Fentanyl (Transdermal-Systemic)
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VA CLASSIFICATION
Primary: CN101
Note: Controlled substance classification
Note: Controlled substance classification—
U.S.—Schedule II {01}
Canada—N {02}
Commonly used brand name(s): Duragesic.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Analgesic.—
Indications
Note: Transdermal fentanyl should be prescribed, and its use monitored, only by persons knowledgeable in the continuous administration of potent opioid analgesics, in the care of patients requiring such treatment, and in the detection and management of hypoventilation {01} {02}.
Use of this formulation requires that the advantages of providing a continuous, prolonged analgesic effect via a noninvasive, non-oral route of administration outweigh the disadvantage of being unable to adjust dosage rapidly should analgesic requirements change or adverse effects occur {05} {09}.
Accepted
Pain, chronic (treatment)—Transdermal fentanyl is indicated to relieve chronic pain that requires continuous treatment with a potent opioid analgesic {01} {02} {03} {04} {05} {06} {07} {08}. Most patients will need supplemental administration of an analgesic with a rapid onset and a short duration of action for pain relief during the interval between application of the first transdermal system and the onset of effective analgesia {01} {02} {03} {04} {05} {06} {07} {08} (24 hours or longer) {01} and for relief of breakthrough pain {01} {02} {03} {04} {05} {06} {07} {08}.
Unaccepted
Transdermal fentanyl is not recommended for treatment of acute pain (including postoperative pain). {01} {02} {31} Use of this formulation for postoperative pain may cause severe hypoventilation {01} {13}; a few fatalities have been reported {13}. Also, clinical trials have shown that application of transdermal fentanyl 2 hours prior to anesthesia does not eliminate the need for postoperative administration of a rapidly acting analgesic, especially in the first 12 to 24 hours after surgery {03} {09} {10} {11} {12} {14} {15} {16}. However, transdermal fentanyl need not be discontinued perioperatively if a patient being treated for chronic pain requires surgery {40}.
This formulation is not recommended for treatment of mild or intermittent pain that can be managed with less potent analgesics or with as-needed administration of short- {13} or intermediate-acting {30} opioid analgesics.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Synthetic.
Chemical group—
Phenylpiperidine derivative; chemically related to meperidine {03} {04}.
Molecular weight—
336.5 {01}
pKa—
8.4 {01} {03}
n-Octanol:water partition coefficient
860:1 {01} {03}.
Note: Physicochemical characteristics that facilitate percutaneous absorption of a medication include high lipid solubility (as indicated by a high n-octanol:water partition coefficient) {03} {09} {18} and relatively low molecular weight (< 1000 daltons) {03} {04} {18}. Lipophilic opioid analgesics such as fentanyl are well absorbed through intact skin; hydrophilic opioid analgesics (e.g., morphine, codeine, and hydromorphone) are not {03}.
Mechanism of action/Effect:
Opioid analgesics such as fentanyl bind with stereospecific receptors at many sites within the central nervous system (CNS) to alter processes affecting both the perception of and emotional response to pain. Although the precise sites and mechanisms of action have not been fully determined, alterations in the release of various neurotransmitters from afferent nerves sensitive to painful stimuli may be partially responsible for the analgesic effects. {17} {23}
Multiple subtypes of opioid receptors, each mediating various therapeutic and/or side effects of opioid analgesics, have been identified. The actions of an opioid analgesic may therefore depend on whether it acts as a full agonist or a partial agonist or is inactive at each type of receptor. {17} {23} Fentanyl probably produces its effects predominantly via agonist actions at the mu receptor {01} {02} {03} {04} {17}.
On a weight basis, fentanyl is considerably more potent than morphine. Transdermal administration of fentanyl at a delivery rate of 100 mcg per hour (mcg/hr) is therapeutically equivalent to intramuscular administration of 60 mg of morphine {01}, chronic oral administration of 180 mg of morphine {41}, or intermittent {41} oral administration of 360 mg of morphine per day {01} in 6 divided doses administered at 4-hour intervals {33}. This high potency permits a therapeutic dose to be applied to a relatively small skin area {27}.
Other actions/effects:
Fentanyl, like other opioid analgesics, may cause respiratory depression (characterized by decreases in respiratory rate, tidal volume, minute ventilation, and ventilatory response to carbon dioxide), increased biliary tone, increased smooth muscle tone in the urinary tract, decreased gastrointestinal motility, euphoria, miosis, hypotension, and bradycardia. However, unlike many other opioid analgesics, fentanyl does not cause clinically significant histamine release with therapeutic doses {01} {02} {03} {04} {17} (as determined by intravenous administration of single doses of up to 50 mcg per kg of body weight [mcg/kg]). {01} {02} {17}
Absorption:
Following application of a transdermal system, some fentanyl is released relatively rapidly from the adhesive layer of the system {03} {04}. Most of the fentanyl is located in a reservoir layer within the system, from which it is released gradually at a rate controlled by a restrictive {32} copolymer membrane located between the reservoir and adhesive layers {01} {04}. A very small quantity of alcohol present in the formulation enhances passage of the medication through both the rate-limiting restrictive membrane and the skin {01} {03}. Less than 0.2 mL of alcohol is released from a transdermal system {01}. The rate at which fentanyl is delivered to the skin may vary across the 72-hour application time {01} {02}. The labeled strength of a transdermal system represents the average quantity of fentanyl delivered to the systemic circulation per hour across intact skin {33} {34}.
Absorption of fentanyl after application of a transdermal system is initially slow because a depot of fentanyl, from which the medication is subsequently absorbed into the systemic circulation, must first form in the upper skin layers {01} {03} {09}. Absorption is subject to intra- as well as interindividual variability {03} {18}. The rate and/or extent of absorption may be altered by the temperature {01} {03}, state of hydration, and integrity of the skin at the application site {03}. Also, absorption may depend on blood flow in the area of application, which may increase or decrease with the patient's level of activity {03}. Despite these variables, the average quantity of fentanyl absorbed per hour into the systemic circulation of an individual patient is sufficiently consistent to permit dosage titration {01} over extended periods of time {32}.
Approximately 92% of the fentanyl contained in a transdermal system is absorbed into the systemic circulation over 72 hours {01} {03} {18} (calculated value) {33}. In a multiple-dose study, absorption from the fifth consecutive transdermal system to be applied and kept in place for 72 hours was 47% complete after 24 hours, 88% complete after 48 hours, and 94% complete after 72 hours {20}.
