FENTANYL
DESCRIPTION:
FULL PRESCRIBING INFORMATION
BECAUSE SERIOUS OR LIFE-THREATENING
HYPOVENTILATION COULD OCCUR, FENT IS
CONTRAINDICATED:
--In the management of acute or post-
operative pain, including use in out-
patient surgeries
--In the management of mild or intermittent
pain responsive to PRN or non-opioid
therapy
--In doses exceeding 25 mcg/hour at the
initiation of opioid therapy
(See CONTRAINDICATIONS for further
information.)
FENT SHOULD NOT BE ADMINISTERED TO
CHILDREN 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 RESEARCH SETTING. (See
PRECAUTIONS - Pediatric Use.)
FENT Is Indicated For Treatment Of
Chronic Pain (Such As That Of Malignancy)
That:
--cannot be managed by lesser means such as
acetaminophen-opioid combinations, non-
steroidal analgesics, or PRN dosing with
short-acting opioids and
--requires continuous opioid
administration.
The 50, 75, and 100 mcg/hour dosages should
ONLY be used in patients who are already on
and are tolerant to opioid therapy.
WARNING: May be habit forming.
FENT ,the chemical name is N-Phenyl-N-(1-2-phenylethyl- 4-piperidyl) propanamide.
The molecular weight of fentanyl base is 336.5, and the empirical formula is
C22H28N2O. The n- octanol:water partition coefficient is 860:1. The pKa is 8.4.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACOLOGY
Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the
opioid mu- receptor. These mu-binding sites are discretely distributed in the
human brain, spinal cord, and other tissues.
In clinical settings, fentanyl exerts its principal pharmacologic effects on the
central nervous system. Its primary actions of therapeutic value are analgesia
and sedation. Fentanyl may increase the patient's tolerance for pain and
decrease 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 depresses the respiratory centers, depresses
the cough reflex, and constricts the pupils. Analgesic blood levels of fentanyl
may cause nausea and vomiting directly by stimulating the chemoreceptor trigger
zone, but nausea and vomiting are significantly more common in ambulatory than
in recumbent patients, as is postural syncope.
Opioids increase the tone and decrease the propulsive contractions of the smooth
muscle of the gastrointestinal tract. The resultant prolongation in
gastrointestinal transit time may be responsible for the constipating effect of
fentanyl. Because opioids may increase biliary tract pressure, some patients
with biliary colic may experience worsening rather than relief of pain.
While opioids generally increase the tone of urinary tract smooth muscle, the
net effect tends to be variable, in some cases producing urinary urgency, in
others, difficulty in urination.
At therapeutic dosages, fentanyl usually does not exert major effects on the
cardiovascular system. However, some patients may exhibit orthostatic
hypotension and fainting.
Histamine assays and skin wheal testing in man indicate that clinically
significant histamine release rarely occurs with fentanyl administration. Assays
in man show no clinically significant histamine release in dosages up to 50
mcgm/kg.
PHARMACOKINETICS (see table and graph)
FENT releases fentanyl from the reservoir at a nearly constant amount per
unit time. The concentration gradient existing between the saturated solution of
drug in the reservoir and the lower concentration in the skin drives drug
release. Fentanyl moves in the direction of the lower concentration at a rate
determined by the copolymer release membrane and the diffusion of fentanyl
through the skin layers. While the actual rate of fentanyl delivery to the skin
varies over the 72 hour application period, each system is labeled with a
nominal flux which represents the average amount of drug delivered to the
systemic circulation per hour across average skin.
While there is variation in dose delivered among patients, the nominal flux of
the systems (25, 50, 75, and 100 mcgm of fentanyl per hour) are sufficiently
accurate as to allow individual titration of dosage for a given patient. The
small amount of alcohol which has been incorporated into the system enhances the
rate of drug flux through the rate-limiting copolymer membrane and increases the
permeability of the skin to fentanyl.
Following FENT application, the skin under the system absorbs fentanyl, and
a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes
available to the systemic circulation. Serum fentanyl concentrations increase
gradually following initial FENT application, generally leveling off
between 12 and 24 hours and remaining relatively constant, with some
fluctuation, for the remainder of the 72 hour application period. Peak serum
levels of fentanyl generally occurred between 24 and 72 hours after initial
application. Serum fentanyl concentrations achieved are proportional to the
FENT delivery rate. With continuous use, serum fentanyl concentrations
continue to rise for the first few system applications. After several sequential
72-hour applications, patients reach and maintain a steady state serum
concentration that is determined by individual variation in skin permeability
and body clearance of fentanyl (see graph and Table A).
