Duragesic

The following serious adverse reactions are discussed elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
• Accidental Exposure [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
• Interactions with Central Nervous System Depressants [see WARNINGS AND PRECAUTIONS]
• Hypotensive Effects [see WARNINGS AND PRECAUTIONS]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Experience

The safety of DURAGESIC was evaluated in 216 patients who took at least one dose of DURAGESIC in a multicenter, double-blind, randomized, placebo-controlled clinical trial of DURAGESIC. This trial examined patients over 40 years of age with severe pain induced  by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.

The most common adverse reactions ( ≥ 5%) in a double-blind, randomized, placebo-controlled clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions ( ≥ 5%) reported in clinical trials in patients with chronic malignant or nonmalignant pain were headache and diarrhea. Adverse reactions reported for ≥ 1% of DURAGESIC-treated patients and with an incidence greater than placebo-treated patients are shown in Table 3.

The most common adverse reactions that were associated with discontinuation in patients with pain (causing discontinuation in ≥ 1% of patients) were depression, dizziness, somnolence, headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.

Table 3: Adverse Reactions Reported by ≥ 1% of DURAGESIC-treated Patients and With an Incidence Greater Than Placebo-treated Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of DURAGESIC

Adverse reactions not reported in Table 1 that were reported by ≥ 1% of DURAGESIC-treated adult and pediatric patients (N=1854) in 11 controlled and uncontrolled clinical trials of DURAGESIC used for the treatment of chronic malignant or nonmalignant pain are shown in Table 4.

Table 4: Adverse Reactions Reported by ≥ 1% of DURAGESIC-treated Patients in 11 Clinical Trials of DURAGESIC

The following adverse reactions occurred in adult and pediatric patients with an overall frequency of < 1% and are listed in descending frequency within each System/Organ Class:

Cardiac disorders: cyanosis

Eye disorders: miosis

Gastrointestinal disorders: subileus

General disorders and administration site conditions: application site reaction, influenza-like illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitis

Musculoskeletal and connective tissue disorders: muscle twitching

Nervous system disorders: hypoesthesia

Psychiatric disorders: disorientation, euphoric mood

Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: respiratory depression

Skin and subcutaneous tissue disorders: eczema, dermatitis allergic, dermatitis contact

The safety of DURAGESIC was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Adverse reactions reported by ≥ 1% of DURAGESIC-treated pediatric patients are shown in Table 5.

Table 5: Adverse Reactions Reported by ≥ 1% of DURAGESIC-treated Pediatric Patients in 3 Clinical Trials of DURAGESIC

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of DURAGESIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Cardiac Disorders: tachycardia, bradycardia

Eye Disorders: vision blurred

Gastrointestinal Disorders: ileus, dyspepsia

General Disorders and Administration Site Conditions: pyrexia

Immune System Disorders: anaphylactic shock, anaphylactic reaction, anaphylactoid reaction

Investigations: weight decreased

Nervous System Disorders: convulsions (including clonic convulsions and grand mal convulsion), amnesia, depressed level of consciousness, loss of consciousness

Psychiatric Disorders: agitation

Respiratory, Thoracic, and Mediastinal Disorders: respiratory distress, apnea, bradypnea, hypoventilation, dyspnea

Vascular Disorders: hypotension, hypertension

Duragesic is a prescription medication used to relieve severe pain in people who need pain medication around the clock for a long time and who cannot be treated with other medications. Duragesic should only be used in opioid-tolerant patients. Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equivalent dose of another opioid.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Janssen Pharmaceuticals, Inc.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and EXPOSURE TO HEAT

Addiction, Abuse, and Misuse

DURAGESIC exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing DURAGESIC, and monitor all patients regularly for the development of these behaviors or conditions.

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of DURAGESIC, even when used as recommended. Monitor for respiratory depression, especially during initiation of DURAGESIC or following a dose increase. Because of the risk of respiratory depression, DURAGESIC is contraindicated for use as an as-needed analgesic, in non-opioid tolerant patients, in acute pain, and in postoperative pain.

