Duragesic Side Effects, and Drug Interactions - Fentanyl Transdermal System

Duragesic Side Effects, and Drug Interactions - Fentanyl Transdermal System

SIDE EFFECTS

In post-marketing experience, deaths from hypoventilation due to inappropriate use of DURAGESIC^® (fentanyl transdermal system) have been reported (see BOX WARNING and CONTRAINDICATIONS).

In adults, the safety of DURAGESIC^® has been evaluated in 357 postoperative patients and 153 cancer patients for a total of 510 patients. Patients with acute pain used DURAGESIC^® for 1 to 3 days. The duration of DURAGESIC^® use varied in cancer patients; 56% of patients used DURAGESIC^® for over 30 days, 28% continued treatment for more than 4 months, and 10% used DURAGESIC^® for more than 1 year.

Hypoventilation was the most serious adverse reaction observed in 13 (4%) postoperative patients and in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.

Various adverse events were reported; a causal relationship to DURAGESIC^® was not always determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who received DURAGESIC^®. There has been no attempt to correct for a placebo effect, concomitant use of other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials.

Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1; similar reactions were seen in the 357 postoperative patients studied.

In the pediatric population, the safety of DURAGESIC^® has been evaluated in 291 patients ages 2-18 years with chronic pain. The duration of DURAGESIC^® use varied; 20% of pediatric patients were treated for £ 15 days; 46% for 16-30 days; 16% for 31-60 days; and 17% for at least 61 days. Twenty-five patients were treated with DURAGESIC^® for at least 4 months and 9 patients for more than 9 months.

There was no apparent pediatric-specific risk associated with DURAGESIC^® use in children as young as 2 years old when used as directed.

The most common adverse events were fever (35%), vomiting (33%), and nausea (24%). Adverse events reported in pediatric patients at a rate of ³1% are presented in Table 1.

The following adverse effects have been reported in less than 1% of the 510 adult postoperative and cancer patients studied; the association between these events and DURAGESIC^® administration is unknown. This information is listed to serve as alerting information for the physician.

Cardiovascular: bradycardia

Digestive: abdominal distention

Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility Respiratory: stertorous breathing, asthma, respiratory disorder

Skin and Appendages, General: exfoliative dermatitis, pustules

Special Senses: amblyopia

Urogenital: bladder pain, oliguria, urinary frequency

The following adverse reactions have been reported in association with the use of DURAGESIC^® and not reported in the pre-marketing adverse reactions section above.

Body as a Whole: edema

Cardiovascular: tachycardia

Metabolic and Nutritional: weight loss

Special Senses: blurred vision

Fentanyl is a Schedule II controlled substance and can produce drug dependence similar to that produced by morphine. DURAGESIC^® (fentanyl transdermal system) therefore has the potential for abuse. Tolerance, physical and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is relatively rare. Physicians should not let concerns of physical dependence deter them from using adequate amounts of opioids in the management of severe pain when such use is indicated.

Central Nervous System Depressants

When patients are receiving DURAGESIC^®, the dose of additional opioids or other CNS depressant drugs (including benzodiazepines) should be reduced by at least 50%. With the concomitant use of CNS depressants, hypotension may occur.

Agents Affecting Cytochrome P450 3A4 Isoenzyme System

CYP3A4 Inhibitors: Since the metabolism of fentanyl is mediated by the CYP3A4 isoenzyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of fentanyl. The expected clinical results would be increased or prolonged opioid effects. Thus patients coadministered with inhibitors of CYP3A4 such as macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) while receiving DURAGESIC^® should be carefully monitored and dosage adjustments made if warranted.

CYP3A4 Inducers: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and as such may cause increased clearance of fentanyl. Caution is advised when administering DURAGESIC^® to patients receiving these medications and if necessary dose adjustments should be considered.

Drug or Alcohol Dependence

Use of DURAGESIC^® in combination with alcoholic beverages and/or other CNS depressants can result in increased risk to the patient. DURAGESIC^® should be used with caution in individuals who have a history of drug or alcohol abuse, especially if they are outside a medically controlled environment.

Ambulatory Patients

Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Patients who have been given DURAGESIC^® should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.