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`

`
`ssen Pharmaceutica Inc.
`j
`TRENTON-HARB0URTON ROAD
`,125
`80X 200
`iJSVIL, NJ 08560-0200
`
`Information Monday through Friday 8 am-8 pm
`Coll
`O
`OT , jA lqsSEN
`(fOO) of 730-2461
`and Weekends:
`After JANsI
`
`’
`
`cransdermal system)
`
`ontany
`prescribing Information
`
`ECAUSE SERIOUS OR LIFE-THREATENING BY-
`3\rTILATION COULD OCCUR, DURAGESICfi IS
`0
`CONTOAINLICATED:
`(cid:149) In tt management of acute or post-operative pain,
`use in out-patient surgeries
`(cid:149)In tin management of mild or intermittent pain re-
`sponsive to PRN or non--opioid therapy
`ti - Ass exceeding 25 pg/hour at the initiation of
`(cid:149) In
`opiOi0 dierapy
`See ONTRA1NDICATI0NS for further information.)
`DTJBAGESICfi SHOULD NOT BE ADMINISTERED
`TO CHILDREN UNDER 12 YEARS OF AGE OR PA-
`TIENTS UNDER 18 YEARS OF AGE WHO WEIGH
`LESS THAN 50 KG (110 LBS) EXCEPT IN AN AUTHO-
`IZED INVESTIGATIONAL RESEARCH SETTING.
`See PRECAUTIONS - Pediatric Use.)
`DL-R-- (3ESICfi is
`indicated for treatment of chronic
`pain such as that of malignancy) that:
`(cid:149) cacnat be managed by lesser means such as acetami-
`0opiten-opieid combinations, non-steroidal analgesics,
`or dRU dosing with short-acting opioids and
`(cid:149) requires continuous opioid administration.
`The 50 7 75, and 100 meg/hour dosages should ONLY be
`used in oatients Who are already on and are tolerant to
`opioti rherapy.
`
`DESCRIPTION
`DTJRAGBSICfi is a transdermal system providing continu-
`ous o:"t’ nOr delivery of fentanyl, a potent opioid analgesic.
`for 72 nurs. The chemical name is N-Phenyl.N-(1-2-phen-
`ylethvi. (iniperidyl) propanamide.
`The mc/ciular weight of fentansi base is 336.5, and the em-
`pirical fm n’ula is C 2 H 5N70. The n-octanol:water partition
`coefficie-n 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 pg/h per 10 cm (cid:176) ). The
`Compusi/-ien per unit area of all system sizes is identical.
`Each s’,nrem also contains 0.1 mL of alcohol USP per 10
`
`Dose’
`(pg/h)
`25
`50--
`75
`100
`
`Size
`(cm (cid:176)
`)
`10
`20
`30
`40
`
`Fentanyl Content
`(mg)
`2.5
`5
`7.5
`10
`
`Nominal delivery rate per hour
`FOR USE ONLY IN OPIOID TOLERANT PATIENTS
`
`PURAGES1Cfi is a rectangular transparent unit compris-
`lOg a protective liner and four functional layers. Proceeding
`from the outer surface toward the surface adhering to skin,
`these layers are:
`a backing laler of polyester film: 2) a drug reservoir of
`eota0g and alcohol USP gelled with hydroxyethyl cellu-
`an ethylene-vinyl acetate copolymer membrane that
`tolltroii the rate of fentanyl delivery to the skin surface:
`1,11,14,
`fentanvl containing silicone adhesive. Before use, a
`P0tectn,s liner covering the adhesive lover is removed and
`I’s
`discard
`
`-.CKING (cid:9)
`
`DOUG (cid:9)
`RESERVOIR
`
`RELEASE
`MEMBRANE
`
`’El to Scale)
`
`ADHESIVE (cid:9)
`
`PROTECTIVE LINER
`
`The VCtie component of the system is fentanyl. The re-
`th O10 g components are pharmacologically inactive. Less
`0 0.2 ml, of alcohol is also released from the system dur-
`He.
