Duragesic (Fentanyl)

DURAGESIC®

Janssen-Ortho

Fentanyl

Opioid Analgesic

Action And Clinical Pharmacology: Fentanyl is an opioid analgesic which interacts predominantly with the opioid receptor. Fentanyl produces analgesia, sedation, respiratory depression, constipation, and physical dependence but appears to have less emetic activity than other opioid analgesics. Fentanyl may produce muscle rigidity, miosis, cough reflex suppression, alterations in mood, bradycardia and broncho-constriction.

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 man indicate that histamine release rarely occurs with fentanyl. Assays in man show no clinically significant histamine release in dosages up to 50 g/kg.

Duragesic provides continuous systemic delivery of fentanyl for up to 72 hours. Fentanyl is released along the concentration gradient existing between the saturated solution of the drug in the reservoir of the system and the lower concentration in the skin. 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.

The total amount of drug released is dependent on the area of the system. The 10, 20, 30 and 40 cmsystems are designed to deliver 25, 50, 75 or 100 g/hour fentanyl to the systemic circulation, representing approximately 0.6, 1.2, 1.8 or 2.4 mg/day. The 50, 75 and 100 g/hour doses are to be used only in opioid-tolerant patients.

Pharmacokinetics: Following initial Duragesic administration, serum fentanyl concentrations increase gradually, generally leveling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72-hour application period. Peak serum levels of fentanyl generally occur between 24 and 72 hours after the first application.

Serum fentanyl concentrations achieved are proportional to the Duragesic 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.

After Duragesic 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 i.v. infusion, where the apparent half-life ranges from 3 to 12 hours.

The average volume of distribution for fentanyl is 6 L/kg (range 3 to 8, n=8). The average clearance in patients undergoing various surgical procedures is 46 L/hour (range 27 to 75, n=8).

Elderly, cachectic or debilitated patients may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance. The clearance of fentanyl may be reduced, and the terminal half-life prolonged.

Skin does not appear to metabolize fentanyl delivered transdermally. Fentanyl is metabolized primarily in the liver. In humans, the drug is metabolized primarily by N-dealkylation to norfentanyl and other inactive metabolites. Approximately 75% of an i.v. fentanyl 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%.

Pharmacodynamics: In controlled clinical trials in nonopioid-tolerant patients, 60 mg/day i.m. morphine was considered to provide analgesia approximately equivalent to Duragesic 100 g/hour in an acute pain model. Minimum effective analgesic serum concentrations of fentanyl in opioid naive patients range from 0.2 to 1.2 ng/mL; side effects increase in frequency at serum levels above 2 ng/mL. Both the minimum effective concentration and the concentration at which toxicity occurs rise with increasing tolerance. The rate of development of tolerance varies widely among individuals.

Clinical Trials: During the premarketing phase, clinical trials were conducted in 153 patients to evaluate the efficacy and safety of Duragesic as therapy for pain due to cancer. The studies were open-labelled with the exception of one trial which incorporated a randomized, double-blind crossover component (Duragesic versus placebo) in 46 patients. Doses in these studies varied between 25 and 600 g/hour. Patients used Duragesic continuously for up to 866 days; 56% received Duragesic for over 30 days, 28% continued treatment for more than 4 months and 10% used Duragesic for more than 1 year. The results of these studies demonstrated that: 1) satisfactory analgesia was achieved in the majority of patients and, 2) Duragesic was accepted by cancer patients, their caregivers and physicians.

Since the introduction of Duragesic, additional trials have been conducted in approximately 350 chronic cancer pain patients to confirm earlier conclusions. In the largest of these, a Canadian postmarketing surveillance study in 199 patients, a reduction in pain intensity and improved pain relief and well-being were observed in the 127 patients evaluable for efficacy. Patient preference for Duragesic over their previous analgesic therapy was also observed. In these patients, the average treatment duration was 68 days (range: 17 to 118). The mean dose for all study patients increased from 51 g/hour at baseline to 128 g/hour at the last dose on therapy.

Indications And Clinical Uses: In the management of chronic cancer pain in patients requiring continuous opioid analgesia.

Duragesic should not be used in the management of postoperative pain because serious or life-threatening hypoventilation may result.