Accidental Exposure

Deaths due to a fatal overdose of fentanyl have occurred when children and adults were accidentally exposed to DURAGESIC. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of DURAGESIC during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Cytochrome P450 3A4 Interaction

The concomitant use of DURAGESIC with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving DURAGESIC and any CYP3A4 inhibitor or inducer.

Exposure to Heat

Exposure of the DURAGESIC application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl and death. Patients wearing DURAGESIC systems who develop fever or increased core body temperature due to strenuous exertion are also at risk for increased fentanyl exposure and may require an adjustment in the dose of DURAGESIC to avoid overdose and death.

Do not use this medication unless you are already being treated with a similar opioid (narcotic) pain medicine and your body is tolerant to it. Opioid medicines include codeine (Tylenol #3), hydrocodone (Lortab, Vicodin, Vicoprofen), hydromorphone (Dilaudid, Exalgo), oxycodone (OxyContin, Combunox, Roxicodone, Percocet), methadone (Methadose, Dolophine), morphine (Kadian, MS Contin, Oramorph), oxymorphone (Opana), and others. Talk with your doctor if you are not sure you are opioid-tolerant.

To make sure you can safely use fentanyl transdermal, tell your doctor if you have any of these other conditions:

• a breathing disorder such as chronic obstructive pulmonary disease (COPD);
• a history of head injury or brain tumor;
• a heart rhythm disorder;
• liver disease; or
• kidney disease.

FDA pregnancy category C. It is not known whether fentanyl will harm an unborn baby. Fentanyl may cause breathing problems, seizure, or addiction and withdrawal symptoms in a newborn if the mother uses the medication during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant while using fentanyl transdermal.

Fentanyl may also cause addiction and withdrawal symptoms in a nursing infant. You should not breast-feed while using fentanyl transdermal.

Older adults may be more likely to have side effects from this medicine.

Fentanyl may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction. Store the medication in a secure place where others cannot get to it.

The fentanyl transdermal patch may burn your skin if you wear the patch during an MRI (magnetic resonance imaging). Remove the patch before undergoing such a test.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Feeling confused.
• Very upset stomach or throwing up.
• Very hard stools (constipation).
• Very bad belly pain.
• Feeling very tired or weak.
• Trouble breathing, slow breathing, or shallow breathing.
• Noisy breathing.
• Shortness of breath.
• Chest pain.
• Fast or slow heartbeat.
• Feeling very sleepy.
• Seizures.
• Very bad irritation where this medicine is used.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take Duragesic (fentanyl transdermal patch) with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• Taking an opioid drug like this medicine may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.
• Long-term use of an opioid drug like Duragesic may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Duragesic is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Duragesic or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Duragesic. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Duragesic is indicated for the management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60 mg morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions (5.1)], reserve Duragesic for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Duragesic is not indicated as an as-needed (prn) analgesic.

Duragesic is available as:

• Duragesic 12 mcg/hour1 Transdermal System (system size 5.25 cm2).
• Duragesic 25 mcg/hour Transdermal System (system size 10.5 cm2).
• Duragesic 50 mcg/hour Transdermal System (system size 21 cm2).
• Duragesic 75 mcg/hour Transdermal System (system size 31.5 cm2).
• Duragesic 100 mcg/hour Transdermal System (system size 42 cm2).

Mechanism of Action

Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

Pharmacodynamics

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

In clinical trials of 357 non-opioid tolerant subjects treated with Duragesic, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with Duragesic.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of Duragesic is contraindicated in patients who are not tolerant to opioid therapy.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

Pharmacokinetics

Absorption

Duragesic is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.

Following Duragesic application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial Duragesic application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 7). Serum fentanyl concentrations achieved are proportional to the Duragesic delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size (see Figure 1). Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20–27 hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3–12) hours.

A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the Duragesic system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.

Distribution

Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3–8; N=8).

Elimination

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.

Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.

Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Specific Populations

Age: Geriatric Population

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the Duragesic fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, a single Duragesic 100 mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The mean Cmax and AUC∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC∞ was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.5)].