Absorption of fentanyl from the depot in the skin continues after removal of the transdermal system {01} {03} {09} {18}. When application sites are rotated, continued absorption prevents plasma concentrations from decreasing to subtherapeutic values while another depot is forming below the new application site. Failure to rotate application sites may lead to more rapid absorption and higher fentanyl concentrations, {03} which may increase the risk of toxicity. {01} {02}
Distribution:
Fentanyl is distributed to and accumulates in adipose tissue {01} {03} and skeletal muscle {01}. The medication is slowly released from these tissues to the systemic circulation {01}. Fentanyl readily crosses the blood/brain barrier {17}. Alterations in pH may affect the medication's distribution between CNS tissues and plasma {01}.
Volume of distribution (determined with intravenous administration to surgical patients)—6 (range, approximately 3 to 8) L per kg of body weight {01}.
Protein binding:
High (79 to 87%) {03}, primarily to albumin and lipoproteins; dependent on plasma pH {17}.
Biotransformation:
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, fentanyl is metabolized mostly by oxidative N-dealkylation to norfentanyl and other inactive metabolites. {45}
Fentanyl delivered transdermally is not metabolized in the skin.{01} {02}{45}
Half-life:
Elimination—Transdermal:
Single application—17 (range, 13 to 22) hours {01} {02}
Multiple applications—21.9±8.9 hours, determined after 5 consecutive 72-hour applications {20}.
Note: The prolonged elimination half-life with transdermal administration (relative to that with intravenous administration—about 3.6 hours) is due to prolonged continued absorption from the skin depot below the transdermal system {01} {02} {03} {04}.
Values may be greatly prolonged in geriatric patients {01}. In a single-dose study the mean value for patients 78 to 88 years of age was 43.1±23.4 hours {22}.
The half-life of transdermal fentanyl has not been assessed in patients with renal or hepatic function impairment {01} {03}.
Onset of action:
Very slow (12 to 24 hours in most studies) because of delayed absorption following application of an initial transdermal dose {03} {04} {09} {11} {12} {15} {16}.
Time to peak concentration:
Single 72-hour application—Generally between 24 and 72 hours {01} {02}.
Multiple applications—Concentrations continue to increase during the first few 72-hour applications {01} {20}.
Peak serum concentration
Serum concentrations achieved with transdermal fentanyl have been studied primarily in clinical trials that investigated whether the formulation might be useful for postoperative pain control. In general, the studies found fentanyl concentrations to be proportional to the transdermal delivery rate in mcg per hour, {34} subject to substantial interpatient variability {05} {18}, and significantly higher in geriatric patients than in younger adults {21} {22}. The concentrations produced were similar to those measured during continuous intravenous infusion of fentanyl at the same rate of administration, but took considerably longer to achieve {03} {18} {19}. In many studies, measurable quantities of fentanyl were not present in serum within the first 2 hours after application of an initial transdermal system {03}. Specific values determined during short-term use in postoperative patients are not likely to be relevant to prolonged use of this medication in chronic pain patients {35}.
Steady-state concentrations
A multiple-dose study in which pharmacokinetics of fentanyl were assessed during 5 consecutive 72-hour applications of a system designed to deliver 100 mcg per hour reported mean trough concentrations of 0.91±0.55 nanograms/mL (0.0027±0.0016 micromoles/L) prior to, and mean maximum concentrations of 2.6±1.3 nanograms/mL (0.0077±0.0039 micromoles/L) during, application of the fifth dose {20}. Steady-state concentrations are subject to substantial interpatient variability {20} because of individual differences in skin permeability and clearance of fentanyl {33}. Although several sequential 72-hour applications may be required to achieve steady-state {01}, measurement of trough concentrations prior to application of each dose in the multiple-dose study suggested that steady-state concentrations are approached by the second dose {20}.
Therapeutic concentrations
Generally 0.2 to 1.2 nanograms/mL (0.0006 to 0.0036 micromoles/L) in patients who are not tolerant to opioid analgesics {01} {02}. Required concentrations increase with the degree of tolerance to opioid analgesics {01} {02}. Fentanyl requirements are highly subject to intrapatient variability and dependent on the intensity of pain {17}.
Effective concentrations were reached between 1.2 and 37.3 hours after application of a transdermal system in various postoperative pain studies {04} {12} {14} {15} {18} {19}. In 1 of these studies, concentrations decreased to subtherapeutic values between 2.3 and > 24.9 hours (mean, 16.1±7.1 hours) after the system was removed {15}.
Duration of action:
Individual transdermal systems are designed to release fentanyl over 72 hours {01}. Analgesic effects may persist for several hours after a system is removed because of continued absorption {01} {03}. This provides relatively constant analgesia during the time required for an effective quantity of fentanyl to be absorbed from the next dose {03}.
Elimination:
Studies with intravenously administered fentanyl have shown that approximately 75% of a dose is eliminated in the urine (10% as unchanged fentanyl and the remainder as metabolites) and another 9% in the feces, mostly as metabolites {01} {02}. These studies also indicated that clearance rates are more variable and prolonged in patients with hepatic or renal function impairment than in patients with normal hepatic and renal function {01}. Clearance rates for transdermally administered fentanyl have not been published.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients hypersensitive to alfentanil or sufentanil may be hypersensitive to fentanyl also {17}.
Carcinogenicity
Long-term studies with fentanyl have not been done {01}.
Mutagenicity
No evidence of mutagenicity was demonstrated in the Ames test, primary rat hepatocyte unscheduled DNA synthesis assay, BALB/c-3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in vitro assays. In the mouse lymphoma assay, fentanyl concentrations more than 2000 times greater than those occurring with chronic systemic use were mutagenic only in the presence of metabolic activation. {01}
Pregnancy/Reproduction
Fertility—
Intravenous administration of 0.3 times the human dose of fentanyl for 12 days impaired fertility in rats {01}.
Pregnancy—
Adequate and well-controlled studies with transdermal fentanyl have not been done in pregnant women {01}. Chronic use of other opioids by pregnant women has caused physical dependence in the fetus, leading to withdrawal symptoms (convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting, diarrhea, sneezing, and yawning) in the neonate {23}. Also, use of opioid analgesics shortly before or during labor may cause respiratory depression in the neonate {23}.