After system removal, serum fentanyl concentrations decline gradually, falling
about 50% 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 ranges
from 3-12 hours.
TABLE A
RANGE OF PHARMACOKINETIC PARAMETERS OF FENTANYL IN PATIENTS
---------------------------------------------------------------------------------------------------------------------------------------------------------------------
VOLUME OF MAXIMAL TIME TO
DISTRIBUTION HALF CONCENTRATION MAXIMAL
LIFE
CLEARANCE VSS T1/2 CMAX CONCENTRATION
(L/H) (L/KG) (H) (NG/ML) (H)
RANGE RANGE RANGE RANGE RANGE
(70 KG)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------
IV Fentanyl
Surgical Patients 27-75 3-8 3-12
Hepatically Impaired 3-80** 0.8-8** 4-12**
Patients
Renally Impaired 30-78
Patients
FENT 25 mcgm/h * 0.3-1.2 26-78
FENT 50 mcgm/h * 0.6-1.8** 24-72**
FENT 75 mcgm/h * 1.1-2.6 24-48
FENT 100 mcgm/h * 1.9-3.8 25-72
-------------------------------------------------------------------------------------------------------------------------------------------------------------------
** Estimated
* After system removal there is continued systemic absorption from residual
fentanyl in the skin so that serum concentrations fall 50%, on average, in
17 hours.
Fentanyl plasma protein binding capacity decreases with increasing ionization of
the drug. Alterations in pH may affect its distribution between plasma and the
central nervous system. Fentanyl accumulates in the skeletal muscle and fat and
is released slowly into the blood.
The average volume of distribution for fentanyl is 6 L/kg (range 3-8, N=8). The
average clearance in patients undergoing various surgical procedures is 46 L/h
(range 27-75, N=8). 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-dealkylation to norfentanyl and other inactive
metabolites that do not contribute materially to the observed activity of the
drug. Within 72 hours of IV fentanyl administration, approximately 75% of the
dose is excreted in urine, mostly as metabolites with less than 10% representing
unchanged drug. Approximately 9% of the dose is recovered in the feces,
primarily as metabolites. Mean values for unbound fractions of fentanyl in
plasma are estimated to be between 13 and 21%.
Skin does not appear to metabolize fentanyl delivered transdermally. This was
determined in a human keratinocyte cell assay and in clinical studies in which
92% of the dose delivered from the system was accounted for as unchanged
fentanyl that appeared in the systemic circulation.
PHARMACODYNAMICS
ANALGESIA
FENT is a strong opioid analgesic. In controlled clinical trials in non-
opioid tolerant patients, 60 mg/day IM morphine was considered to provide
analgesia approximately equivalent to FENT 100 mcgm/h 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.
VENTILATORY EFFECTS
At equivalent analgesic serum concentrations, fentanyl and morphine produce a
similar degree of hypoventilation. A small number of patients have experienced
clinically significant hypoventilation with FENT. Hypoventilation was
manifest by respiratory rates of less than 8 breaths/minute or a pCO2 greater
than 55 mm Hg. In clinical trials of 357 postoperative (acute pain) patients
treated with FENT, 13 patients experienced hypoventilation. As a
consequence, 10 of these 13 patients received naloxone, two patients had their
dose reduced and one patient required no treatment beyond verbal stimulation. Of
the 13 events, seven were associated with FENT 100 mcgm/h and six were
associated with FENT 75 mcgm/h. 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.
While most patients using FENT chronically develop tolerance to fentanyl
induced hypoventilation, episodes of slowed respirations may occur at any time
during therapy; medical intervention generally was not required in these
instances.
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 non opioid-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 FENT. The use of FENT should be monitored by clinical evaluation.
As with other drug level measurements, serum fentanyl concentrations may be
useful clinically, although they do not reflect patient sensitivity to fentanyl
and should not be used by physicians as a sole indicator of effectiveness or
toxicity.
See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS,
and OVERDOSAGE for additional information on hypoventilation.
CARDIOVASCULAR EFFECTS
Intravenous fentanyl may infrequently produce bradycardia. The incidence of
bradycardia in clinical trials with FENT was less than 1%.
