Included as part of the PRECAUTIONS section.

See BOXED WARNING - WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE

Hypoventilation (Respiratory Depression)

As with all opioids, there is a risk of clinically significant hypoventilation in patients using Actiq . Accordingly, follow all patients for symptoms of respiratory depression. Hypoventilation may occur more readily when opioids are given in conjunction with other agents that depress respiration.

Patient/Caregiver Instructions

Patients and their caregivers must be instructed that Actiq contains a medicine in an amount which can be fatal to a child. 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, and Patient Counseling Information].

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., hypoventilation, 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].

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 hypoventilation, titrate Actiq with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to hypoventilation. 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.

Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use Actiq with caution in patients with bradyarrhythmias

MAO Inhibitors

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.

Patient Counseling Information

See the Medication Guide for specific patient instructions.

Patient/Caregiver Instructions

Patients and their caregivers must be instructed that Actiq contains medicine in an amount that could be fatal to a child. Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. 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, WARNINGS and PRECAUTIONS, and Patient Counseling Information].

Dental Care

Because each Actiq unit contains approximately 2 grams of sugar (hydrated dextrates), frequent consumption may increase the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk.

Post-marketing reports of dental decay have been received in patients taking Actiq [see ADVERSE REACTIONS]. In some of these patients, dental decay occurred despite reported routine oral hygiene. As dental decay in cancer patients may be multi-factorial, patients using Actiq should consult their dentist to ensure appropriate oral hygiene.

Diabetic Patients

Advise diabetic patients that Actiq contains approximately 2 grams of sugar per unit.

Actiq Welcome Kit

Provide patients and their caregivers with an Actiq Welcome Kit, which contains educational materials and safe interim storage containers to help patients store Actiq and other medicines out of the reach of children. Patients and their caregivers should also have an opportunity to watch the patient safety video, which provides proper product use, storage, handling and disposal directions. Patients should also have an opportunity to discuss the video with their health care providers. To obtain a supply of welcome kits or videos for patient viewing, health care professionals can call Cephalon, Inc. at 1-800-896-5855.

Disposal of Used Actiq Units

Patients must be instructed to dispose of completely used and partially used Actiq units.

1. After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children.
2. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children.
3. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day.

If the patient does not entirely consume the unit and the remaining drug cannot be immediately dissolved under hot running water, the patient or caregiver must temporarily store the Actiq unit in the specially provided child-resistant container out of the reach of children until proper disposal is possible.

Disposal of Unopened Actiq Units When No Longer Needed

Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed.

To dispose of the unused Actiq units:

1. Remove the Actiq unit from its blister package using scissors, and hold the Actiq by its handle over the toilet bowl.
2. Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet.
3. Dispose of the handle in a place that is out of the reach of children.
4. Repeat steps 1, 2, and 3 for each Actiq unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet.

Do not flush the entire Actiq units, Actiq handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it [see HOW SUPPLIED, Storage and Handling].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of Actiq are provided in the Actiq Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Cephalon, Inc. (1-800-896-5855) or seek assistance from their local DEA office.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl.

Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for Actiq .

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.

Pregnant female New Zealand white rabbits were treated with fentanyl (0, 25, 100, 400 mcg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 400 mcg/kg (approximately 5-times the human dose of 1600 mcg every 6 hours on a mg/m² basis).

Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore do not use Actiq during labor and delivery.

Nursing Mothers

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 .

Pediatric Use

Safety and efficacy in pediatric patients below the age of 16 years 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 AUC_0-8 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).

Geriatric Use

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.

Gender

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.

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