Contra-Indications: Because serious or life-threatening hypoventilation could occur, Duragesic is contraindicated in: 1) the management of acute or postoperative pain, including use in out-patient surgeries, 2) the management of mild or intermittent pain that can otherwise be managed, and 3) doses exceeding 25 g/hour at the initiation of Duragesic therapy in nonopioid-tolerant patients.

Patients with known hypersensitivity to fentanyl or to the adhesives present in the system.

Manufacturers’ Warnings In Clinical States: Duragesic should not be used in the management of acute or postoperative pain since there is no opportunity for dose titration during short-term use and because serious or life-threatening hypoventilation could result.

As with other CNS depressants, patients who have received Duragesic should be monitored until stabilized.

Since serum fentanyl concentrations decline gradually after system removal, patients who have experienced adverse events should be monitored for at least 12 hours after Duragesic removal or until the adverse reaction has subsided.

Duragesic should only be prescribed 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 respiratory depression including the use of opioid antagonists.

Patients with Fever/External Heat: Patients who develop fever should be monitored for opioid side effects and the Duragesic dose adjusted if necessary. Serum fentanyl concentrations could theoretically increase by approximately one third for patients with a body temperature of 40°C due to temperature dependent increases in fentanyl release from the system and increased skin permeability. All patients should be advised to avoid exposing the Duragesic application site to direct external heat sources, such as heating pads, electric blankets, heated water beds, heat lamps, hot water bottles, saunas and hot whirlpool spa baths, intensive sunbathing, etc.

Drug Interactions: The concomitant use of other CNS depressants (including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers), skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects. Hypoventilation, hypotension and profound sedation or coma may occur. When combined therapy is contemplated, the dose of each agent should be reduced by at least 50%.

Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Since the safety of fentanyl in this regard has not been established, the use of fentanyl in patients who have received MAO inhibitors during the previous 14-day period is not recommended.

Children: The use of Duragesic in children under 18 years of age is not recommended as efficacy, safety, and dosage requirements have not been established for this patient population. Life-threatening hypoventilation has been reported in some pediatric patients receiving Duragesic.

Precautions: General: Duragesic doses greater than 25 g/hour are too high for initiation of therapy in nonopioid-tolerant patients and should not be used to begin Duragesic therapy in these patients (see Dosage).

Occupational Hazards: Psychomotor Impairment: Duragesic may impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients using Duragesic should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.

Disposal of Duragesic: Duragesic should be kept out of the reach of children before and after use.

Used systems should be folded so that the adhesive side of the system adheres to itself, then flushed down the toilet immediately upon removal. If the gel from the drug reservoir accidentally contacts the skin, the area should be washed with clear water. Patients should dispose of any systems remaining from a prescription as soon as they are no longer needed. Unused systems should be removed from their pouch and flushed down the toilet.

Respiratory Depression: As with all potent opioids, some patients may experience significant respiratory depression with Duragesic; caution must be exercised and patients carefully observed for untoward reactions. While most patients using Duragesic chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy. A small number of patients have experienced clinically significant hypoventilation with Duragesic; medical intervention generally was not required in these instances. The incidence of respiratory depression increases as the Duragesic dose is increased.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations. However, the risk of hypoventilation increases at serum fentanyl concentrations greater than 2 ng/mL in nonopioid-tolerant patients, 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 (see Warnings regarding the use of concomitant CNS active drugs). The use of Duragesic should be monitored by clinical evaluation. As with other drug level measurements, serum fentanyl concentrations may be useful clinically, although they do not reflect patients sensitivity to fentanyl and should not be used by physicians as a sole indicator of effectiveness or toxicity.

The duration of the respiratory depressant effect of Duragesic may extend beyond the removal of the system. (See also Overdose concerning respiratory depression).

Drug Dependence: Fentanyl is an opioid substance and can produce drug dependence similar to that produced by morphine. Duragesic therefore has the potential for abuse. Tolerance, physical and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is relatively rare. Physicians should not let concerns of physical dependence deter them from using adequate amounts of opioids in the management of severe pain when such use is indicated.

Patients with Chronic Pulmonary Disease: Fentanyl should be used with caution in patients with chronic pulmonary disease, patients with decreased respiratory reserve and others with potentially compromised respiration. Normal analgesic doses of opioids may further decrease respiratory drive in these patients to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure: Duragesic 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. Duragesic should be used with caution in patients with brain tumors.