Studies in rats have not shown that fentanyl is teratogenic {01}.
FDA Pregnancy Category C {01}.
Labor and delivery—
Use of transdermal fentanyl to provide analgesia during labor and delivery is not recommended {01}.
Breast-feeding
Fentanyl is distributed into human breast milk. Nursing infants may ingest quantities of fentanyl sufficient to produce adverse effects typical of potent opioid analgesics, including sedation, respiratory depression, and physical dependence when the mother is receiving chronic, high-dose treatment. Use of transdermal fentanyl by nursing women is therefore not recommended. {01} {02}
Pediatrics
No information is available on the relationship of age to the effects of transdermal fentanyl in pediatric patients. Safety and efficacy have not been established. {01} {02} Administration to children younger than 12 years of age is not recommended except in an authorized investigational research setting. {13}
Adolescents
No information is available on the relationship of age to the effects of transdermal fentanyl in adolescents up to 18 years of age. Safety and efficacy have not been established. {01} {02} Administration to patients younger than 18 years of age who weigh less than 50 kg is not recommended except in an authorized investigational research setting. {13}
Geriatrics
No information is available on the relationship of age to the effects of transdermal fentanyl in geriatric patients with chronic pain {04}. However, it is known that geriatric patients are generally more susceptible to the effects, especially the respiratory depressant effects, of opioid analgesics {17} {23}. Short-term pharmacokinetic studies with transdermal fentanyl have shown that the elimination half-life {22} and serum concentrations {21} {22} are significantly higher in elderly individuals than in younger people. Also, in a study that utilized an investigational 24-hour transdermal system {33} with a delivery rate of 50 mcg per hour, the systems were removed earlier than anticipated from all of the elderly subjects (planned application time 24 hours; mean time of removal 11.7 ± 4.9 hours), but none of the younger individuals, because of adverse effects {21}. Caution and careful attention to dosage are recommended, especially if the patient is not tolerant to opioid analgesics {01} {02}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
» Alcohol or
» CNS depression–producing medications, other (See Appendix II ) (concurrent or sequential use with fentanyl may result in increased CNS depressant, respiratory depressant, and hypotensive effects; caution and careful titration of the dose of each agent are recommended {01} {02} {17})
(concurrent use of fentanyl with other CNS depressants that may cause habituation may increase the risk of habituation {23})
Anticholinergics or other medications with anticholinergic activity (See Appendix II ) (concurrent use with fentanyl may result in increased risk of severe constipation, which may lead to paralytic ileus, and/or urinary retention {23})
Antidiarrheals, antiperistaltic, such as:
Difenoxin and atropine
Diphenoxylate and atropine
Loperamide
Opium tincture
Paregoric (repeated administration of any of these antidiarrheals with fentanyl, especially during chronic, high-dose fentanyl therapy, may increase the risk of severe constipation and CNS depression {23})
Antihypertensives, especially ganglionic blockers such as guanadrel, guanethidine, and mecamylamine or
Diuretics or
Hypotension-producing medications, other (see Appendix II ) (hypotensive effects of these medications may be potentiated when they are used concurrently with fentanyl; patients should be monitored for excessive fall in blood pressure {17})
(concurrent use of a beta-adrenergic blocking agent with fentanyl may also increase the risk of bradycardia {17})
» CYP3A4 Inducers, such as:
Carbamazepine,
Phenytoin or
Rifampin (concurrent use of CYP3A4 inducers with fentanyl may cause increased clearance of fentanyl, resulting in decreased opioid effects{45})
» CYP3A4 Inhibitors, such as:
Azole antifungal agents (e.g., ketoconazole),
Macrolide antibiotics (e.g., erythromycin) or
Protease inhibitors (e.g., ritonavir) (concurrent use of CYP3A4 inhibitors with fentanyl may cause decreased clearance of fentanyl, resulting in increased or prolonged opioid effects{45})
Hydroxyzine (concurrent use with fentanyl may result in increased analgesia as well as increased CNS depressant and hypotensive effects {23})
Metoclopramide (fentanyl may antagonize the effects of metoclopramide on gastrointestinal motility {23})
Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline (caution is recommended when any opioid analgesic is given to patients who have received an MAO inhibitor within 14 days because administration of meperidine to patients receiving MAO inhibitors has caused unpredictable, severe, and sometimes fatal reactions, including immediate excitation, sweating, rigidity, and severe hypertension, or, in some patients, hypotension, severe respiratory depression, coma, seizures, hyperpyrexia, and vascular collapse; although a few reports indicated that intravenous injections of fentanyl did not cause adverse reactions when administered perioperatively to patients receiving MAO inhibitor therapy, {17} administration of an intravenous test dose of fentanyl [to detect any possible interaction] may be advisable prior to initiation of transdermal therapy because the effects of transdermal fentanyl cannot be terminated rapidly)
Naloxone (antagonizes the analgesic, CNS, and respiratory depressant effects of opioid analgesics; however, because naloxone may precipitate withdrawal symptoms in physically dependent patients, dosage of naloxone should be carefully titrated when it is used to treat opioid overdosage in dependent patients; also, because absorption of fentanyl from the depot that forms in the skin layers below the transdermal system continues after the system has been removed, prolonged infusion or repeated administration of naloxone may be required {17} {23})
» Naltrexone (fentanyl will be ineffective if administered to a patient receiving naltrexone, which blocks the therapeutic effects of opioid analgesics; administration of increased doses of an opioid analgesic to override naltrexone blockade of opioid receptors may result in increased and prolonged respiratory depression and/or circulatory collapse and is not recommended)
(administration of naltrexone to a patient who is physically dependent on fentanyl will precipitate withdrawal symptoms; symptoms may appear within 5 minutes of naltrexone administration, persist for up to 48 hours, and be very difficult to reverse {23})
Neuromuscular blocking agents and possibly other medications having some neuromuscular blocking activity (respiratory suppressant effects of neuromuscular blockade may be additive to the central respiratory depressant effects of opioid analgesics; increased or prolonged respiratory depression [apnea] may occur but is of minor clinical significance if the patient is being ventilated mechanically; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade {23})