`riot cut or damage DURAGESICfi. If (cid:176)he DURAGESICfi
`10 cut or damaged, controlled drug delivery will not
`Possible.
`
`Serum
`Fentanyl Concentrations
`Following Multiple Applications
`of DURAGESIC(cid:176) 100
`
`pg/h (n=10)
`
`DLIRAGESIC0
`
`Applied
`
`DUIRAGESIC(cid:176) Removed
`
`DURAGESIC"
`Applies (t) and
`Removed (/1
`
`Group MAX
`V
`
`)
`
`-
`
`
`
`5.0
`
`45
`
`4.0
`
`0
`
`3.0
`
`2.5
`
`fr2.O
`1. -
`
`Lu5
`O
`
`i.o
`
`if)
`
`0.5
`
`’
`
`a
`a
`/
`
`Day Day Day Day 10 Day 13 (cid:9)
`(t (cid:9)
`0 (cid:9)
`t (cid:9)
`t (cid:9)
`)f
`Repeat 72-h Applications (cid:9)
`
`A
`Gnup.MIN
`
`Day 14 Day 15 (cid:9) Day 16 Day 17 Da IS Day -19
`
`Single 72-h Application (cid:9)
`
`After System Removal
`
`CLINICAL PHARMACOLOGY
`Pharmacology
`Fentanyl is an opioid analgesic. Fentanyl interacts predom-
`inately with the opioid p-receptor. These ii-binding sites are
`discretely distributed in the human brain, spinal cord, and
`other tissues.
`In clinical settings, fentanyl exerts its principal pharmaco-
`logic effects on the central nervous system. Its primary ac-
`tions of therapeutic value are analgesia and sedation. Fen-
`tanvl may increase the patient’s tolerance for pain and de-
`crease the perception of suffering, although the presence of
`the pain itself may still be recognized.
`In addition to analgesia, alterations in mood, euphoria and
`dysphoria, and drowsiness commonly occur. Fentanyl de-
`presses 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
`chemorecepror trigger zone, but nausea and vomiting are
`significantly more common in ambulatory than in recum-
`bent patients, as is postural syncope.
`Opiolds increase the tone and decrease the propulsive con-
`tractions of the smooth muscle of the gastrointestinal tract.
`The resultant prolongation in gastrointestinal transit time
`map’ be responsible for the constipating effect of fentanyl.
`Because opioids may increase binary tract pressure, some
`patients with biliary colic may experience worsening rather
`than relief of pain.
`While oploids 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 uri-
`nation.
`At therapeutic dosages, fentanyl usually does not exert ma-
`jor effects on the cardiovascular system. However, some pa-
`tients may, exhibit orthostatic hypotension and fainting.
`Histamine assays and skin wheal testing in man indicate
`that clinically significant histamine release rarely occurs
`with fentanyl administration. Assays in man show no clini-
`cally significant histamine release in dosages up to 50 jig/
`kg.
`Pharmacokinetics (see graph and tables)
`DURAGESICfi 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 hourapplication 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 pg of
`fentanyl per hour) are sufficiently accurate as to allow indi-
`vidual titration of dosage for a given patient. The small
`amount of alcohol which has been incorporated into the sys-
`tem enhances the rate of drug flux through the rate-limiting
`copolymer membrane and increases the permeability of the
`skin to fentunyl.
`Following DURAGESICfi application, the skin under the
`system absorbs fentanyl, and a depot of fentanvl concen-
`trates in the upper skin layers. Fentanyl then becomes
`available to the systemic circulation. Serum fentanyl con-
`centrations increase gradually following initial DURAG-
`ESICfi application, generally leveling off between 12 and 24
`hours and remaining relatively constant, with some fluctu-
`ation, for the remainder of the 72 hour application period.
`Peak serum concentrations of fentanvi generally occurred
`between 24 and 72 hours after initial application )see Table
`A). Serum fentanyl concentrations achieved are propor-
`tional to the DURAGESICfi 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 fenta-
`nyl (see graph and Table B).
