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All about: Fentanyl Transdermal

Big Image Dosage Form: Patch, extended release

Full Prescribing Information
FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

BOXED WARNING

Fentanyl Transdermal system 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 may be a particular target for abuse and diversion.

Fentanyl Transdermal system is indicated for management of persistent, moderate to severe chronic pain that:

  • requires continuous, around-the-clock opioid administration for an extended period of time, and

  • cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids

Fentanyl Transdermal system 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 Fentanyl Transdermal system 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, Fentanyl Transdermal system is contraindicated:

  • in patients who are not opioid-tolerant

  • in the management of acute pain or in patients who require opioid analgesia for a short period of time

  • in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies)

  • in the management of mild pain

  • in the management of intermittent pain [e.g., use on an as needed basis (prn)]

(See CONTRAINDICATIONS for further information.)

Since the peak fentanyl levels occur between 24 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 Fentanyl Transdermal system with potent cytochrome P450 3A4 inhibitors (ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) 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 Fentanyl Transdermal system and potent CYP3A4 inhibitors 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 Fentanyl Transdermal system has not been established in children under 2 years of age.  Fentanyl Transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use.)

Fentanyl Transdermal system 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 Fentanyl Transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean elimination half-life of 17 hours of Fentanyl Transdermal system, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.

Fentanyl Transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. This risk should be considered when administering, prescribing, or dispensing Fentanyl Transdermal system 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.

Fentanyl Transdermal system patches are intended for transdermal use (on intact skin) only.  Using damaged or cut Fentanyl Transdermal system patches can lead to the rapid release of the contents of the Fentanyl Transdermal system patch and absorption of a potentially fatal dose of fentanyl.

Fentanyl Transdermal Description

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 molecular formula is C22H28N2O. The n-octanol:water partition coefficient is 860:1. The pKa is 8.4.

System Components and Structure

The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/h per 10 cm2). The composition per unit area of all system sizes is identical.  Each system also contains 0.1 mL of alcohol USP per 10 cm2.

Dose* Size Fentanyl Content
(mcg/h) (cm2) (mg)
*      Nominal delivery rate per hour
25 10 2.5
50 20 5
75 30 7.5
100 40 10

Fentanyl Transdermal system is a rectangular transparent unit comprising a protective liner and four functional layers.  Proceeding from the outer surface toward the surface adhering to the skin, these layers are:
1) a backing layer of polyester film; 2) a drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetate copolymer membrane that controls the rate of fentanyl delivery to the skin surface; and 4 ) a fentanyl containing silicone adhesive. 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. Less than 0.2 mL of alcohol is also released from the system during use.

Do not cut or damage Fentanyl Transdermal system. If the Fentanyl Transdermal system is cut or damaged, controlled drug delivery will not be possible, which can lead to the rapid release and absorption of a potentially fatal dose of fentanyl.

Fentanyl Transdermal - Clinical Pharmacology

Pharmacology

Fentanyl is an opioid analgesic. Fentanyl interacts predominantly with the opioid µ-receptor. These μ-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 levels 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.

Pharmacokinetics

(see graph and tables)

Fentanyl Transdermal system releases fentanyl from the reservoir at a nearly constant amount per unit time. The concentration gradient existing between the saturated solution of drug in the reservoir 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 copolymer release membrane 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 (25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. The small amount of alcohol which has been incorporated into the system enhances the rate of drug flux through the rate-limiting copolymer membrane and increases the permeability of the skin to fentanyl.

Following Fentanyl Transdermal system 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 Fentanyl Transdermal system 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 24 and 72 hours after initial application (see Table A). Serum fentanyl concentrations achieved are proportional to the Fentanyl Transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first few system applications. After several sequential 72-hour applications, patients reach and maintain a steady state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl (see graph and Table B).

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 17 (range 13 to 22) 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 to 12) hours.

TABLE A FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF Fentanyl Transdermal SYSTEM
Mean (SD) Time to Maximal Mean (SD)
Concentration Maximal
Tmax Concentration
(h) Cmax
(ng/mL)
Fentanyl Transdermal System 25 38.1 (18.0) 0.6 (0.3)
mcg/h
Fentanyl Transdermal System 50 34.8 (15.4) 1.4 (0.5)
mcg/h
Fentanyl Transdermal System 75 33.5 (14.5) 1.7 (0.7)
mcg/h
Fentanyl Transdermal System 100 36.8 (15.7) 2.5 (1.2)
mcg/h

NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in 17 hours.

TABLE B RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS
Clearance Volume of Distribution Half-life
(L/h) VSS T1/2
Range (L/kg) (h)
[70 kg] Range Range
+Estimated
Surgical Patients 27 – 75 3 – 8 3 – 12
Hepatically Impaired Patients 3 – 80+ 0.8 – 8+ 4 – 12+
Renally Impaired Patients 30 – 78 -- --

NOTE: Information on volume of distribution and half-life not available for renally impaired patients.

