Risk of Respiratory Depression, Medication Errors, and Abuse Potential; Risk Evaluation and Mitigation Strategy 

Life-Threathening Respiratory Depression

• Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ACTIQ, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ACTIQ or following a dose increase [see Warnings and Precautions (5.1)]. The substitution of ACTIQ for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.1)].

• Due to the risk of respiratory depression, ACTIQ is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [see Contraindications (4)].

Accidnetal Ingestion

• Accidental ingestion of even one dose of ACTIQ, especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions (5.2)].
• Death has been reported in children who have accidentally ingested ACTIQ. ACTIQ must be kept out of reach of children [see PATIENT COUNSELING INFORMATION and How Supplied/Storage and Handling (16)].

Cytochrome P450 3A4 Interaction

• The concomitant use of ACTIQ with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving ACTIQ and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.3), Drug Interactions (7), Clinical Pharmacology (12.3)].

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)].

• Reserve concomitant prescribing of ACTIQ and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Risk of Medication Errors

Substantial differences exist in the pharmacokinetic profile of ACTIQ compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose [see Dosage and Administration (2.1), Warnings and Precautions (5.5)].

• When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ACTIQ [see Dosage and Administration (2.1)].
• When dispensing, do not substitute an ACTIQ prescription for other fentanyl products.

Addiction, Abuse, Misuse

• ACTIQ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ACTIQ, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.6)].
• Patients at increased risk may be prescribed opioids, but use in such patients necessitates intensive counseling about the risks and proper use along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose. 

Risk Evaluation and Mitigation Strategy (REMS)

• Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose, ACTIQ is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS, pharmacies, outpatients, and healthcare professionals who prescribe to outpatients must enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require ACTIQ while hospitalized [see Warnings and Precautions (5.7)]. Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Neonatal Opioid Withdrawal Syndrome

• Prolonged use of ACTIQ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.8)].