CNS EFFECTS
In opioid naive patients, central nervous system effects increase when serum
fentanyl concentrations are greater than 3 ng/mL.
INDICATIONS AND USAGE:
FENT is indicated in the management of chronic pain in patients who require
continuous opioid analgesia for pain that cannot be managed by lesser means such
as acetaminophen-opioid combinations, non-steroidal analgesics, or PRN dosing
with short-acting opioids.
FENT should not be used in the management of acute or postoperative pain
because serious or life-threatening 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, FENT is a safe and
effective alternative to other opioid regimens. (See DOSAGE AND ADMINISTRATION.)
CONTRAINDICATIONS:
BECAUSE SERIOUS OR LIFE-THREATENING HYPOVENTILATION COULD OCCUR, FENT IS
CONTRAINDICATED:
--IN THE MANAGEMENT OF ACUTE OR POST-OPERATIVE PAIN, INCLUDING USE IN OUT-
PATIENT SURGERIES BECAUSE THERE IS NO OPPORTUNITY FOR PROPER DOSE TITRATION (SEE
ACTIONS/CLINICAL PHARMACOLOGY AND DOSAGE AND ADMINISTRATION),
--IN THE MANAGEMENT OF MILD OR INTERMITTENT PAIN THAT CAN OTHERWISE BE MANAGED
BY LESSER MEANS SUCH AS ACETAMINOPHEN-OPIOID COMBINATIONS, NON- STEROIDAL
ANALGESICS, OR PRN DOSING WITH SHORT- ACTING OPIOIDS, AND
--IN DOSES EXCEEDING 25 MCG/HOUR AT THE INITIATION OF OPIOID THERAPY BECAUSE OF
THE NEED TO INDIVIDUALIZE DOSING BY TITRATING TO THE DESIRED ANALGESIC EFFECT.
FENT is also contraindicated in patients with known hypersensitivity to
fentanyl or adhesives.
WARNINGS:
BECAUSE SERIOUS OR LIFE-THREATENING
HYPOVENTILATION COULD OCCUR, FENT IS
CONTRAINDICATED:
--In the management of acute or post-
operative pain, including use in out-
patient surgeries
--In the management of mild or intermittent
pain responsive to PRN or non-opioid
therapy
--In doses exceeding 25 mcg/hour at the
initiation of opioid therapy
(See CONTRAINDICATIONS for further
information.)
FENT SHOULD NOT BE ADMINISTERED TO
CHILDREN 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 RESEARCH SETTING. (See
PRECAUTIONS - Pediatric Use.)
FENT Is Indicated For Treatment Of
Chronic Pain (Such As That Of Malignancy)
That:
--cannot be managed by lesser means such as
acetaminophen-opioid combinations, non-
steroidal analgesics, or PRN dosing with
short-acting opioids and
--requires continuous opioid
administration.
The 50, 75, and 100 mcg/hour dosages should
ONLY be used in patients who are already on
and are tolerant to opioid therapy.
FENT SHOULD NOT BE ADMINISTERED TO CHILDREN 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 RESEARCH SETTING. (SEE PRECAUTIONS-PEDIATRIC USE.)
PATIENTS WHO HAVE EXPERIENCED ADVERSE EVENTS SHOULD BE MONITORED FOR AT LEAST 12
HOURS AFTER FENT REMOVAL SINCE SERUM FENTANYL CONCENTRATIONS DECLINE
GRADUALLY AND REACH AN APPROXIMATE 50% REDUCTION IN SERUM CONCENTRATIONS 17
HOURS AFTER SYSTEM REMOVAL.
FENT SHOULD BE PRESCRIBED ONLY BY PERSONS KNOWLEDGEABLE IN THE CONTINUOUS
ADMINISTRATION OF POTENT OPIOIDS, IN THE MANAGEMENT OF PATIENTS RECEIVING POTENT
OPIOIDS FOR TREATMENT OF PAIN, AND IN THE DETECTION AND MANAGEMENT OF
HYPOVENTILATION INCLUDING THE USE OF OPIOID ANTAGONISTS.
THE CONCOMITANT USE OF OTHER CENTRAL NERVOUS SYSTEM 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 SUCH COMBINED THERAPY IS
CONTEMPLATED, THE DOSE OF ONE OR BOTH AGENTS SHOULD BE REDUCED BY AT LEAST 50%.