`
`After system removal, serum fentanyl concentrations de-
`cline gradually, falling about 5011 in approximately 17
`(range 13.22) 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 3-12) hours,
`[See graphic shovel
`[See table A at top of next page)
`[See table B at top of next page]
`Fentanyl plasma protein binding capacity decreases with
`increasing ionization of the drug. Alterations in pH may af-
`fect 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 fentsnyl is 6 1/kg
`(range 3-8, N=/i). The average clearance in patients under-
`going various surgical procedures is 46 IJh (range 27-75,
`N=81. The kinetics of fentanyl in geriatric patients has 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 in the liver. In humans
`the drug appears to be metabolized primarily by N-dsalky-
`latiou to norfentanyl and ether inactive metabolites that do
`not contribute materially to the observed activity of the
`drug. Within 72 hours of IV fentanyl administration, ap-
`proximately 75 17, 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 frac-
`tions 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 keratino-
`cyte cell assay and in clinical studies in which 92% of the
`dose delivered from the system was accounted for as un-
`changed fentanyl that appeared in the systemic circulation.
`Pharmacodynamics
`Analgesia
`DURAGESICfi is a strong opioid analgesic. In controlled
`clinical trials in non-opioid tolerant patients. 60 mg/day 151
`morphine was considered to provide analgesia approxi-
`mately equivalent to DURAGESICfi 100 pg/h in an acute
`pain model.
`Minimum effective analgesic serum concentrations of fenta-
`nyl in opinid naive patients range from 0.2 to 1.2 ng/mL;
`side effects increase in frequency at serum levels above 2
`ng’niL. 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.
`Ventilatory Effects
`At equivalent analgesic serum concentrations, fentanyl and
`morphine produce a similar degree of hypoventilatien. A
`small number of patients have experienced clinically signif-
`icant hypoventilation with DURAGESICfi. Hypoventilation
`was manifest by respiratory rates of less than 8 breaths/
`minute or a pCO, greater than 55 oi.m Hg. In clinical trials
`of 3357 postoperative (acute pain) patients treated with DU-
`RAGESICfi, 11 patients experienced hvpoventilation. 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-mar-
`keting reports have been received of opioid-naive post-oper-
`ative patients who have experienced clinically significant
`hypoventilation with DURAGESICfi. DURAGESICfi is con-
`traindicated in the treatment of postoperative and acute
`pain.
`While most patients using DURAGESICfi chronically de-
`velop tolerance to fentanyl induced hypoventilation, epi-
`sodes of slowed respirations may occur at any time during
`therapy: medical intervention generally was not required in
`these instances.
`
`Consult 2000 PDR 1 supplements and future editions for revisions
`
`Continued on next page
`
`2
`
`(cid:9)
`

`
`1446/JANSSEN
`
`Duragesic(cid:151)Cont.
`
`Hypoventilation can occur throughout the therapeutic
`range of fentanyl serum concentrations. However, in non-
`opioid-tolerant patients the risk of hypoventilation in-
`creases at serum fentanyl concentrations greater than 2 ng/
`mL, especially for patients who have an underlying pulmo-
`nary condition or who receive usual doses of opioids or other
`CNS drugs associated with hypoventilation in addition to
`DURAGESICfi. The use of initial doses exceeding 25 pg/h is
`contraindicated in patients who are not tolerant to opioid
`therapy. The use of DUTRAGESICfi should be monitored by
`clinical evaluation. As with other drug level measurements,
`serum fentanyl concentrations may be useful clinically, al-
`though they do not reflect patient sensitivity to fentanyl and
`should not be used by physicians as a sole indicator of effec-
`tiveness or toxicity.
`See BOX WARNING, CONTRAINDICATIONS, WARN -
`INGS, PRECAUTIONS, ADVERSE REACTIONS, and
`OVERDOSAGE for additional information on hypoventila-
`tion.