» Opioid analgesics, other (although most patients require supplemental administration of an analgesic with a rapid onset of action for pain relief during the interval between application of the first transdermal system and the onset of effective analgesia [24 hours or longer] and for relief of breakthrough pain, {01} {02} {03} {04} {05} {06} {07} {08} {09} {11} {12} {15} {16} the risk of additive CNS and/or respiratory depression or other adverse effects must be considered, especially in patients who are not tolerant to opioid analgesics; {01} {02} use of long-acting opioid analgesics [or extended-release dosage forms of short-acting opioids] in conjunction with transdermal fentanyl may be especially hazardous and is not recommended {05})
(in addition to their potential for causing additive effects when used concurrently with fentanyl, opioids having partial mu-receptor activity [e.g., buprenorphine and dezocine] and some opioids having mixed agonist/antagonist activity [i.e., nalbuphine and pentazocine] have the potential to antagonize fentanyl's therapeutic and adverse effects; whether additive or antagonistic effects occur may depend on the dose of each medication as well as on the order in which the medications are given and the extent to which physical dependence has developed; administration of a partial mu-receptor agonist prior to an initial dose of fentanyl may reduce the therapeutic response to fentanyl, whereas administration of a partial mu-receptor agonist, nalbuphine, or pentazocine to a patient who is receiving fentanyl may antagonize fentanyl's effects to the extent of precipitating withdrawal symptoms in physically dependent patients {17} {23})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Gastric emptying studies (opioid analgesics may delay gastric emptying, thereby invalidating test results {17})
Hepatobiliary imaging using a technetium Tc 99m–labeled iminodiacetic acid derivative (delivery of the radiopharmaceutical to the small bowel may be slowed because of fentanyl-induced constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization, which may be falsely interpreted as indicating obstruction of the common bile duct {17})
With physiology/laboratory test values
Amylase, plasma and
Lipase, plasma (enzyme values may be increased because fentanyl can cause contractions of the sphincter of Oddi and increased biliary tract pressure; the diagnostic utility of determinations of these enzymes may be compromised during, and for a time following discontinuation of, transdermal fentanyl therapy {17})
Cerebrospinal fluid pressure (fentanyl may increase cerebrospinal fluid pressure; effect is secondary to respiratory depression–induced carbon dioxide retention {17})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Diarrhea associated with pseudomembranous colitis caused by cephalosporins, lincomycins (possibly including topical clindamycin), or penicillins or
» Diarrhea caused by poisoning, until toxic material has been eliminated from the gastrointestinal tract (opioid analgesics may slow elimination of toxic material, thereby worsening and/or prolonging the diarrhea {23})
» Respiratory depression, acute (may be exacerbated {23})
Risk-benefit should be considered when the following medical problems exist
Abdominal conditions, acute (diagnosis or clinical course may be obscured {23})
Allergic reaction to fentanyl, alfentanil, or sufentanil, or to the adhesives in the transdermal system {01} {02} {03} (risk of hypersensitivity reaction)
» Asthma, acute attack {23} or
» Respiratory impairment or disease, chronic {01} {02} {03} {23} (opioids may decrease respiratory drive and increase airway resistance in patients with these conditions)
Bradyarrhythmias (may be exacerbated {01} {02} {03})
Drug abuse or dependence, current or history of, including alcoholism {01} {23} or
Emotional instability or {23}
Suicidal ideation or attempts {23} (patient predisposition to drug abuse; possibility of adverse effects if patient uses nonprescribed CNS depressants concurrently with fentanyl)
(although this medication should not be withheld from known opioid addicts who require treatment for chronic pain, caution is recommended; addicts treated with fentanyl transdermal systems have been reported to increase the rate of fentanyl release by disrupting the restrictive membrane and to remove fentanyl from the reservoir for rapid administration by other routes {42})
Fever (temperature-dependent changes in fentanyl release from the transdermal system and increased skin permeability may result in a 33% increase in fentanyl plasma concentrations in patients with a fever of 40 °C [102 °F]; patients who develop a fever while a system is in place should be monitored for adverse effects and fentanyl dosage adjusted and/or treatment instituted as needed {01} {02})
Gallbladder disease or gallstones (fentanyl may cause biliary contraction and increased biliary tract pressure; biliary colic may be exacerbated rather than relieved {01} {23})
Gastrointestinal tract surgery, current or recent (alteration of gastrointestinal motility by fentanyl may be undesirable {23})
Head injury or
Increased intracranial pressure, pre-existing or
Intracranial lesions (risk of respiratory depression and further elevation of cerebrospinal fluid pressure, which may lead to complications such as impaired consciousness, is increased; also, opioid analgesics may cause sedation and pupillary changes that may obscure the clinical course of patients with head injury {01} {02} {23})
Hepatic function impairment or
Renal function impairment (potential for reduced clearance of fentanyl, leading to higher plasma concentrations {01} {23}; pharmacokinetic studies on which recommendations regarding use of transdermal fentanyl could be based have not been done in patients with these conditions {03})
(fluid retention associated with renal function impairment may be exacerbated because fentanyl may also cause urinary retention {23})
Hypothyroidism (risk of respiratory depression and prolonged CNS depression is greatly increased {23})
» Inflammatory bowel disease, severe (risk of toxic megacolon, especially with prolonged use of fentanyl {23})
Prostatic hypertrophy or obstruction or
Urethral stricture or
Urinary tract surgery, current or recent (patient predisposition to urinary retention {23})
Caution is also recommended in administration to elderly or very ill or debilitated patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of opioid analgesics. {02} {23}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood pressure and
Heart rate and
» Respiratory rate and
» Sedation, degree of (should be monitored at periodic intervals, especially at the beginning of therapy and after increases in dosage; if the system is removed because of adverse effects, monitoring should continue for at least 12 hours because absorption of fentanyl continues, and serum concentrations decrease slowly, after the system is removed {01} {02})
Side/Adverse Effects
Note: The frequencies of the adverse effects reported below were obtained in clinical studies in 510 patients (153 cancer patients, 56% of whom received treatment lasting from 30 days to more than a year, and 357 surgical patients who received the medication for 1 to 3 days) {01}, almost all of whom received supplemental doses of other opioid analgesics {01} {02} {03} {04} {05} {06} {07} {08} {09} {11} {12} {15} {16}. The relative contribution of fentanyl, other opioid analgesic(s), the patient's underlying condition, and/or various surgical procedures to the occurrence of specific symptoms has not been established {01} {03} {04} {05}.
