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Actiq (Fentanyl Citrate Oral Transmucosal) - Warnings and Precautions

 
 



BOX WARNING

PHYSICIANS AND OTHER HEALTHCARE PROVIDERS MUST BECOME FAMILIAR WITH THE IMPORTANT WARNINGS IN THIS LABEL.

Actiq is indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain.

Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer.

Because life-threatening hypoventilation could occur at any dose in patients not taking chronic opiates, Actiq is contraindicated in the management of acute or postoperative pain. This product must not be used in opioid non-tolerant patients.

Actiq is intended to be used only in the care of cancer patients and only by oncologists and pain specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.

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 all units out of the reach of children and to discard opened units properly. (See Information for Patients and Their Caregivers for disposal instructions.)

WARNING:

May be habit forming

 

WARNINGS

See BOX WARNING.)

The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors), and alcoholic beverages may produce increased depressant effects. Hypoventilation, hypotension, and profound sedation may occur.

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.

Pediatric Use: The appropriate dosing and safety of Actiq in opioid tolerant children with breakthrough cancer pain have not been established below the age of 16 years.

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 SAFETY AND HANDLING, PRECAUTIONS, and PATIENT LEAFLET for specific patient instructions.)

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.

PRECAUTIONS

GENERAL

The initial dose of Actiq to treat episodes of breakthrough cancer pain should be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects.

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). Patients taking Actiq should be warned of these dangers and should be counseled accordingly.

The use of concomitant CNS active drugs requires special patient care and observation. (See WARNINGS.)

HYPOVENTILATION (RESPIRATORY DEPRESSION)

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

CHRONIC PULMONARY DISEASE

Because potent opioids can cause hypoventilation, Actiq should be titrated 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

Actiq should only be administered 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, Actiq should be used with caution in patients with bradyarrhythmias.

HEPATIC OR RENAL DISEASE

Actiq should be administered with caution to patients with liver or kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs and effects on plasma binding proteins (see PHARMACOKINETICS).

INFORMATION FOR PATIENTS AND THEIR CAREGIVERS

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 SAFETY AND HANDLING, WARNINGS, and PATIENT LEAFLET for specific patient instructions.)

Frequent consumption of sugar-containing products may increase the risk of dental caries (each Actiq unit contains approximately 2 grams of sugar {hydrated dextrates}). 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 -- Post Marketing Experience). In some of these patients, dental decay occurred despite reported oral hygiene. Therefore, patients using Actiq should consult their dentist to ensure appropriate oral hygiene.

Diabetic patients should be advised that Actiq contains approximately 2 grams of sugar per unit.

Patients and their caregivers should be provided with an Actiq Welcome Kit, which contains educational materials and safe 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. Health care professionals should call 1-800-896-5855 to obtain a supply of welcome kits or videos for patient viewing.

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. Handles in the child-resistant container should be disposed of (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. The handle should be disposed of where children cannot reach it (see SAFETY AND HANDLING).

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of Actiq are provided in the Actiq Patient Leaflet. Patients should be encouraged to read this information in its entirety and be given 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, they should be instructed to call the toll-free number (1-800-896-5855) or seek assistance from their local DEA office.

LABORATORY TESTS

The effects of Actiq on laboratory tests have not been evaluated.

DRUG INTERACTIONS

See WARNINGS.

Fentanyl is metabolized in the liver and intestinal mucosa to norfentanyl by the cytochrome P450 3A4 isoform. Drugs that inhibit P450 3A4 activity may increase the bioavailability of swallowed fentanyl (by decreasing intestinal and hepatic first pass metabolism) and may decrease the systemic clearance of fentanyl. The expected clinical results would be increased or prolonged opioid effects. Drugs that induce cytochrome P450 3A4 activity may have the opposite effects. However, no in vitro or in vivo studies have been performed to assess the impact of those potential interactions on the administration of Actiq. Thus patients who begin or end therapy with potent inhibitors of CYP450 3A4 such as macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole and itraconazole), and protease inhibitors (e.g., ritanovir) while receiving Actiq should be monitored for a change in opioid effects and, if warranted, the dose of Actiq should be adjusted.

CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY

Because animal carcinogenicity studies have not been conducted with fentanyl citrate, the potential carcinogenic effect of Actiq is unknown.

Standard mutagenicity testing of fentanyl citrate has been conducted. There was no evidence of mutagenicity in the Ames Salmonella or Escherichia mutagenicity assay, the in-vitro mouse lymphoma mutagenesis assay, and the in-vivo micronucleus cytogenetic assay in the mouse.

Reproduction studies in rats revealed a significant decrease in the pregnancy rate of all experimental groups. This decrease was most pronounced in the high dose group (1.25 mg/kg subcutaneously) in which one of twenty animals became pregnant.

PREGNANCY--CATEGORY C

Fentanyl has been shown to impair fertility and to have an embryocidal effect with an increase in resorptions in rats when given for a period of 12 to 21 days in doses of 30 mcg/kg IV or 160 mcg/kg subcutaneously.

No evidence of teratogenic effects has been observed after administration of fentanyl citrate to rats. 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.

LABOR AND DELIVERY

Actiq is not indicated for use in labor and delivery.

NURSING MOTHERS

Fentanyl is excreted in human milk; therefore Actiq should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants.

PEDIATRIC USE

See WARNINGS

GERIATRIC USE

Of the 257 patients in clinical studies of Actiq in breakthrough cancer pain, 61 (24%) were 65 and over, while 15 (6%) were 75 and over.

Those patients over the age of 65 titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. Previous studies with intravenous fentanyl showed that elderly patients are twice as sensitive to the effects of fentanyl as the younger population.

No difference was noted in the safety profile of the group over 65 as compared to younger patients in Actiq clinical trials. However, greater sensitivity in older individuals cannot be ruled out. Therefore, caution should be exercised in individually titrating Actiq in elderly patients to provide adequate efficacy while minimizing risk.

Page last updated: 2006-07-23

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