`Cardiovascular Effects
`Intravenous fentanyl may infrequently produce bradycar-
`dia. The incidence of bradycardia in clinical trials with DU-
`RAGESICfi was less than 1%.
`CNS Effects
`In opioid naive patients, central nervous system effects in-
`crease when serum fentanyl concentrations are greater
`than 3 ng/mL.
`CLINICAL TRIALS
`DURAGESICfi (fentanyl transdermal system) was studied
`in patients with acute and chronic pain (postoperative and
`cancer pain models); however. DURAGESICfi is contraindi-
`cated for postoperative analgesia.
`The analgesic efficacy of DURAGESICfi was demonstrated
`in an acute pain model with surgical procedures expected to
`produce various intensities of pain leg hysterectomy, major
`orthopedic surgery). Clinical use and safety was evaluated
`in patients experiencing chronic pain due to malignancy.
`Based on the results of these trials. DUBAGESICfi was de-
`termined to be effective in both populations, but safe only
`for use in patients with chronic pain. Because of the risk of
`hvpoventilation (49c incidence) in postoperative patients
`with actue pain. DIJRAGESICfi is contraindicated for post-
`operative analgesia. (See BOX WARNING, CLINICAL
`PH.ARMACOLOGY(cid:151)Ventjlatorv Effects, and CONTRAIN-
`DICATIONS.)
`DURAGESICfi as therapy for pain due to cancer has been
`studied in 153 patients. In this patient population, DUTRAG-
`ESICfi has been administered in doses of 25 pg/h to 600
`pg/h. Individual patients have used DURAGESICfi contin-
`uously for up to 366 days. At one month alter initiation of
`DURAGESICfi therapy, patients generally reported lower
`pain intensity scores as compared to a prestudy analgesic
`regimen of oral morphine (see graph).
`
`Visual Analogue Snore it Pain Intensity Ratings at Entry in the Study
`and After One Month of DURAGESIC(cid:176) One
`
`SIfia(N=to.Ct )
`
`
`
`Pain Intensity (cid:9)
`Slier 1 Month
`on DURAGESIC-
`
`0
`
`0
`
`.t (cid:9)
`0 0 (cid:9)
`
`/ 00 - (cid:9)
`0 (cid:9)
`/ (cid:9)
`
`.. (cid:9)
`
`0
`Pain better on
`DuRAGE5IC
`0
`
`(0=2101)
`
`1 (cid:9)
`
`a (cid:9)
`5 (cid:9)
`3 (cid:9)
`2 (cid:9)
`5 (cid:9)
`5 (cid:9)
`7 (cid:9)
`0 (cid:9)
`5 tO
`Pain Intensity on Pre-Study Analgesic Regimen
`
`INDICATIONS AND USAGE
`DURAGESICfi (fentanyl transdermai system) is indicated
`in the management of chronic pain in patients who require
`continuous opioid analgesia for pain that cannot be man-
`aged by lesser means such as acetaminophen-opioid combi-
`nations. non-steroidal analgesics, or PEN dosing with short-
`acting opioids.
`DUTRAGESICfi should not be used in the management of
`acute or postoperative pain because serious or life-threaten-
`ing hypoventilation could result. (See BOX WARNING and
`CONTRAINDICATIONS.)
`In patients with chronic pain, it is possible to individually
`titrate the dose of the transdermal system to minimize the
`risk of adverse effects while providing analgesia. In properly
`selected patients. DUTRAGESICfi is a safe and effective al-
`ternative to other opioid regimens. (See DOSAGE AND AD-
`MINISTRATION.)