Age: Pediatric Population

In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration (2.2)].

Hepatic Impairment

Information on the effect of hepatic impairment on the pharmacokinetics of Duragesic is limited. The pharmacokinetics of Duragesic delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), Cmax and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.

Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of Duragesic, hepatic impairment would be expected to have significant effects on the pharmacokinetics of Duragesic. Avoid use of Duragesic in patients with severe hepatic impairment [see Dosing and Administration (2.4), Warnings and Precautions (5.15), and Use in Specific Populations (8.6)].

Renal Impairment

Information on the effect of renal impairment on the pharmacokinetics of Duragesic is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found.

Because there is in-vivo evidence of renal contribution to the elimination of Duragesic, renal impairment would be expected to have significant effects on the pharmacokinetics of Duragesic. Avoid the use of Duragesic in patients with severe renal impairment [see Dosing and Administration (2.5), Warnings and Precautions (5.16) and Use in Specific Populations (8.7)].

Drug Interaction Studies

CYP3A4 Inhibitors

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg three times a day on Day 1 and 300 mg three times a day on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%–420%) increase in fentanyl AUC0–∞. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving Duragesic and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Boxed Warning and Warnings and Precautions (5.5), and Drug Interactions (7)].

CYP3A4 Inducers

Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of Duragesic.

Duragesic as therapy for pain due to cancer has been studied in 153 patients. In this patient population, Duragesic has been administered in doses of 25 mcg/h to 600 mcg/h. Individual patients have used Duragesic continuously for up to 866 days. At one month after initiation of Duragesic therapy, patients generally reported lower pain intensity scores as compared to a pre-study analgesic regimen of oral morphine.

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.

In the pediatric population, the safety of Duragesic has been evaluated in 289 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.

Now More
Visible Patch!

NDC 50458-093-05
Five (75mcg/h) Systems

Duragesic® 75 mcg/h
(FENTANYL TRANSDERMAL SYSTEM)
CII

In vivo delivery of 75mcg/h fentanyl for 72 hours

Because serious or life-threatening breathing problems could
result, DO NOT USE Duragesic:

• for pain that can be treated with immediate-release opioids or
  non-opioid analgesics
• for intermittent (on an as-needed basis) pain
• for any postoperative pain
• unless you are opioid tolerant (have been using other narcotic
  opioid medicines)

Each transdermal system contains: 12.6mg fentanyl

DO NOT USE IF SEAL ON POUCH IS BROKEN

KEEP OUT OF REACH OF CHILDREN

Read enclosed Duragesic® Medication Guide
for important safety information.

Rx only

For Opioid-Tolerant
Patients Only

janssen

Now More
Visible Patch!

NDC 50458-094-05
Five (100mcg/h) Systems

Duragesic® 100 mcg/h
(FENTANYL TRANSDERMAL SYSTEM)
CII

In vivo delivery of 100mcg/h fentanyl for 72 hours

Because serious or life-threatening breathing problems could
result, DO NOT USE Duragesic:

• for pain that can be treated with immediate-release opioids or
  non-opioid analgesics
• for intermittent (on an as-needed basis) pain
• for any postoperative pain
• unless you are opioid tolerant (have been using other narcotic
  opioid medicines)

Each transdermal system contains: 16.8mg fentanyl

DO NOT USE IF SEAL ON POUCH IS BROKEN

KEEP OUT OF REACH OF CHILDREN

Read enclosed Duragesic® Medication Guide
for important safety information.

Rx only

For Opioid-Tolerant
Patients Only

janssen

Fentanyl may impair your thinking or reactions. Do not drive or operate machinery until you know how fentanyl will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Do not drink alcohol or dangerous side effects and death could occur. Check your food and medicine labels to be sure these products do not contain alcohol.

Avoid wearing a Duragesic skin patch on a part of your body where a child could reach or remove the patch from your skin. Avoid allowing children to watch you put on a skin patch. Never tell a child that the Duragesic skin patch is a "bandage."