ALL PATIENTS SHOULD BE ADVISED TO AVOID EXPOSING THE FENT APPLICATION SITE
TO DIRECT EXTERNAL HEAT SOURCES, SUCH AS HEATING PADS OR ELECTRIC BLANKETS, HEAT
LAMPS, SAUNAS, HOT TUBS, AND HEATED WATER BEDS, ETC, WHILE WEARING THE SYSTEM.
THERE IS A POTENTIAL FOR TEMPERATURE-DEPENDENT INCREASES IN FENTANYL RELEASE
FROM THE SYSTEM. (See PRECAUTIONS, Patients with Fever/External Heat.)
PRECAUTIONS:
GENERAL
FENT doses greater than 25 mcgm/h are too high for initiation of therapy in
non opioid- tolerant patients and should not be used to begin FENT therapy
in these patients. (See BOX WARNING.)
FENT may impair mental and/or physical ability required for the performance
of potentially hazardous tasks (eg driving, operating machinery). Patients who
have been given FENT 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 itself and flushed down the toilet immediately upon
removal. Patients should be advised to 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.
HYPOVENTILATION (RESPIRATORY DEPRESSION)
Hypoventilation may occur at any time during the use of FENT.
Because significant amounts of fentanyl are absorbed from the skin for 17 hours
or more after the system is removed, hypoventilation may persist beyond the
removal of FENT. Consequently, patients with hypoventilation should be
carefully observed for degree of sedation and their respiratory rate monitored
until respiration has stabilized.
The use of concomitant CNS active drugs requires special patient care and
observation. See WARNINGS.
CHRONIC PULMONARY DISEASE
Because potent opioids can cause hypoventilation, FENT(R) (fentanyl
transdermal system) should be administered with caution to patients with
preexisting medical conditions predisposing them to hypoventilation. In such
patients, normal analgesic doses of opioids may further decrease respiratory
drive to the point of respiratory failure.
HEAD INJURIES AND INCREASED INTRACRANIAL PRESSURE
FENT 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. FENT should be
used with caution in patients with brain tumors.
CARDIAC DISEASE
Intravenous fentanyl may produce bradycardia. Fentanyl should be administered
with caution to patients with bradyarrhythmias.
HEPATIC OR RENAL DISEASE
At the present time insufficient information exists to make recommendations
regarding the use of FENT in patients with impaired renal or hepatic
function. If the drug is used in these patients, it should be used with caution
because of the hepatic metabolism and renal excretion of fentanyl.
PATIENTS WITH FEVER/EXTERNAL HEAT
Based on a pharmacokinetic model, serum fentanyl concentrations could
theoretically increase by approximately one third for patients with a body
temperature of 40 deg C (102 deg F) due to temperature-dependent increases in
fentanyl release from the system and increased skin permeability. Therefore,
patients wearing FENT systems who develop fever should be monitored for
opioid side effects and the FENT dose should be adjusted if necessary.
ALL PATIENTS SHOULD BE ADVISED TO AVOID EXPOSING THE FENT APPLICATION SITE
TO DIRECT EXTERNAL HEAT SOURCES, SUCH AS HEATING PADS OR ELECTRIC BLANKETS, HEAT
LAMPS, SAUNAS, HOT TUBS, AND HEATED WATER BEDS, ETC, WHILE WEARING THE SYSTEM.
THERE IS A POTENTIAL FOR TEMPERATURE-DEPENDENT INCREASES IN FENTANYL RELEASE
FROM THE SYSTEM.
CENTRAL NERVOUS SYSTEM DEPRESSANTS
When patients are receiving FENT, 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 FENT in combination with alcoholic beverages and/or other CNS
depressants can result in increased risk to the patient. FENT should be
used with caution in individuals who have a history of drug or alcohol abuse,
especially if they are outside a medically controlled environment.
AMBULATORY PATIENTS
Strong opioid analgesics impair the mental or physical abilities required for
the performance of potentially dangerous tasks such as driving a car or
operating machinery. Patients who have been given FENT should not drive or
operate dangerous machinery unless they are tolerant to the effects of the drug.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Because long-term animal studies have not been conducted, the potential
carcinogenic effects of FENT are unknown. There was no evidence of
mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat
hepatocyte unscheduled DNA synthesis assay, the BALB/c-3T3 transformation test,
and the human lymphocyte and CHO chromosomal aberration in-vitro assays.
