DURAGESIC (Fentanyl Transdermal System) | DURAGESIC

22:04 EDT 20th September 2014 | BioPortfolio
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CII

Full Prescribing Information

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

DURAGESIC contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl 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.

DURAGESIC is indicated for management of persistent, moderate to severe chronic pain that:

DURAGESIC should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to DURAGESIC 25 mcg/h. Patients who are considered opioid-tolerant are those who have been taking, for a 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 equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could occur, DURAGESIC (fentanyl transdermal system) is contraindicated:

(See CONTRAINDICATIONS for further information.)

Since the peak fentanyl concentrations generally occur between 20 and 72 hours of treatment, prescribers should be aware that serious or life threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period.

The concomitant use of DURAGESIC with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY – Drug Interactions, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information).

The safety of DURAGESIC has not been established in children under 2 years of age. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS - Pediatric Use).

DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the DURAGESIC dose when converting patients from another opioid medication can result in fatal overdose with the first dose (see DOSAGE AND ADMINISTRATON – Initial DURAGESIC® Dose Selection). Due to the mean half-life of approximately 20–27 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.

DURAGESIC can be abused in a manner similar to other opioid agonists, legal or illicit. This risk should be considered when administering, prescribing, or dispensing DURAGESIC in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion.

Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

DURAGESIC patches are intended for transdermal use (on intact skin) only. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

Avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. Patients wearing DURAGESIC systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the DURAGESIC dose should be adjusted if necessary.

DURAGESIC (fentanyl transdermal system) is a transdermal system providing continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours. The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:

The molecular weight of fentanyl base is 336.5, and the empirical formula is CHNO. The n-octanol:water partition coefficient is 860:1. The pKa is 8.4.

IMAGE duragesic-01.jpg

The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/h per 10.5 cm). The composition per unit area of all system sizes is identical.

DURAGESIC is a rectangular transparent unit comprising a protective liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are:

1) a backing layer of polyester/ethyl vinyl acetate film; 2) a drug-in-adhesive layer. Before use, a protective liner covering the adhesive layer is removed and discarded.

The active component of the system is fentanyl. The remaining components are pharmacologically inactive.

IMAGE duragesic-02.jpg
DoseNominal delivery rate per hour
(mcg/h)
Size
(cm2)
Fentanyl Content
(mg)
12Nominal delivery rate is 12.5 mcg/hr 5.25 2.1
25 10.5 4.2
50 21 8.4
75 31.5 12.6
100 42 16.8

Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, fentanyl exerts its principal pharmacologic effects on the central nervous system.

In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting directly by stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope.

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.

While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination. At therapeutic dosages, fentanyl usually does not exert major effects on the cardiovascular system. However, some patients may exhibit orthostatic hypotension and fainting.

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.

(see graph and tables)

The DURAGESIC (fentanyl transdermal system) 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 A). 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. 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.

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).

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. 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%.

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.

Serum Fentanyl Concentrations
Following Single and Multiple Applications of DURAGESIC ® 100 mcg/h
TABLE A: FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF DURAGESIC®
Mean (SD) Time to Maximal Concentration
Tmax
(h)
Mean (SD) Maximal Concentration
Cmax
(ng/mL)
NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20–27 hours.
DURAGESIC® 12 mcg/h 28.8 (13.7) 0.38 (0.13)Cmax values dose normalized from 4 × 12.5 mcg/h
DURAGESIC® 25 mcg/h 31.7 (16.5) 0.85 (0.26)
DURAGESIC® 50 mcg/h 32.8 (15.6) 1.72 (0.53)
DURAGESIC® 75 mcg/h 35.8 (14.1) 2.32 (0.86)
DURAGESIC® 100 mcg/h 29.9 (13.3) 3.36 (1.28)
TABLE B: RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS
Clearance
(L/h)
Range
[70 kg]
Volume of Distribution
VSS
(L/kg)
Range
Half-Life
t1/2
(h)
Range
NOTE: Information on volume of distribution and half-life not available for renally impaired patients.
Surgical Patients 27 – 75 3 – 8 3 – 12
Hepatically Impaired Patients 3 – 80Estimated 0.8 – 8 4 – 12
Renally Impaired Patients 30 – 78

Insufficient information exists to make recommendations regarding the use of DURAGESIC 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.

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 DOSAGE AND ADMINISTRATION section.

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.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

DURAGESIC should be used with caution in elderly, cachectic or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see DOSAGE AND ADMINISTRATION ).

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 tid on Day 1 and 300 mg tid 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 AUC. Coadministration of ritonavir in patients receiving DURAGESIC has not been studied; however, an increase in fentanyl AUC is expected (see BOX WARNING , WARNINGS , PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

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 CYP3A4 activity may reduce the efficacy of DURAGESIC. 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, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING, WARNINGS , PRECAUTIONS , and DOSAGE AND ADMINISTRATION for further information).