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 to 8; N=8).

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.

The kinetics of fentanyl in geriatric patients have not been well studied, but in geriatric patients the clearance of IV fentanyl may be reduced and the terminal half-life greatly prolonged (see PRECAUTIONS).

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.

Drug Interactions

The interaction between ritonavir 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% to 420%) increase in fentanyl AUC0-∞. Coadministration of ritonavir in patients receiving Fentanyl Transdermal system has not been studied; however, an increase in fentanyl AUC is expected. (See BOX WARNING, WARNINGS, DOSAGE AND ADMINISTRATION and PRECAUTIONS.)

Pharmacodynamics

Ventilatory Effects

Because of the risk for serious or life-threatening hypoventilation, Fentanyl Transdermal system 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 Fentanyl Transdermal system, 13 patients 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 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-naïve post-operative patients who have experienced clinically significant hypoventilation and death with Fentanyl Transdermal system.

While most patients using Fentanyl Transdermal system 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 Fentanyl Transdermal system. The use of Fentanyl Transdermal system is contraindicated in patients who are not tolerant to opioid therapy. The use of Fentanyl Transdermal system should be monitored by clinical evaluation, especially within the initial 24 to 72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Fentanyl Transdermal system 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.

Cardiovascular Effects

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

CNS Effects

Central nervous system effects increase with increasing serum fentanyl concentrations.

Indications and Usage for Fentanyl Transdermal

Fentanyl Transdermal system is indicated for management of persistent, moderate to severe chronic pain that:

  • requires continuous, around-the-clock opioid administration for an extended period of time, and

  • cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids.

Fentanyl Transdermal system 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 Fentanyl Transdermal system 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, Fentanyl Transdermal system 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.

Contraindications

Because serious or life-threatening hypoventilation could occur, Fentanyl Transdermal system is contraindicated:

  • in patients who are not opioid-tolerant

  • in the management of acute pain or in patients who require opioid analgesia for a short period of time

  • in the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies)

  • in the management of mild pain

  • in the management of intermittent pain (e.g., use on an as needed basis [prn])

  • in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment

  • in patients who have acute or severe bronchial asthma

Fentanyl Transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.

Fentanyl Transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product.

Warnings

Fentanyl Transdermal system patches are intended for transdermal use (on intact skin) only. Using damaged or cut Fentanyl Transdermal system patches can lead to the rapid release of the contents of the Fentanyl Transdermal system patch and absorption of a potentially fatal dose of fentanyl.

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

Fentanyl Transdermal system 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 Fentanyl Transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean elimination half-life of Fentanyl Transdermal system is 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after Fentanyl Transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.

Fentanyl Transdermal system 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 Fentanyl Transdermal system application site to direct external heat sources, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death (see PRECAUTIONS – Patients with Fever/External Heat).

Death and other serious medical problems have occurred when people were accidentally exposed to Fentanyl Transdermal system.  Examples of accidental exposure include transfer of a Fentanyl Transdermal system 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 Fentanyl Transdermal system 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.

Misuse, Abuse and Diversion of Opioids

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 Fentanyl Transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Fentanyl Transdermal system 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.

Hypoventilation (Respiratory Depression)

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

Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of Fentanyl Transdermal system. 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 Fentanyl Transdermal system. 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.

Fentanyl Transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Fentanyl Transdermal system 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.

Chronic Pulmonary Disease

Because potent opioids can cause serious or life-threatening hypoventilation, Fentanyl Transdermal system 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.

Head Injuries and Increased Intracranial Pressure

Fentanyl Transdermal system should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 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. Fentanyl Transdermal system should be used with caution in patients with brain tumors.

Interactions with other CNS Depressants

The concomitant use of 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.

Interactions with Alcohol and Drugs of Abuse

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.

Interactions with CYP3A4 Inhibitors

The concomitant use of Fentanyl Transdermal system with potent cytochrome P450 3A4 inhibitors (ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) 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 Fentanyl Transdermal system and potent CYP3A4 inhibitors 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.)

Precautions

General

Fentanyl Transdermal system should not be used to initiate opioid therapy in patients who are not opioid-tolerant. Children converting to Fentanyl Transdermal system 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 Fentanyl Transdermal system was not prescribed. A considerable amount of active fentanyl remains in Fentanyl Transdermal system 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.

Cardiac Disease

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

Hepatic or Renal Disease

Insufficient information exists to make recommendations regarding the use of Fentanyl Transdermal system 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.

Patients with Fever/External Heat

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. Therefore, patients wearing Fentanyl Transdermal systems who develop fever should be monitored for opioid side effects and the Fentanyl Transdermal system dose should be adjusted if necessary.

All patients and their caregivers should be advised to avoid exposing the Fentanyl Transdermal system application site to direct external heat sources, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. There is a potential for temperature-dependent increases in fentanyl release from the system.

Use in Pancreatic/Biliary Tract Disease

Fentanyl Transdermal system 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 Fentanyl Transdermal system may cause increases in the serum amylase concentration.

