WARNINGS AND PRECAUTIONS
See Boxed Warning - WARNING:
RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL
Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in ACTIQ. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
Important Information Regarding Prescribing and Dispensing
When prescribing, DO NOT convert a patient to ACTIQ from any other fentanyl product on a mcg per mcg basis as ACTIQ and other fentanyl products are not equivalent on a microgram per microgram basis.
ACTIQ is NOT a generic version of Fentora®. When dispensing, DO NOT substitute an ACTIQ prescription for a Fentora prescription under any circumstances. Fentora and ACTIQ are not equivalent. Substantial differences exist in the pharmacokinetic profile of ACTIQ compared to other fentanyl products including Fentora that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of ACTIQ for any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of ACTIQ should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects
[see Dosage and Administration]
Patients and their caregivers must be instructed that ACTIQ contains a medicine in an amount which can be fatal to a child. Death has been reported in children who have accidentally ingested ACTIQ. Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [see How Supplied/Storage and Handling (16.1, 16.2), Patient Counseling Information and Medication Guide ].
Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.
ACTIQ could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.
Additive CNS Depressant Effects
The concomitant use of ACTIQ with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., respiratory depression, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions (7)].
Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of ACTIQ if warranted.
Effects on Ability to Drive and Use Machines
Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking ACTIQ of these dangers and counsel them accordingly.
Chronic Pulmonary Disease
Because potent opioids can cause respiratory depression, titrate ACTIQ with caution in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of ACTIQ may further decrease respiratory drive to the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure
Administer ACTIQ with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.
Intravenous fentanyl may produce bradycardia. Therefore, use ACTIQ with caution in patients with bradyarrhythmias.
ACTIQ is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction, and overdose
[see Drug Abuse and Dependence]
, ACTIQ is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of ACTIQ, patient and prescriber enrollment is not required.
Required components of the TIRF REMS Access program are:
• Healthcare professionals, who prescribe ACTIQ for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
• To receive ACTIQ, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
• Pharmacies that dispense ACTIQ must enroll in the program, and agree to comply with the REMS requirements.
• Wholesalers and distributors that distribute ACTIQ must enroll in the program, and distribute only to authorized pharmacies.
Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.
USE IN SPECIFIC POPULATIONS
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. ACTIQ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.
In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.
Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for ACTIQ.
Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/m2 basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not teratogenic.
Labor and Delivery
Fentanyl readily passes across the placenta to the fetus; therefore do not use ACTIQ during labor and delivery (including caesarean section) since it may cause respiratory depression in the fetus or in the newborn infant.
Fentanyl is excreted in human milk; therefore, do not use ACTIQ in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using ACTIQ.
Safety and effectiveness in pediatric patients below 16 years of age have not been established.
In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with ACTIQ. The study was too small to allow conclusions on safety and efficacy in this patient population. Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received ACTIQ at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) Cmax and AUC0-8 values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng•h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (N = 9).
Of the 257 patients in clinical studies of ACTIQ in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in ACTIQ clinical trials.
Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, exercise caution when individually titrating ACTIQ in elderly patients to provide adequate efficacy while minimizing risk.
Patients with Renal or Hepatic Impairment
Insufficient information exists to make recommendations regarding the use of ACTIQ in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.
Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in observed adverse reactions.