`
`CONTRAINDICATIONS
`BECAUSE SERIOUS OR LIFE-THREATENING HYPOVENTI-
`COULD OCCUR, DURAGESICfi IS CONTRAINDI-
`Clding o:p,
`nn cf acute or post-operative pain, in-
`opportunity for (cid:9)
`because there is no
`PHARMACOLOGY and 0O (cid:176) A
`050 fl (See CLINICAL
`
`TION), (cid:9)
`ANDADMINISTRA-
`(cid:149) in the management of mild or intermittent pain that
`
`c an
`
`TABLE A
`FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF DURAGESICfi
`
`PHYSICIANS’ DESK REFEREN0
`
`Dose
`
`DTJRAGESICfi 25 pg/h
`
`DURAGESICfi 50 pg/h
`
`DURAGESICfi 75 pg/h
`
`DURAGESICfi 100 pg/h
`
`Mean (SD) Time to
`Maximal Concentration
`Tmas
`(h)
`
`Mean (SD)
`Maximal Concentration
`Cn,ax
`(ng/mL)
`
`38.1 (18.0)
`
`34.8 (15.4)
`
`33.5 (14.5)
`
`36.8 (15.7)
`
`0.6 (0.3)
`
`1.4 (0.5)
`
`1.7 (0.7)
`
`2.5(l.2)
`
`NOTE: After system removal there is continued systemic absorption from residual fentanvl in the skin so theiuss
`centratious fall 50%, on average, in 17 hours.
`
`55
`
`TABLE B
`RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS
`
`Surgical Patients
`
`Hepatically Impaired
`Patients
`
`Renally Impaired Patients
`
`Clearance
`IL/hI
`Range
`(70 kg]
`
`27-75
`
`I-80
`
`10-78
`
`Volume of Distribution
`V55
`(L/kg)
`Range
`
`3-8
`
`0 .8_81
`
`-
`
`Half-Life
`t‰
`(h)
`Range
`
`3-12
`
`4-12’
`
`Estimated
`NOTE:Information on volume of distribution and half-life not available for renally impaired patients.
`
`otherwise be managed by lesser means such as acetam-
`inophen-oploid combinations, non-steriodal analgesics,
`or PRN dosing with short-acting opiolds, and
`(cid:149) in doses exceeding 25 pg/hour at the initiation of opiold
`therapy because of the need to individualize dosing by
`titrating to the desired analgesic effect.
`DURAGESICfi is also contraindicated in patients with
`known hypersensitivity to fentanyl or adhesives.
`WARNINGS
`DURAGESICfi (FENTANYL TRANSDERMAL SYSTEM(
`SHOULD NOT BE ADMINISTERED TO CHILDREN UNDER 12
`YEARS OF AGE OR PATIENTS UNDER 18 YEARS OF AGE
`WHO WEIGH LESS THAN 50 KG 1110 LBSI EXCEPT IN AN
`AUTHORIZED INVESTIGATIONAL RESEARCH SETTING.
`(See PRECAUTIONS-Pediatric Use.)
`PATIENTS WHO HAVE EXPERIENCED ADVERSE
`EVENTS SHOULD BE MONITORED FOR AT LEAST 12
`HOURS AFTER DUTRAGESICfi REMOVAL SINCE
`SERUM FENTANYL CONCENTRATIONS DECLINE
`GRADUALLY AND REACH AN APPROXIMATE 50% RE-
`DUCTION IN SERUM CONCENTRATIONS 17 HOURS
`AFTER SYSTEM REMOVAL.
`DURAGESICfi SHOULD BE PRESCRIBED ONLY BY
`PERSONS KNOWLEDGEABLE IN THE CONTINUOUS
`ADMINISTRATION OF POTENT OPIOIDS, IN THE MAN-
`AGEMENT OF PATIENTS RECEIVING POTENT OPIO-
`lBS FOR TREATMENT OF PAIN, AND IN THE DETEC-
`TION AND MANAGEMENT OF HYPO VENTILATION IN-
`CLUDING THE USE OF OPIOID ANTAGONISTS.