Patients with Cardiac Disease: I.V. fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias.

Patients with Hepatic or Renal Disease: Because of the hepatic metabolism and renal excretion of fentanyl, Duragesic should be used with caution in patients with liver or kidney dysfunction.

Geriatrics and Debilitated Patients: Elderly, cachectic or debilitated patients may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance. These patients should be started on Duragesic 25 g/hour unless they are taking at least 135 mg of oral morphine a day or an equivalent dose of another opioid (see Dosage).

Pregnancy: Fentanyl has been shown to impair fertility and to have an embryocidal effect in rats when given in i.v. doses 0.3 times the human dose for a period of 12 days. No evidence of teratogenic effects has been observed after the administration of fentanyl to rats.

The safe use of fentanyl has not been established with respect to possible adverse effects upon human fetal development. Therefore, Duragesic should not be used in women of childbearing potential unless, in the judgment of the physician, the potential benefits outweigh the possible hazards.

Labor and Delivery: Duragesic is not recommended for analgesia during labor and delivery.

Lactation: 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.

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

Drug or Alcohol Dependence: Use of Duragesic in combination with alcoholic beverages and/or other CNS depressants can result in increased risk to the patient. Duragesic should be used with caution in individuals who have a history of drug or alcohol abuse, especially those outside a medically controlled environment.

Adverse Reactions: In postmarketing experience, deaths from hypoventilation have been reported in cases of inappropriate use of Duragesic.

Premarketing Clinical Trial Experience: The safety of Duragesic has been evaluated in 153 cancer patients and 357 postoperative patients. The duration of use varied in cancer patients; 56% of patients used Duragesic for over 30 days, 28% continued treatment for more than 4 months, and 10% used Duragesic for more than 1 year. In cancer patients, Duragesic was administered in doses of 25 to 600 g/hour. Patients with acute pain used Duragesic for 1 to 3 days.

Respiratory depression, the most serious adverse reaction, was observed in 3 (2%) of the cancer patients and 13 (4%) of the postoperative patients.

Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.

A causal relationship of adverse events 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.

The adverse reactions in Table II were reported in 153 cancer patients at a frequency of 1% or greater; a higher incidence of adverse reactions was seen in the 357 postoperative patients studied.

Symptoms And Treatment Of Overdose: Symptoms: The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious effect being respiratory depression.

Treatment: For management of respiratory depression, immediate countermeasures include removing the Duragesic and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone. The duration of respiratory depression following an overdose may be longer than the effects of the opioid antagonist’s action (the half-life of naloxone ranges from 30 to 81 minutes). The interval between i.v. 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 opioid effect may result in acute onset of pain and release of catecholamines.

If the clinical situation warrants, establish and maintain a patent airway, administer oxygen and assist or control respiration as indicated, and use an oropharyngeal airway or endotracheal tube if necessary. If depressed respiration is associated with muscular rigidity, an i.v. neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. 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.

Dosage And Administration: Duragesic doses must be individualized based upon the status of each patient and should be assessed at regular intervals after application. Each patient should be maintained at the lowest dose providing acceptable pain control. The most important factor to be considered in determining the appropriate dose is the extent of pre-existing opioid tolerance. Reduced doses of Duragesic are suggested for the elderly and other groups discussed in Precautions.

Duragesic should be applied to nonirritated and nonirradiated skin on a flat surface such as the chest, back, flank, or upper arm. Hair at the application site should be clipped (not shaved) prior to application. If the site of application must be cleansed prior to application of the system, 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 system application.

Duragesic should be applied immediately upon removal from the sealed package. The system should not be altered, e.g., cut, in any way prior to its application. The transdermal system 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.

Each Duragesic may be worn continuously for 72 hours. A new system should be applied on a different skin site after removal of the previous transdermal system.

Initial Dose Selection: In selecting an initial Duragesic dose, attention should be given to 1) the daily dose, potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist-antagonist), 2) the reliability of the relative potency estimates used to calculate the Duragesic dose needed (potency estimates may vary with the route of administration), 3) the degree of opioid tolerance, if any, and 4) the general condition and medical status of the patient.