In the mouse lymphoma assay, fentanyl concentrations 2000 times greater than
those seen with chronic FENT use were only mutagenic in the presence of
metabolic activation.
PREGNANCY--PREGNANCY CATEGORY C
Fentanyl has been shown to impair fertility and to have an embryocidal effect in
rats when given in intravenous doses 0.3 times the human dose for a period of 12
days. No evidence of teratogenic effects has been observed after administration
of fentanyl to rats. There are no adequate and well- controlled studies in
pregnant women. FENT should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
LABOR AND DELIVERY
FENT is not recommended for analgesia during labor and delivery.
NURSING MOTHERS
Fentanyl is excreted in human milk; therefore FENT is not recommended for
use in nursing women because of the possibility of effects in their infants.
PEDIATRIC USE
The safety and efficacy of FENT in children has not been established. (See
BOX WARNING and CONTRAINDICATIONS.)
FENT SHOULD NOT BE ADMINISTERED TO CHILDREN 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 RESEARCH SETTING.
GERIATRIC USE
Information from a pilot study of the pharmacokinetics of IV fentanyl 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 transdermal fentanyl is unknown at this time.
Since elderly, cachectic, or debilitated patients may have altered
pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance,
they should not be started on FENT doses higher than 25 mcgm/h unless they
are already taking more than 135 mg of oral morphine a day or an equivalent dose
of another opioid (see DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
Instructions for the application, removal, and disposal of FENT are
provided in each carton.
DISPOSAL OF FENT
FENT should be kept out of the reach of children. FENT systems should
be folded so that the adhesive side of the system adheres to itself, then the
system should be flushed down the toilet immediately upon removal. 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.
If the gel from the drug reservoir accidentally contacts the skin, the area
should be washed with clear water.
DRUG INTERACTIONS:
SEE PRECAUTIONS.
ADVERSE REACTIONS:
IN POST-MARKETING EXPERIENCE, DEATHS FROM HYPOVENTILATION DUE TO INAPPROPRIATE
USE OF FENT HAVE BEEN REPORTED. (See BOX WARNING and CONTRAINDICATIONS.)
PRE-MARKETING CLINICAL TRIAL EXPERIENCE:
The safety of FENT has been evaluated in 357 postoperative patients and 153
cancer patients for a total of 510 patients. Patients with acute pain used
FENT for 1 to 3 days. The duration of FENT use varied in cancer
patients; 56% of patients used FENT for over 30 days, 28% continued
treatment for more than 4 months, and 10% used FENT for more than 1 year.
Hypoventilation was the most serious adverse reaction observed in 13 (4%)
postoperative patients and in 3 (2%) of the cancer patients. Hypotension and
hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.
Various adverse events were reported; a causal relationship to FENT was not
always determined. The frequencies presented here reflect the actual frequency
of each adverse effect in patients who received FENT. 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 following adverse reactions were reported in 153 cancer patients at a
frequency of 1% or greater; similar reactions were seen in the 357 postoperative
patients studied.
BODY AS A WHOLE: abdominal pain*, headache*
CARDIOVASCULAR: arrhythmia, chest pain
DIGESTIVE: nausea**, vomiting**, constipation**, dry mouth**, anorexia*,
diarrhea*, dyspepsia*, flatulence
NERVOUS: somnolence**, confusion**, asthenia**, dizziness*, nervousness*,
hallucinations*, anxiety*, depression*, euphoria*, tremor, abnormal
coordination, speech disorder, abnormal thinking, abnormal gait, abnormal
dreams, agitation, paresthesia, amnesia, syncope, paranoid reaction
RESPIRATORY: dyspnea*, hypoventilation*, apnea*, hemoptysis, pharyngitis,
hiccups
SKIN AND APPENDAGES: sweating**, pruritus*, rash, application site reaction -
erythema, papules, itching, edema
UROGENITAL: urinary retention*
* Reactions occurring in 3%-10% of FENT patients
** Reactions occurring in 10% or more of FENT patients
The following adverse effects have been reported in less than 1% of the 510
postoperative and cancer patients studied; the association between these events
and FENT administration is unknown. This information is listed to serve as
alerting information for the physician.