`THE CONCOMITANT USE OF OTHER CENTRAL NER-
`VOUS SYSTEM DEPRESSANTS, INCLUDING OTHER
`OPIOIDS, SEDATIVES OR HYPNOTICS, GENERAL AN-
`ESTHETICS, PHENOTHIAZINES, TRANQUILIZERS,
`SKELETAL MUSCLE RELAXANTS, SEDATING ANTI-
`HISTAMINES, AND ALCOHOLIC BEVERAGES MAY
`PRODUCE ADDITIVE DEPRESSANT EFFECTS. HYPO-
`VENTILATION, HYPOTENSION AND PROFOUND SE-
`DATION OR COMA MAY OCCUR. WHEN SUCH COM-
`BINED THERAPY IS CONTEMPLATED. THE DOSE OF
`ONE OR BOTH AGENTS SHOULD BE REDUCED BY AT
`LEAST 50%.
`ALL PATIENTS SHOULD BE ADVISED TO AVOID EX-
`POSING THE DUIIAGESICfi APPLICATION SITE TO DI-
`RECT EXTERNAL HEAT SOURCES, SUCH AS HEATING
`PADS OR ELECTRIC BLANKETS, HEAT LAMPS, SAU-
`NAS, HOT TUBS, AND HEATED WATER BEDS, ETC.
`WHILE WEARING THE SYSTEM. THERE IS A POTEN-
`TIAL FOR TEMPERATURE-DEPENDENT INCREASES
`IN FENTANYL RELEASE FROM THE SYSTEM. (See
`PRECAUTIONS, Patients with Fever/External Heat.)
`PRECAUTIONS
`General
`DURAGESICfi doses greater than 25 pg/h are too high for
`initiation of therapy in non opioid-tolerant patients and
`should not be used to begin DURAGESICfi therapy in these
`patients. (See BOX WARNING.)
`DURAGESICfi may impair mental and/or physical ability
`required for the performance of potentially hazardous tasks
`(og driving, operating machinery). Patients who have been
`given DURAGESICfi should not drive or operate dangerous
`machinery unless they are tolerant to the side effects of the
`drug.
`Patients should be instructed to keep both used and unused
`systems out of the reach of children. Used systems should
`be folded so that the adhesive side of the system adheres to
`otseif and flushed down the toilet immediately upon re-
`moval Patients should he adr,-ie1 5. ,l, ---------------
`
`remaining from a proscription as soon as they are no longer
`needed, Unused systems should be removed from their
`pouch and flushed down the toilet.
`Hypoventilation (Respiratory Depression)
`Hvpoventilation may occur at any time during the use of
`DURAGESICfi.
`Because significant amounts of fentanyl are absorbed from
`the skin for 17 hours or more alter the system is remeved_,
`hvpoventilation may persist beyond the removal of DUP5AG-
`ESICfi. Consequently, patients with hypoventilation should
`be carefully observed for degree of sedation and their respi-
`ratory rate monitored until respiration has stabilized.
`The use of concomitant CNS active drugs requires special
`patient care and observation. See WARNINGS.
`Chronic Pulmonary Disease
`Because potent opioids can cause hypoventilation. DURAG-
`ESICfi (fentanyl transdermal system) should be adminis-
`tered with caution to patients with preexisting medical con-
`ditions predisposing them to hypoventilation. In such pa-
`tients, normal analgesic doses of opioids may further
`decrease respiratory drive to the point of respiratorY ailtsro.
`Head Injuries and Increased Intracranial Pressure
`DURAGESICfi should not be used in patients who may be
`particularly susceptible to the intracranial effects of CO, re-
`tention such as those with evidence of increased intracra-
`nial pressure, impaired consciousness, or coma. Opioids
`may obscure the clinical course of patients with hey) tODWY.
`DURAGESICfi should be used with caution in patients with
`brain tumors.
`Cardiac Disease
`Intravenous fentanyl may produce bradycardia. FantasY 1
`should be administered with caution to patients with brad ,
`yarrha-thmias.
`Hepatic or Renal Disease
`
`At the present time insufficient information exists to ma ke
`in
`recommendations regarding the use of DURAGESICfi
`patients with impaired renal or hepatic function. If the 1s9
`is used in these patients, it should be used with cautiefl be,
`cause of the hepatic metabolism and renal excretion of fell’
`tanyl.