The risk of hypoventilation and of CNS adverse effects in opioid-naive individuals {33} is increased when serum concentrations of fentanyl reach 2 nanograms per mL (nanograms/mL) (0.006 micromoles/liter [micromoles/L]) {01} {02} and more than 3 nanograms/mL (0.009 micromoles/L), {01} respectively. The concentration at which toxicity occurs increases with increasing tolerance to the opioid analgesic {01} {02}.
In addition to the side/adverse effects listed below, a case of toxic delirium has been reported {24} in an elderly patient receiving 125 mcg per hour of transdermal fentanyl together with other CNS depressants {33}.
Physical dependence, with or without psychological dependence, may occur with chronic administration of fentanyl; an abstinence syndrome may occur when the medication is discontinued abruptly {01} {02}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent (3 to 10%)
Apnea
CNS depression
difficult breathing
hypoventilation —respiratory rate < 8 breaths per minute, pCO 2 > 55 mm Hg
hallucinations (seeing, hearing, or feeling things that are not there)
urinary retention (decreased frequency of urination; decrease in urine volume)
Note: The risk of hypoventilation is higher in nontolerant women than in men, in patients weighing less than 63 kg, in patients with pre-existing respiratory function impairment, and in patients receiving doses of 75 mcg per hour or higher {01}.
Incidence less frequent (1 to 3%)
Chest pain
CNS effects (abnormal thinking; difficulty in speaking; fainting; problems with coordination or gait), paranoia (delusions of persecution, mistrust, suspiciousness, and/or combativeness)—frequency of CNS effects and paranoia symptoms is 1 to 3% in clinical studies
irregular heartbeat
localized skin reaction (redness, swelling, and/or bumps on the skin, with or without itching, at place of application )
spitting blood
Note: Fainting occurs more frequently in ambulatory than in recumbent patients {01} and may be associated with postural hypotension {23}. Localized reactions to the transdermal system are probably caused by the adhesive rather than by fentanyl. These reactions have been characterized as mild, transient (generally disappearing within 6 to 24 hours after removal of the transdermal system), and more typical of local irritation and occlusion than of allergic contact dermatitis {03}. Generalized skin reactions also may occur; at least 1 case of diffuse, nonpruritic macular papules has been attributed to transdermal fentanyl therapy {25}.
Incidence rare (less than 1%) {01}
Abdominal distention (swelling of abdominal area)
amblyopia (any change in vision)
bladder pain
bradycardia ( slow heartbeat)
cessation of urination
CNS toxicity (inability to speak; depersonalization ; stupor)
dermatitis, exfoliative (fever with or without chills; red, thickened, or scaly skin; swollen and/or painful glands ; unexplained bruising)
fluid-filled blisters
frequent urge to urinate
respiratory problems, including asthma (noisy breathing; shortness of breath; troubled breathing; tightness in chest; wheezing)
Incidence not determined
—Observed during clinical practice; estimates of frequency cannot be determined{45}
Edema {45}(decreased urination; rapid weight gain; bloating or swelling of face, hands, lower legs, and/or feet )
tachycardia {45}(fast, pounding, or irregular heartbeat or pulse)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (each symptom 3% or higher) {01} {02}
CNS effects (anxiety; confusion; dizziness; drowsiness; false sense of well-being; nervousness; weakness)
gastrointestinal effects ( abdominal pain; constipation; diarrhea; indigestion; loss of appetite)
headache
itching of skin
nausea
sweating
vomiting
Note: Nausea and vomiting are more likely to occur in ambulatory than in recumbent patients {01}. These effects may be induced by a direct effect on the chemoreceptor trigger zone in the CNS {01}.
Incidence less frequent (1 to 3%)
Agitation (feeling anxious and restless)
bloated feeling or gas
feeling of crawling, tingling, or burning of the skin
memory loss
unusual dreams
Incidence not determined
—Observed during clinical practice; estimates of frequency cannot be determined {45}
Blurred vision {45}
weight loss {45}
Those indicating possible withdrawal and the need for medical attention if they occur after medication is discontinued
Body aches
diarrhea
fast heartbeat
fever, runny nose, or sneezing
gooseflesh
increased sweating
increased yawning
loss of appetite
nausea or vomiting
nervousness, restlessness, or irritability
shivering or trembling
stomach cramps
trouble in sleeping
unusually large pupils
weakness
Note: Opioid withdrawal symptoms, such as nausea, vomiting, diarrhea, anxiety and shivering, are possible following a conversion or dose adjustment. {45}
Overdose
For specific information on the agents used in the management of fentanyl overdose, see: • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
• Naloxone (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Listing ).
Clinical effects of overdose
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic {23}
Cold, clammy skin
confusion
convulsions
severe dizziness, drowsiness, nervousness, restlessness, or weakness
low blood pressure
pinpoint pupils of eyes
slow heartbeat
slow or troubled breathing
unconsciousness
Treatment of overdose
General measures—Removing the transdermal system (if symptoms are judged sufficiently severe to warrant removal) and monitoring the patient, keeping in mind that fentanyl absorption continues and plasma concentrations decline slowly after the system has been removed {01} {05}. Prolonged monitoring may be needed {02}.
Specific treatment—
For hypoventilation:
Verbal stimulation or waking the patient (if bradypnea occurs during sleep) may be sufficient to increase the respiratory rate and provide adequate ventilation {01} {02} {05} {09} {27}.
Use of the opioid antagonist naloxone {01} {02} {05} {23} if necessary. However, usual doses of naloxone may reverse analgesia {37} and precipitate withdrawal in opioid-dependent patients {33} {38}. Since naloxone's duration of action is considerably shorter than that of transdermal fentanyl, administration via continuous intravenous infusion at a rate titrated to the needs of the individual patient may be necessary {05}.
For bradycardia: Use of atropine {04}.
For hypotension: Use of intravenous fluids and/or vasopressors and using other supportive measures as needed {23}.