Because of the risk for serious or life-threatening hypoventilation, DURAGESIC is CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not opioid-tolerant. In clinical trials of 357 patients with acute pain treated with DURAGESIC, 13 patients experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in patients weighing less than 63 kg (9 of 13). Although patients with 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.

While most adult and pediatric patients using DURAGESIC chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy.

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

The use of DURAGESIC should be monitored by clinical evaluation, especially within the initial 24–72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older.

See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation.

Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with DURAGESIC was less than 1%.

Central nervous system effects increase with increasing serum fentanyl concentrations.

DURAGESIC is indicated for management of persistent, moderate to severe chronic pain that:

DURAGESIC should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to DURAGESIC 25 mcg/h (see DOSAGE AND ADMINISTRATION ). Patients who are considered opioid-tolerant are those who have been taking, for a 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 equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could result, DURAGESIC is contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS ).

An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

Because serious or life-threatening hypoventilation could occur, DURAGESIC (fentanyl transdermal system) is contraindicated:

DURAGESIC (fentanyl transdermal system) is contraindicated in patients who have or are suspected of having paralytic ileus.

DURAGESIC (fentanyl transdermal system) is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product.

DURAGESIC patches are intended for transdermal use (on intact skin) only. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

The safety of DURAGESIC (fentanyl transdermal system) has not been established in children under 2 years of age. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use).

DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the DURAGESIC dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean half-life is approximately 20–27 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after DURAGESIC removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 20–27 hours after system removal.

DURAGESIC should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists.

All patients and their caregivers should be advised to avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over the DURAGESICsystem increased mean fentanyl AUC values by 120% and mean C values by 61%.

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing DURAGESIC systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the DURAGESIC dose should be adjusted if necessary.

Death and other serious medical problems have occurred when people were accidentally exposed to DURAGESIC. Examples of accidental exposure include transfer of a DURAGESIC patch from an adult's body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver's skin to the medication in the patch while the caregiver was applying or removing the patch.

Placing DURAGESIC in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.

Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing DURAGESIC in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

DURAGESIC has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION ).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious or life-threatening hypoventilation may occur at any time during the use of DURAGESIC especially during the initial 24–72 hours following initiation of therapy and following increases in dose.

Because significant amounts of fentanyl continue to be absorbed from the skin for 20–27 hours or more after the patch is removed, hypoventilation may persist beyond the removal of DURAGESIC. Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized.

The use of concomitant CNS active drugs requires special patient care and observation.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in DURAGESIC. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

DURAGESIC should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of DURAGESIC may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Because potent opioids can cause serious or life-threatening hypoventilation, DURAGESIC should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.

DURAGESIC should not be used in patients who may be particularly susceptible to the intracranial effects of CO retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. DURAGESIC should be used with caution in patients with brain tumors.

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. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

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, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY – Drug Interactions, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information).

DURAGESIC (fentanyl transdermal system) should not be used to initiate opioid therapy in patients who are not opioid-tolerant. Children converting to DURAGESIC should be opioid-tolerant and 2 years of age or older (see BOX WARNING).

Patients, family members, and caregivers should be instructed to keep patches (new and used) out of the reach of children and others for whom DURAGESIC was not prescribed. A considerable amount of active fentanyl remains in DURAGESIC even after use as directed. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death.

Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias.

Insufficient information exists to make recommendations regarding the use of DURAGESIC in patients with impaired renal or hepatic function. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

DURAGESIC may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like DURAGESIC may cause increases in the serum amylase concentration.

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood concentration of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION – Discontinuation of DURAGESIC® ).

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.

Patients and their caregivers should be provided with a Medication Guide each time DURAGESIC is dispensed because new information may be available.

Patients receiving DURAGESIC patches should be given the following instructions by the physician:

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 CYP3A4 activity may reduce the efficacy of DURAGESIC. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY – Drug Interactions, WARNINGS, and DOSAGE AND ADMINISTRATION for further information).

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.

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.

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 µg/kg/day in males or 100 µg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC comparison). There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays.

The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.

No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 µg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/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 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m basis).

There are no adequate and well-controlled studies in pregnant women. DURAGESIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m basis.

Fentanyl readily passes across the placenta to the fetus; therefore, DURAGESIC is not recommended for analgesia during labor and delivery.

Fentanyl is excreted in human milk; therefore, DURAGESIC is not recommended for use in nursing women because of the possibility of effects in their infants.

The safety of DURAGESIC was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of DURAGESIC therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. Approximately 90% of the total daily opioid requirement (DURAGESIC plus rescue medication) was provided by DURAGESIC.

DURAGESIC was not studied in children under 2 years of age.

DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see DOSAGE AND ADMINISTRATION and BOX WARNING ).

To guard against accidental ingestion by children, use caution when choosing the application site for DURAGESIC (see DOSAGE AND ADMINISTRATION ) and monitor adhesion of the system closely.

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.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

DURAGESIC should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND ADMINISTRATION ).

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

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.

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

TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%) Adult (N=380) and Pediatric (N=291) Clinical Trial Experience
Body System Adults Pediatrics
Body as a Whole Abdominal painReactions occurring in 3% – 10% of DURAGESIC® patients, headache, fatigue, back pain, fever, influenza-like symptoms, accidental injury, rigors Pain, headache, fever, syncope, abdominal pain, allergic reaction, flushing
Cardiovascular Arrhythmia, chest pain Hypertension, tachycardia
Digestive NauseaReactions occurring in 10% or more of DURAGESIC® patients, vomiting, constipation, dry mouth, anorexia, diarrhea, dyspepsia, flatulence Nausea, vomiting, constipation, dry mouth, diarrhea
Nervous Somnolence, insomnia, confusion, asthenia, dizziness, nervousness, hallucinations, anxiety, depression, euphoria, tremor, abnormal coordination, speech disorder, abnormal thinking, abnormal gait, abnormal dreams, agitation, paresthesia, amnesia, syncope, paranoid reaction Somnolence, nervousness, insomnia, asthenia, hallucinations, anxiety, depression, convulsions, dizziness, tremor, speech disorder, agitation, stupor, confusion, paranoid reaction
Respiratory Dyspnea, hypoventilation, apnea, hemoptysis, pharyngitis, hiccups, bronchitis, rhinitis, sinusitis, upper respiratory tract infection Dyspnea, respiratory depression, rhinitis, coughing
Skin and Appendages Sweating, pruritus, rash, application site reaction – erythema, papules, itching, edema Pruritus, application site reaction, sweating increased, rash, rash erythematous, skin reaction localized
Urogenital Urinary retention, Micturition disorder Urinary retention

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

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. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious significant effect being hypoventilation.

For the management of hypoventilation, immediate countermeasures include removing the DURAGESIC (fentanyl transdermal system) system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an overdose may be longer than the effects of the narcotic antagonist's action (the half-life of naloxone ranges from 30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility of re-narcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines.

Always ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body temperature and fluid intake should be maintained.

If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy.

DURAGESIC contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl 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.

DURAGESIC patches are intended for transdermal use (on intact skin) only. The DURAGESIC patch should not be used if the pouch seal is broken, or the patch is cut, damaged, or changed in any way.

Each DURAGESIC patch may be worn continuously for 72 hours. The next patch should be applied to a different skin site after removal of the previous transdermal system.

If problems with adhesion of the DURAGESIC patch occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing (e.g., Bioclusive™ or Tegaderm™).

If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site.

DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of

Manufacturer

Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Active Ingredients

Source

Clinical Trials [7 Associated Clinical Trials listed on BioPortfolio]

A Study to Assess the Safety, Dose Conversion, and Dose Individualization of Duragesic® (Fentanyl Transdermal Patch) in the Treatment of Children With Chronic Pain Requiring Narcotic Pain Relief Therapy

The objective of this study is to assess the safety of treatment with Duragesic® (a transdermal patch delivering the narcotic pain-reliever fentanyl) in doses of 12.5, 25, 50, 75 and 100 ...

Study of the Effect of Clinical Procedures on Drug Delivery of Mylan Fentanyl Transdermal System 25 µg/hr and Duragesic® 25 µg/hr

The objective of this study was to investigate the effect of clinical procedures on the drug delivery of Fentanyl Transdermal Systems, 25 mcg/h manufactured for Mylan Pharmaceuticals Inc. ...

Bioequivalence and Wear Study of Mylan Fentanyl Transdermal System 25 µg/h and Mylan Fentanyl Transdermal System

The objective of this study was to investigate the effect of three different types of occlusive overlays on the drug delivery of Fentanyl Transdermal Systems, 25 mcg/h manufactured for Myl...

A 15-day Study to Assess the Safety and Clinical Utility of Duragesic (Fentanyl Transdermal Patch) in the Treatment of Children With Continuous Pain Requiring Narcotic Pain Relief Therapy

The objective of this study is to assess the safety and clinical utility of Duragesic® 12.5 micrograms/hour (a transdermal patch delivering the narcotic pain-reliever fentanyl) in the t...

A Relative Bioavailability Study of Fentanyl 25 μg/h Transdermal System

To compare the rate and extent of absorption of fentanyl 25 μg/h transdermal system (test) and Duragesic (reference) administrated as 1 x 25 μg/h single transdermal system application.

PubMed Articles [0 Results]

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