There has been no systematic evaluation of Duragesic as an initial opioid analgesic in the management of chronic pain, since most patients in the clinical trials were converted to Duragesic from other opioids. In nonopioid- tolerant patients, the initial dose of Duragesic should not exceed 25 g/hour.

Elderly, cachectic or debilitated patients may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance. These patients should be started on Duragesic 25 g/hour unless they are taking at least 135 mg of oral morphine a day or an equivalent dose of another opioid.

To convert opioid-tolerant patients from oral or parenteral opioids to Duragesic, the following methodology should be used:

1. Calculate the previous 24-hour analgesic requirement.

2. Convert this amount to the equianalgesic oral morphine dose.

3. Table IV displays the range of 24-hour oral doses that are recommended for conversion to each Duragesic dose. Use this table to find the calculated 24-hour morphine dose and the corresponding DuragEsic dose. This conversion recommendation is intentionally conservative to minimize the potential for Duragesic overdosage.

Initiate Duragesic treatment using the recommended dose and titrate patients upward (no sooner than 3 days after the initial dose or every 6 days thereafter) until analgesic efficacy is attained. For delivery rates in excess of 100 g/hour, multiple systems may be used.

The majority of patients are adequately maintained with Duragesic administered every 72 hours. A small number of patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied every 48 hours rather than every 72 hours. An increase in the Duragesic dose should be considered before changing dosing intervals in order to maintain patients on a 72-hour regimen.

Because of the gradual increase in serum fentanyl concentration over the first 24 hours following initial system application, the initial evaluation of the maximum analgesic effect of Duragesic cannot be made before 24 hours of wearing.

Patients should use short-acting analgesics after the initial dose application as needed until analgesic efficacy with Duragesic is attained. Thereafter, some patients still may require periodic supplemental doses of a short-acting analgesic for breakthrough pain.

Dose Titration: The conversion ratio from oral morphine to Duragesic is conservative, and 50% of patients are likely to require a dose increase after initial application of Duragesic. The initial Duragesic dosage may be increased after 3 days, based on the daily dose of supplemental analgesics required by the patient in the second or third day of the initial application.

Physicians are advised that it may take up to 6 days after increasing the dose of Duragesic for the patient to reach equilibrium on the new dose. Therefore, patients should wear a higher dose through 2 applications before any further increase in dosage is made on the basis of the average daily use of a supplemental analgesic.

Appropriate dosage increments should be based on the daily dose of supplementary opioids, using the ratio of 45 to 134 mg/24 hours of oral morphine to a 25 g/hour increase in Duragesic dose.

Some patients may require additional or alternative methods of opioid administration when the Duragesic dose exceeds 300 g/hour.

Discontinuation of Duragesic: To convert patients to another opioid, remove Duragesic and titrate the dose of the new analgesic, based upon the patient’s report of pain, until adequate analgesia has been attained. It should be noted that it takes 17 hours or more for the fentanyl serum concentration to fall by 50% after system removal. For patients requiring discontinuation of opioids, a gradual downward titration is recommended since it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.

Stability and Storage: Store in sealed pouch between 15 and 25°C. Keep out of reach of children before and after use.

Special Instructions: To dispose of Duragesic, fold the system so that the adhesive side of the system adheres to itself. The system should be flushed down the toilet immediately upon removal. If the gel from the drug reservoir accidentally contacts the skin, the area should be washed with clear water. Do not use soap, alcohol or other solvents to remove the gel because they may enhance the drug’s ability to penetrate the skin. Patients should dispose of any systems remaining from a prescription as soon as they are no longer needed. Unused systems should be removed from their protective pouch and flushed down the toilet.

Availability And Storage: Each transdermal system provides continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours. Duragesic is a rectangular transparent unit comprising a protective liner and 4 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 layer of silicone adhesive. A peelable protective liner covering the adhesive layer must be removed before the system can be applied.

The active component of the system is fentanyl. The amount of fentanyl released from each system per hour is proportional to the surface area (25 g/hour per 10 cm. The remaining components are pharmacologically inactive. Less than 0.2 mL of alcohol is released from the system during a 72-hour use. The composition per unit area of all system sizes is identical.

DURAGESIC® Janssen-Ortho Fentanyl Opioid Analgesic

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