Supportive care—May include establishing adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled respiration {01} {02} {23}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Fentanyl (Transdermal-Systemic)
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to fentanyl, alfentanil, or sufentanil
Pregnancy—Opioids cross the placenta; use by pregnant women may cause physical dependence in the fetus and withdrawal symptoms and/or respiratory depression in the neonate
Breast-feeding—Fentanyl is distributed into breast milk; opioid effects including sedation, respiratory depression, and physical dependence may occur in the infant if the mother is receiving chronic, high-dose therapy
Use in the elderly—Geriatric patients are more susceptible to the effects of opioids, especially respiratory depression
Other medications, especially alcohol or other CNS depressants (including other opioid analgesics), CYP3A inducers (such as carbamazepine, phenytoin or rifampin), CYP3A inhibitors (such as ketoconazole, erythromycin or ritonavir) and naltrexone
Other medical problems, especially asthma or other acute or chronic respiratory problems, diarrhea caused by poisoning or antibiotic therapy, and severe inflammatory bowel disease
Proper use of this medication
» Reading patient instructions carefully before using
» Proper application technique
Keeping medication in sealed pouch until ready to apply
Using caution in handling; not touching adhesive surface with the hand; washing area with clear water if medication does touch the skin in an unintended location
Using care not to damage (puncture or tear) the surface of the transdermal system
Applying to clean, dry skin area of upper arm or torso that is free of oil, hair, scars, cuts, burns, or irritation; avoiding areas that have been irradiated
Clipping, not shaving, hair at application site, if necessary
If cleansing site prior to application, using only clear water (not soaps, lotions, or cleansers that contain oils, alcohol, or other agents) and allowing area to dry completely prior to application
Removing liner from adhesive layer, then pressing system in place with palm of hand for a minimum of 30 seconds; making sure that good contact is achieved, especially around the edges
If the patch does not stick well or loosens after application, tape the edges down with first aid tape {46}
If the patch falls off after application, discard it and apply a new patch on a different skin site{46}
If dose requires applying 2 or more systems, keeping them far enough apart so that the edges do not touch or overlap {32} {43}
Washing hands with clear water after applying or handling transdermal system
Removing system after 3 days; applying next system, if treatment is being continued, at new site, preferably on opposite side of the body; {32} {43} not reusing a site for at least 3 days {32} {36} {43}
Disposing of used or unneeded systems by folding in half with adhesive layer inside the fold, then flushing down the toilet
» Not using more transdermal fentanyl than directed, even if medication appears ineffective; onset of action may require 24 hours or longer and several dosage adjustments may be required to achieve maximum effectiveness
» Taking “rescue”doses of short-acting opioid for first few days after initiation of therapy and for breakthrough pain, but not using more than prescribed because of danger of overdose
» Proper dosing
Missed dose: Applying as soon as possible
» Proper storage
Precautions while using this medication
Regular consultations with health care professional during long-term therapy
» Checking with health care professional before increasing dose of transdermal fentanyl and/or “rescue” medication if treatment becomes less effective
» Avoiding use of alcoholic beverages or other CNS depressants during therapy, unless prescribed or otherwise approved by physician
» Caution if dizziness, drowsiness, lightheadedness, or false sense of well-being occurs; checking with health care professional if severe drowsiness persists for more than a few days
» Getting up slowly from a lying or sitting position; lying down for a while may provide relief if patient becomes dizzy, lightheaded, or faint
Caution that nausea or vomiting may occur, especially during first several days of treatment, and may be relieved by lying down; checking with health care professional if severe, since an antiemetic may be needed
» Compliance with regimen for preventing severe constipation, if prescribed
» Avoiding external sources of heat (e.g., heating pad, sunlamps, heated water beds, electric blankets, sunbathing, prolonged baths or showers in hot water) and checking with health care professional if fever occurs; absorption of fentanyl may be accelerated {44}
» Informing physician or dentist of use of medication if any kind of surgery (including dental surgery) or emergency treatment is required
System may be worn while bathing, showering, or swimming, but should not be rubbed vigorously because it may become loose or detached; discarding system and applying a new one in an alternate, dry location if this occurs
» Not discontinuing medication abruptly after prolonged use; checking with physician instead, since gradual withdrawal may be needed to minimize risk of precipitating abstinence syndrome
» Suspected overdose: Getting emergency help at once
Side/adverse effects
Getting emergency help if symptoms of overdose occur, i.e., very slow (fewer than 8 breaths per minute) or troubled breathing, extreme drowsiness, convulsions, low blood pressure, or slow heartbeat
Other potential side effects, especially hallucinations or other CNS effects, urinary retention, chest pain, irregular heartbeat, localized skin reactions, skin rash or blisters, spitting blood, abdominal distention, amblyopia, bladder pain, bradycardia, exfoliative dermatitis, urinary frequency, edema and tachycardia
General Dosing Information
Transdermal fentanyl may cause respiratory depression, especially in elderly, very ill, or debilitated patients and patients with pre-existing respiratory problems {01}. Lower doses may be required for these patients, at least initially {01}. However, elderly patients may also be more sensitive to the analgesic effects of opioid analgesics, and lower doses may be sufficient to provide effective analgesia {23}.
Dosage must be individualized {01} {02} {03}. Pre-existing tolerance to opioid analgesics is the primary factor to be considered in determining the appropriate initial dose of transdermal fentanyl {01} {02}. The rate at which tolerance develops varies widely among individuals {01} {02}. For patients who have been receiving chronic therapy with another opioid analgesic, initial dosage of transdermal fentanyl should be based on the patient's daily opioid requirement {01} {02} {03}.
The transdermal system should be kept in the protective packaging until it is used. It should be applied to a dry, flat, nonirritated, non-irradiated skin surface of the upper arm or torso. If necessary, hair at the application site may be clipped (but not shaved) prior to application. Also, if the site is cleansed prior to application, clear water should be used; soaps, oils, lotions, alcohol, or other agents that may irritate the skin or change its characteristics should be avoided. The system should be pressed firmly in place with the palm of the hand for about 30 seconds, making sure that contact is complete, especially around the edges. {01} {02} {13}
Because of the delayed onset of action after initial application of a fentanyl transdermal system, the adequacy of analgesia cannot be evaluated for 24 hours {01} {02}. A short-acting opioid analgesic must be administered as needed to relieve pain {01} {02} {03} {04} {05} {06} {07} {08} {09} {11} {12} {15} {16}. If necessary, a higher dose may be applied for the second 72 hours, based on the quantity of supplemental opioid required during the second or third day of the first 72-hour application {01} {02}. Subsequent increases in dosage, if needed, should be made at 6-day intervals {01} {02}, with "rescue" doses continuing to be administered as needed until maximum analgesia has been attained {05}. Some patients may require "rescue" dosing with a short-acting opioid analgesic for breakthrough pain throughout transdermal fentanyl therapy {01} {02}.
