-threatening hypoventilation (even in opiate-tolerant patients) may occur at any time, but particularly during initial application period and after increases in dosage. (See Respiratory Depression under Cautions.)
• Risk of fatal overdose secondary to respiratory depression. Fatal overdose is possible with the first transdermal dose in patients being switched from other opiate preparations if the transdermal dose is overestimated. Due to long elimination half-life (17 hours), patients experiencing severe adverse effects (including overdosage) should be monitored and treated for ≥24 hours.
• Concomitant use with any CYP3A4 inhibitor may result in increased plasma fentanyl concentrations, which could increase or prolong adverse effects, potentially resulting in fatal respiratory depression. (See Interactions.) If used concomitantly, carefully monitor patients for an extended period and adjust dosage if warranted.
• Do not expose transdermal application site or surrounding area to direct external heat sources, since this could increase release of fentanyl from the transdermal system and potentially result in overdosage and death. Closely observe febrile patients and individuals whose core body temperature increases following strenuous exercise for manifestations of opiate toxicity; adjust dosage accordingly. (See Patients with Fever or Exposure to High Temperatures under Cautions.)
• For transdermal use on intact skin only. Do not use transdermal system if the seal is broken or if the system is damaged, cut, or altered. Use of such systems may expose the patient or caregiver to the contents of the system and result in rapid release of fentanyl and absorption of a potentially fatal dose of the drug.
• Safety in children <2 years of age not established. Use in children ≥2 years of age only if opiate tolerant.
• Potential for abuse of fentanyl is similar to that of other opiates. Transdermal systems may be a particular target for abuse and diversion because of high fentanyl content. Clinicians should consider abuse potential when administering, prescribing, or dispensing fentanyl transdermal systems in situations where they are concerned about an increased risk of misuse, abuse, or diversion. Individuals at risk for opiate abuse include those with a personal or family history of substance abuse (e.g., alcohol or drug abuse or addiction) or psychiatric disorders (e.g., major depression). Assess patient for abuse or addiction potential before prescribing opiates; monitor for misuse, abuse, and addiction during therapy. Patients at risk of abuse may be treated with modified-release opiate preparations; however, intensive monitoring is needed.

Buccal (Transmucosal) Tablets and Lozenges
• Serious adverse events, including deaths, have occurred because of improper patient selection (e.g., use in non-opiate-tolerant patients) and/or improper dosage in patients receiving the buccal tablets. Substitution of buccal tablets for any other fentanyl preparation may result in fatal overdosage. (See Dosage: Breakthrough Malignant [Cancer] Pain under Dosage and Administration.)
• Do not use buccal tablets and lozenges interchangeably (e.g., on a mcg-per-mcg basis); buccal tablets are more bioavailable than buccal lozenges. Dosage adjustment required. (See Table 1 in Dosage and Administration.)
• Buccal tablets and lozenges indicated only for the management of breakthrough malignant (cancer) pain in patients who already are receiving and tolerant of around-the-clock opiate therapy for their underlying persistent cancer pain.
• Opiate-tolerant patients are those who have been receiving around-the-clock therapy with ≥60 mg of morphine sulfate daily, ≥25 mcg of transdermal fentanyl per hour, ≥30 mg of oral oxycodone hydrochloride daily, ≥8 mg of oral hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate for ≥1 week.
• Buccal preparations contraindicated in the management of acute pain (e.g., injuries, migraine, other headaches) or postoperative pain because serious or life-threatening hypoventilation can occur at any dose in patients not chronically taking opiates.
• Buccal preparations contraindicated in patients not already opiate tolerant. Deaths reported in non-opiate-tolerant patients.
• Buccal preparations intended for use only in cancer care and only by oncologists and pain specialists knowledgeable about the use of schedule II opiates in such patients.
• Buccal tablets require special care in dosing. If breakthrough pain is not relieved after 30 minutes, the patient may take only 1 additional dose (using the same-strength tablet) and then must wait at least 4 hours before taking another dose. (See Dosage: Breakthrough Malignant [Cancer] Pain under Dosage and Administration.)
• Instruct patients and their caregivers that the buccal tablets and lozenges contain fentanyl in an amount that can be fatal to a child. Instruct patients and their caregivers to keep the buccal tablets and lozenges out of reach of children and to discard open units properly.
• Concomitant use of buccal preparations with potent or moderately potent CYP3A4 inhibitors may result in increased plasma fentanyl concentrations, which could potentially result in fatal respiratory depression. (See Interactions.)
• Potential for abuse is similar to that of other opiates. Clinicians should consider abuse potential when administering, prescribing, or dispensing fentanyl buccal preparations in situations where they are concerned about an increased risk of misuse, abuse, or diversion.

REMS:

FDA approved a REMS for fentanyl to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of fentanyl and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).