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

Pre-Marketing Clinical Trial Experience

Although DURAGESIC® use in post-operative or acute pain and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of DURAGESIC® was originally evaluated in 357 post-operative adult patients for 1 to 3 days and 153 cancer patients for a total of 510 patients. 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%) post-operative 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 post-operative patients.

In the pediatric population, the safety of DURAGESIC® has been evaluated in 291 patients with chronic pain 2-18 years of age. 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 ≥ 1% are presented in Table 1.

TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%)
Adult (N=380) and Pediatric (N=291) Clinical Trial Experience

The following adverse effects have been reported in less than 1% of the 510 adult post-operative and cancer patients studied:
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

Post-Marketing Experience - Adults

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
Urogenital: decreased libido, anorgasmia, ejaculatory difficulty

DRUG ABUSE AND ADDICTION

DURAGESIC® contains a high concentration of fentanyl, a potent Schedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.

The high content of fentanyl in the patches (DURAGESIC®) may be a particular target for abuse and diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

"Drug seeking" behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). "Doctor shopping" to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since DURAGESIC® may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

DURAGESIC® patches are intended for transdermal use (to be applied on the skin) only. Using cut or damaged DURAGESIC® patches or its contents can lead to the rapid release and absorption of a potentially fatal dose of fentanyl.

Agents Affecting Cytochrome P450 3A4 Isoenzyme System

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when DURAGESIC® is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce 3A4 activity may reduce the efficacy of DURAGESIC®. The concomitant use of transdermal fentanyl with ritonavir or other potent 3A4 inhibitors such as ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone may result in an increase in fentanyl plasma concentrations (see BOX WARNING, CLINICAL PHARMACOLOGY - Drug Interactions , WARNINGS, and DOSAGE AND ADMINISTRATION ). The concomitant use of other CYP3A4 inhibitors such as diltiazem and erythromycin with transdermal fentanyl may also result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause serious respiratory depression. In this situation, special patient care and observation are appropriate.

Central Nervous System Depressants

The concomitant use of DURAGESIC® (fentanyl transdermal system) with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

MAO Inhibitors

DURAGESIC® is not recommended for use in patients who have received MAOI within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

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