Some patients may not achieve adequate analgesia using a 72 hour dosing interval and may require systems to be applied every 48 hours. However, an increase in the fentanyl dose should be evaluated before reducing the dosing interval.{46}
The fentanyl transdermal system should be removed after 72 hours. If treatment is being continued, a new system should be applied at a new site after the prior one has been removed. {01} {02}
Concurrent administration of a nonopioid analgesic (such as aspirin or other salicylates, other nonsteroidal anti-inflammatory drugs, or acetaminophen) with opioid analgesics provides additive analgesia and may permit lower doses of the opioid analgesic to be utilized {23}.
The overall treatment regimen for chronic pain patients who are receiving long-term opioid analgesic therapy includes management of common side effects such as sedation, nausea and vomiting, and constipation {05} {26}. An antiemetic may be needed, especially during the first few weeks of therapy {26}. Also, measures to prevent constipation and decrease the risk of intestinal obstruction may be needed, such as administration of a laxative (a bowel stimulant and/or a stool softener) {26}, a high fluid intake {37}, and an increase in dietary fiber. Appropriate medications and dosages must be determined according to the physical condition and the needs of the individual patient {26}.
Increases in the dosage of transdermal fentanyl and/or "rescue" medications may be required as tolerance to the medication develops or increases and/or the intensity of pain increases {01} {02}. Tolerance to the respiratory depressant effects of an opioid analgesic develops concurrently with tolerance to its analgesic effects. Careful adjustment of dosage as required to provide adequate analgesia is not likely to increase the risk of respiratory depression. {23} However, a reduction in dose may be needed to prevent respiratory depression, which may occur even at a previously well-tolerated opioid dose, if the intensity of pain decreases {27} because of changes in the patient's condition or institution of other pain-relieving treatments.
Psychological and physical dependence may occur with chronic administration of an opioid analgesic; an abstinence syndrome may occur when the medication is discontinued. However, physical dependence in patients receiving prolonged therapy for severe chronic pain rarely leads to true addiction, i.e., a desire to continue taking the medication (for its euphoric effect) after it is no longer required for pain relief. Fear of causing addiction should not result in failure to provide adequate pain relief, although caution is advised if patient predisposition toward drug abuse is known or strongly suspected. {02} {23} Reducing the dose gradually prior to discontinuation may minimize the development of withdrawal symptoms following prolonged use {01} {02} {03} {23}.
If a patient is being changed from transdermal fentanyl to another opioid analgesic, the transdermal system should be removed and the new analgesic administered in a low dose that may be gradually increased according to the patient's report of pain until adequate analgesia is achieved {01} {02}. The fact that fentanyl concentrations decrease very slowly after removal of the system must be considered when selecting a starting dose of the new agent. Also, the oral morphine–to–transdermal fentanyl conversion ratios recommended by the manufacturer for determining initial doses of transdermal fentanyl for opioid-tolerant patients are very conservative. Using the reverse of these ratios to calculate an appropriate dose of a subsequently administered opioid could result in an overdose and is not recommended. {33}
Safety considerations for handling this medication
The transdermal system is supplied in sealed systems that pose little risk of exposure to health care personnel. If any of the gel in the reservoir should contact the skin, the area should be flushed with copious quantities of water. Soap, alcohol, or other solvents may enhance penetration of fentanyl through the skin and should not be used. {01} {02}
Transdermal Dosage Forms
FENTANYL TRANSDERMAL SYSTEM
Note: The doses and strengths of the fentanyl transdermal system are expressed in terms of the delivery rate in mcg per hour.
Usual adult dose
Analgesic
For chronic pain: Transdermal, the appropriate number of transdermal systems to be applied and kept in place for seventy-two hours.
For patients who are not opioid-tolerant—Not more than one transdermal system rated to deliver 25 mcg (0.025 mg) per hour, initially. Dosage may be increased gradually as needed and tolerated until an adequate response has been attained. {01} {02}
For opioid-tolerant patients—Initially, a quantity of fentanyl (in mcg per hour) equivalent to the patient's current twenty-four-hour oral morphine requirement, as follows {01} {02}:
Note: The oral morphine-to-transdermal fentanyl conversion ratios listed above are conservative; the need for an increase in dose should be anticipated {01}. The second dose of transdermal fentanyl may be increased by 25 mcg per hour for each 90 mg per day of supplemental oral morphine (or equivalent dosage of other opioid analgesics) required during the second or third day of the first application {01}. Six days may be required to reach equilibrium after each increase in dose; therefore, the higher dose should be worn for seventy-two-hour applications before further increases are made {01}{02}. If necessary, more than one transdermal system may be applied at a time {01}{02}.
A few patients may need replacement of the transdermal system(s) every forty-eight hours {01}. Before the interval between applications is decreased, an attempt should be made to maintain the seventy-two-hour interval {01}.
| Fentanyl (mcg/hr) |
Morphine * (mg/24 hr) |
|---|---|
| Oral |
|
| 25 |
45–134 |
| 50 |
135–224 |
| 75 |
225–314 |
| 100 |
315–404 |
| 125 |
405–494 |
| 150 |
495–584 |
| 175 |
585–674 |
| 200 |
675–764 |
| 225 |
765–854 |
| 250 |
855–944 |
| 275 |
945–1034 |
| 300 |
1035–1124 |
• For buprenorphine—300 mcg (0.3 mg) IM {28}.
• For butorphanol—2 mg IM {23}.
• For codeine—200 mg orally; 130 mg IM {01}.
• For dezocine—10 mg IM {29}.
• For heroin—60 mg orally; 5 mg IM {01}.
• For hydromorphone—7.5 mg orally; 1.5 mg IM {01} {23}.
• For levorphanol—4 mg orally; 2 mg IM {01} {23}.
• For meperidine—300 mg orally; {01} 75 mg IM {01} {23}.