`Patients with Fever/External Heat
`Based on a pharmacokinetic model, serum fentanyl con ceit
`trations could theoretically increase by approvima 4’S)
`third for patients with a body temperature of 40’C 110
`due to temperature-dependent increases in fentanyl rel ease 0
`from the system and increased skin permeability. Thete
`patients wearing DURAGESICfi systems who develop
`should be monitored for opioid side effects and the OUR
`ESICfi dose should be adjusted if necessary.
`ALL PATIENTS SHOULD BE ADVISED TO AVOW
`POSING THE DURAGESICfi APPLICATION SITE TO 50
`RECT EXTERNAL HEAT SOURCES. SUCH AS HEA.
`PADS OR ELECTRIC BLANKETS, HEAT LAMPS, 5 f0
`NAS, HOT TUBS, AND HEATED WATER BEDS
`oTfN-
`WHILE WEARING THE SYSTEM. THERE IS A
`TIAI,AL FOR TEMPERATURE-DEPENDENT INCXE
`IN FENTA.NYL RELEASE FROM THE SYSTEM.
`Central Nervous System Depressants (cid:9)
`When patients are receiving DURAGESICfi, the dose
`clitional opioids or other CNS depressant drugs (in
`benzodiazepines) should be reduced by at least 501
`the concomitant use of CNS depressants, h ypotensie(cid:176)
`occur.
`Drug or Alcohol Dependence (cid:9)
`n et"
`Use of DURAGESICfi in combination with alcoholic be0
`ages and/or other CNS depressants can result i
`1flir ,
`
`fad-
`
`3
`
`(cid:9)
`

`
`INFORMATION
`
`Ssl(cid:176)
`
`jdividua1s who have a history of drug or alcohol
`pfl in spe ciallyif they are outside a medically controlled
`i5 ’ "nt.
`it0(cid:176) te ry patients
`1b0 5 oid analgesics impair the mental or physical abil-
`tr(cid:176) (cid:176)8 8uired for the performance of potentially dangerous
`itior as driving a car or operating machinery. Patients
`te been given DURAGESICfi should not drive or op-
`eilW hfl ’ gerous machinery unless they are tolerant to the
`sal
`crate of the drug.
`ttSogenesis, Mutagenesis, and Impairment of Fertility
`c
`so long-term animal studies have not been conducted,
`0
`Sec9o 00tjal carcinogenic effects of DURAGESICfi are on-
`the There was no evidence of mutagenicity in the Ames
`jyphimurium mutagenicity assay the primary
`epatocvte unscheduled DNA synthesis assay, th
`e
`3T3 transformation test, the mouse lymphoma as-
`human lymphocyte and CHO chromosomal aberra-
`’jtto assays or the in-viva micronucleus test.
`555cy(cid:151)Pregnancy Category C
`lass been shown to impair fertility and to have an
`al effect in rats when given in intravenous doses
`Fe"
` human dose for a period of 12 days. No evi-
`(cid:176)5’ 0times the
`e of sratogsnlc effects has been observed after admin-
`tion of fentanyl to rats. There are no adequate and
`te5lcositroi1ed studies in pregnant women. DURAGESICfi
`be used during pregnancy only if the potential ben-
`the potential risk to the fetus.
`Labor ar. Delivery
`piftinGuSICfi is not recommended for analgesia during la-
`her and delivery.
`Nursing Mothers
`FentanYt as excreted in human milk; therefore DURAG-
`SICfi is not recommended for use in nursing women be-
`muse of the possibility of effects in their infants.
`pediatric Use
`The safety and efficacy of DURAGESICfi in pediatric pa-
`tients has not been established. (See BOX WARNING and
`CONT1NNCATI0)
`DURAGICfi SHOULD NOT BE ADMINISTERED TO CHIL-
`DREN UNDER 12 YEARS OF AGE OR PATIENTS UNDER 18
`YEARS OF AGE WHO WEIGH LESS THAN 50 KG (110 LBS)
`EXCEPT iN AN AUTHORIZED INVESTIGATIONAL RE-
`SEARCh CETTING.