Tolerance

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

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 level 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: Cessation of Therapy).

Ambulatory Patients

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

Information for Patients

A patient information sheet is included in the package of Fentanyl Transdermal system patches dispensed to the patient.

Patients receiving Fentanyl Transdermal system patches should be given the following instructions by the physician:

  1. Patients should be advised that Fentanyl Transdermal system patches contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.

  2. Patients should be advised that each Fentanyl Transdermal system patch may be worn continuously for 72 hours, and that each patch should be applied to a different skin site after removal of the previous transdermal patch.

  3. Patients should be advised that Fentanyl Transdermal system patches should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm.  Additionally, patients should be advised of the following:
        •     In young children or persons with cognitive impairment, the patch should be put on the upper back to lower the chances that the patch will be removed and placed in the mouth.
        •     Hair at the application site should be clipped (not shaved) prior to patch application.
        •     If the site of Fentanyl Transdermal system application must be cleansed prior to application of the patch, do so with clear water.
        •     Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics.
        •     Allow the skin to dry completely prior to patch application.

  4. Patients should be advised that Fentanyl Transdermal system should be applied immediately upon removal from the sealed package and after removal of the protective liner. Additionally the patient should be advised of the following:
        •     The Fentanyl Transdermal system patch should not be used if the seal is broken, or if it is altered, cut, or damaged in any way prior to application. This could lead to the rapid release of the contents of the Fentanyl Transdermal system patch and absorption of a potentially fatal dose of fentanyl. The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.
        •     The patch should not be folded so that only part of the patch is exposed.

  5. Patients should be advised that while wearing the patch, they should avoid exposing the Fentanyl Transdermal system application site to direct external heat sources, such as:
        •     heating pads,
        •     electric blankets,
        •     heat lamps,
        •     saunas,
        •     hot tubs, and
        •     heated water beds, etc.

  6. Patients should be advised that there is a potential for temperature-dependent increase in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, if patients develop a high fever while wearing the patch they should contact their physician.

  7. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down the toilet used Fentanyl Transdermal patches after removal from the skin.

  8. Patients should be instructed that, if the gel from the drug reservoir accidentally contacts the skin, the area should be washed clean with clear water and not soap, alcohol, or other chemicals, because these products may increase the ability of fentanyl to go through the skin.

  9. Patients should be advised that the dose of Fentanyl Transdermal system should NEVER be adjusted without the prescribing health care professional’s instruction.

  10. Patients should be advised that Fentanyl Transdermal system may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).

  11. Patients should be advised to refrain from any potentially dangerous activity when starting on Fentanyl Transdermal system or when their dose is being adjusted, until it is established that they have not been adversely affected.

  12. Patients should be advised that Fentanyl Transdermal system should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death.

  13. Patients should be advised to consult their physician or pharmacist if other medications are being or will be used with Fentanyl Transdermal system.

  14. Patients should be advised of the potential for severe constipation.

  15. Patients should be advised that if they have been receiving treatment with Fentanyl Transdermal system and cessation of therapy is indicated, it may be appropriate to taper the Fentanyl Transdermal system dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.

  16. Patients should be advised that Fentanyl Transdermal system contains fentanyl, a drug with a high potential for abuse.

  17. Patients, family members and caregivers should be advised to protect Fentanyl Transdermal system from theft or misuse in the work or home environment.

  18. Patients should be advised that Fentanyl Transdermal system should never be given to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended.

  19. Patients should be instructed to keep Fentanyl Transdermal system in a secure place out of the reach of children due to the high risk of fatal respiratory depression.

  20. When Fentanyl Transdermal system is no longer needed, the unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.

  21. Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult a physician prior to initiating or continuing therapy with Fentanyl Transdermal system.

  22. Patients should be informed that accidental exposure or misuse may lead to death or other serious medical problems.

  23. Patients should be informed that, if the patch dislodges and accidentally sticks to skin of another person, they should immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual.

Drug Interactions

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 Fentanyl Transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce 3A4 activity may reduce the efficacy of Fentanyl Transdermal system. The concomitant use of transdermal fentanyl with ritonavir or other potent 3A4 inhibitors such as ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone 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 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

Fentanyl Transdermal system 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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in animals to evaluate the carcinogenic potential of fentanyl HCl have not been conducted. 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/m2 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.

Pregnancy – Pregnancy Category C

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 mcg/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/m2 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/m2 basis).

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

Nonteratogenic Effects

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 though 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/m2 basis.

Labor and Delivery

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

Nursing Mothers

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

Pediatric Use

The safety of Fentanyl Transdermal system 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 or oral morphine or an equianalgesic dose of another opioid. Initiation of Fentanyl Transdermal system 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 (Fentanyl Transdermal system plus rescue medication) was provided by Fentanyl Transdermal system.

Fentanyl Transdermal system was not studied in children under 2 years of age.

Fentanyl Transdermal system should be administ

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