• For methadone—20 mg orally; 10 mg IM {01} {23}.
• For nalbuphine—10 mg IM {01}.
• For oxycodone—30 mg orally {01} {23}.
• For oxymorphone—1 mg IM; 10 mg rectally {01} {23}.
• For pentazocine—180 mg orally; 60 mg IM {23}.
Note: This table should not be used to convert from fentanyl to other analgesic therapies. Use of the above table can overestimate the dosage of the new agent. Overdosage of the new analgesic agent is possible.{46}
Usual pediatric dose
Children up to 18 years of age—Safety and efficacy have not been established {01} {02}.
Usual geriatric dose
See Usual adult dose
Note: It is recommended that initial dosage not exceed 25 mcg (0.025 mg) per hour unless the patient has been receiving chronic therapy with more than 135 mg per day of oral morphine or an equivalent dose of another opioid analgesic {01} {02}.
Strength(s) usually available
U.S.—
25 mcg (0.025 mg) per hour (a total of 2.5 mg of fentanyl per 10 square centimeters [cm 2]) (Rx) [Duragesic ( alcohol 0.1 mL)]
50 mcg (0.05 mg) per hour (a total of 5 mg of fentanyl per 20 cm 2) (Rx) [Duragesic (alcohol 0.2 mL )]
75 mcg (0.075 mg) per hour (a total of 7.5 mg of fentanyl per 30 cm 2) (Rx) [Duragesic (alcohol 0.3 mL )]
100 mcg (0.1 mg) per hour (a total of 10 mg of fentanyl per 40 cm 2) (Rx) [Duragesic (alcohol 0.4 mL )]
Canada—
25 mcg (0.025 mg) per hour (a total of 2.5 mg of fentanyl per 10 cm 2) (Rx) [Duragesic (alcohol 0.1 mL )]
50 mcg (0.05 mg) per hour (a total of 5 mg of fentanyl per 20 cm 2) (Rx) [Duragesic (alcohol 0.2 mL )]
75 mcg (0.075 mg) per hour (a total of 7.5 mg of fentanyl per 30 cm 2) (Rx) [Duragesic (alcohol 0.3 mL )]
100 mcg (0.1 mg) per hour (a total of 10 mg of fentanyl per 40 cm 2) (Rx) [Duragesic (alcohol 0.4 mL )]
Packaging and storage:
Store below 25 °C (77 °F) {46}, unless otherwise specified by manufacturer {01}.
Auxiliary labeling:
• May cause drowsiness.
• Avoid alcoholic beverages.
• May be habit-forming.
Developed: 06/29/1994
Revised: 04/15/2002
References
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- Duragesic product monograph (Janssen). In: Krogh, CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 388-90.
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- Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Szekely SM, Mather LE, et al. The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems. Pain 1990; 40: 21-8.
- Supplemental product information (Janssen—US), 1/17/94, Rec 1/27/94.
- Caplan RA, Ready B, Oden RB, Matsen FA III, Nessly ML, Olsson GL. Transdermal fentanyl for postoperative pain management. JAMA 1989; 260: 1036-9.
- Gourlay GK, Kowalski SR, Plummer JL, Cherry DA, Gaukroger P, Cousins MJ. The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain 1989; 37: 193-202.
- Holley FO, van Steennis C. Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodymanics of constant-rate IV and transdermal delivery. Br J Anaesth 1988; 60: 608-13.
- Panel consensus, Fentanyl Derivatives (Systemic) monograph revision 7/87.
- Varvel JR, Shafer SL, Hwang SS, Coen PA, Stanski DR. Absorption characteristics of transdermally administered fentanyl. Anesthesiology 1989; 70: 928-34.
- Duthie DJR, Rowbotham DJ, Wyld R, Henderson PD, Nimmo WS. Plasma fentanyl concentrations during transdermal delivery of fentanyl to surgical patients. Br J Anaesth 1988; 60: 614-8.
- Portenoy RK, Southam MA, Gupta SK, Lapin J, Layman M, Inturrisi CE, et al. Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics. Anesthesiology 1993; 78: 36-43.
- Holdsworth MT, Forman WB, Nystrom KM, Brand SC, Stein DA, Hsu FW, et al. Transdermal fentanyl disposition in elderly subjects [abstract]. Clin Pharmacol Ther 1992; 51: 176.
- Esteve M, Levron JC, Flaisler B, Schoefler P, Duvaldestin P, Chauvin M. Does aging modify pharmacokinetics of transdermal fentanyl [abstract]? Anesthesiology 1991; 75: A705.
- Panel consensus, Opioid (Narcotic) Analgesics (Systemic) monograph revision 11/86.
- Steinberg RB, Gilman DE, Johnson F III. Acute toxic delirium in a patient using transdermal fentanyl. Anesth Analg 1992; 75: 1014-6.
- Stoukides CA, Stegman M. Diffuse rash associated with transdermal fentanyl [letter]. Clin Pharm 1992; 11: 222.
- Diamond AW, Coniam SW. The management of chronic pain. New York: Oxford University Press, 1991: 58.
- Lehmann KA, Zech D. Transdermal fentanyl: clinical pharmacology. J Pain Symptom Manage 1992; 7 No 3 (suppl): S8-S16.
- Buprenex (Reckitt & Colman). In: PDR Physicians' Desk Reference. 48th ed. 1994; Montvale, NJ: Medical Economics Data, 1994: 1834-5.
- Dalgan (Astra). In: PDR Physicians' Desk Reference. 48th ed. 1994; Montvale, NJ: Medical Economics Data, 1994: 537-9.
- Panel comment, 2/94.
- Reviewers' consensus on monograph revision of 2/94.
- Panel comment, draft 2/94.
- Manufacturer comment, draft 2/94.
- Duragesic package insert (Janssen—US), Rev 1/94, Rec 4/94.
- Reviewers' consensus on monograph revision of 2/94.
- Reviewer comment, 2/94.
- Panel comment, 2/94.
- Panel comments, 2/94.
- Manufacturer comment, 2/94.
- Panel comment, 5/94.
- Panel comments, 2/94.
- Panel comments, 5/94.
- Reviewers' consensus on ballot 5/94.
- Duragesic patient information sheet (Janssen—US), Rev 4/94, Rec 6/94.
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