`Geriatric Use
`Information from a pilot study of the pharmacokinetics of
`IV fentanpi in geriatric patients indicates that the clearance
`of fentanyl may be greatly decreased in the population
`above the age of 60. The relevance of these findings to trans-
`dermal fentanyl is unknown at this time.
`Since eldecly, cachectic. or debilitated patients may have al-
`tered phao’macokinetics due to poor fat stores, muscle wast-
`ing, or altered clearance, they should not be started on DU-
`RAGESIC% doses higher than 25 pg/h unless they are al-
`ready tatting more than 135 mg of oral morphine a day or an
`equivalent dose of another opieid (see DOSAGE AND AD-
`MiNISTRATION),
`Information for Patients
`A patie:,t instruction sheet is included in the package of
`DURAGESICfi systems dispensed to the patient.
`Disposal of DURAGESICfi
`DLIRAGESICfi should be kept out of the reach of children.
`OURAGESICfi systems should he folded so that the adhe-
`sive side of the svsteno adheres to itself, then the system
`should its flushed down the toilet immediately upon re-
`moval. Patients should dispose of any systems remaining
`from a prescription as soon as they are no longer needed.
`Unused st -stems should be removed from their pouch and
`flushed down the toilet.
`If the gel from the drug reservoir accidentally contacts the
`Skill, the area should he washed with clear water.
`ADVERSE REACTIONS
`POSt.marketing experience, deaths from hypoventilation
`due to inappropriate use of DURAGESICfi have been re-
`ported See BOX WARNING and CONTRAINDICA-
`TIONS
`
`ia1Experieioce
`safety of DURAGESICfi has been evaluated in 357 post-
`(cid:176)perative patients and 153 cancer patients for a total of 510
`stients. Patients with acute pain used DURAGESICfi for 1
`10
`3 da y5 The duration of DUBAGESICfi use varied in can-
`Patients; 56% of patients used DURAGESICfi for over
`day5 28% continued treatment for more than 4 months,
`aisd 10% used DURAGESICfi for more than 1 year.
`o B50
`uilatien was the most serious adverse reaction oh-
`sd in 1314%) postoperative patients and in 3 (2%) of the
`Se tea atatients. Hvpotension and hypertension were ob-
`m 11 (3%) and 4 (lO) of the opioid-naive patients.
`011 -1 adverse events were reported; a causal relationship
`to
`Cl50 URAGESICfi was not always determined. The frequen-
`0or presented here reflect the actual frequency of each ad-
`effect in patients who received DU’RAGESICfi. There
`itt,ea no attempt to correct for a placebo effect. concern-
`sos of other opioids, or to subtract the frequencies re-
`
`by placebo-treated patients in controlled trials.
`following
`(cid:9) reactions were reported in 153 cancer
`1%
`leoita at a frequency of 1% or greater: similar reactions
`ao seen in the 357 postoperative patients studied.
`d V OS a Whole: abdominal pain’, headache"
`arrhythmia, chest pain
`0tive: nausea t, vomiting 5 ’, constipation*’
`anorexia5 , diarrhea*, dyspepsia*, flatulence
`snmnolence t*, confusion"*, , asthenia"*, dizzi-
`85 5 Us:
`nervousness 5 , hallucinations". anxiety(cid:176), depression*,
`
`euphoria", tremor, abnormal coordination, speech disorder,
`abnormal thinking, abnormal gait, abnormal dreams, agita-
`tion, paresthesia, amnesia, syncope, paranoid reaction
`Respiratory: dyspnea", hypoventilation 5, apnea", hemop-
`tyois, pharyngitis, hiccups
`Skin and Appendages: sweating*, pruritus", rash, appli-
`cation site reaction - erythema, papules, itching, edema
`Urogenital: urinary retention"
`Reactions occur