DIGESTIVE: abdominal distention
NERVOUS: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization,
hostility
RESPIRATORY: stertorous breathing, asthma, respiratory disorder
SKIN AND APPENDAGES, GENERAL: exfoliative dermatitis, pustules
SPECIAL SENSES: amblyopia
UROGENITAL: bladder pain, oliguria, urinary frequency
DRUG ABUSE AND DEPENDENCE:
Fentanyl is a Schedule II controlled substance and can produce drug dependence
similar to that produced by morphine. FENT 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.
OVERDOSAGE:
CLINICAL PRESENTATION
The manifestations of fentanyl overdosage are an extension of its pharmacologic
actions with the most serious significant effect being hypoventilation.
TREATMENT
For the management of hypoventilation immediate countermeasures include removing
the FENT system and physically or verbally stimulating the patient. These
actions can be followed by administration of a specific narcotic antagonist such
as naloxone. The duration of hypoventilation following an overdose may be longer
than the effects of the narcotic antagonist's action (the half-life of naloxone
ranges from 30 to 81 minutes). The interval between IV antagonist doses should
be carefully chosen because of the possibility of re-narcotization after system
removal; repeated administration of naloxone may be necessary. Reversal of the
narcotic effect may result in acute onset of pain and the release of
catecholamines.
If the clinical situation warrants, ensure a patent airway is established and
maintained, administer oxygen and assist or control respiration as indicated and
use an oropharyngeal airway or endotracheal tube if necessary. Adequate body
temperature and fluid intake should be maintained.
If severe or persistent hypotension occurs, the possibility of hypovolemia
should be considered and managed with appropriate parenteral fluid therapy.
DOSAGE AND ADMINISTRATION:
With all opioids, the safety of patients using the products is dependent on
health care practitioners prescribing them in strict conformity with their
approved labeling with respect to patient selection, dosing, and proper
conditions for use.
As with all opioids, dosage should be individualized. The most important factor
to be considered in determining the appropriate dose is the extent of
preexisting opioid tolerance. (See BOX WARNING and CONTRAINDICATIONS.) Initial
doses should be reduced in elderly or debilitated patients (see PRECAUTIONS).
FENT should be applied to non-irritated and non-irradiated skin on a flat
surface such as chest, back, flank or upper arm. Hair at the application site
should be clipped (not shaved) prior to system application. If the site of
FENT 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.
FENT should be applied immediately upon removal from the sealed package. Do
not alter the system, e.g., cut, in any way prior to 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 FENT may be worn continuously for 72 hours. If analgesia for more than
72 hours is required, a new system should be applied to a different skin site
after removal of the previous transdermal system.
FENT should be kept out of the reach of children. Used systems should be
folded so that the adhesive side of the system adheres to itself, then the
system should be flushed down the toilet immediately upon removal. 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.
DOSE SELECTION
DOSES MUST BE INDIVIDUALIZED BASED UPON THE STATUS OF EACH PATIENT AND SHOULD BE
ASSESSED AT REGULAR INTERVALS AFTER FENT APPLICATION. REDUCED DOSES OF
FENT ARE SUGGESTED FOR THE ELDERLY AND OTHER GROUPS DISCUSSED IN
PRECAUTIONS.
FENT DOSES GREATER THAN 25 MCGM/H SHOULD NOT BE USED FOR INITIATION OF
FENT THERAPY IN NON-OPIOID TOLERANT PATIENTS.
In selecting an initial FENT dose, attention should be given to 1) the
daily dose, potency, and characteristics of the opioid the patient has been
taking previously (eg whether it is a pure agonist or mixed agonist-antagonist),
2) the reliability of the relative potency estimates used to calculate the
FENT 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. Each patient should be maintained
at the lowest dose providing acceptable pain control.
INITIAL FENT DOSE SELECTION
There has been no systematic evaluation of FENT as an initial opioid
analgesic in the management of chronic pain, since most patients in the clinical
trials were converted to FENT from other narcotics. Therefore, unless the
patient has pre-existing opioid tolerance, the lowest FENT dose, 25 mcgm/h,
should be used as the initial dose.
To convert patients from oral or parenteral opioids to FENT use the
following methodology:
1. Calculate the previous 24-hour analgesic requirement.
2. Convert this amount to the equianalgesic oral morphine dose using Table B.
3. Table C displays the range of 24-hour oral morphine doses that are
recommended for conversion to each FENT dose. Use this table to find the
calculated 24-hour morphine dose and the corresponding FENT dose. Initiate
FENT treatment using the recommended dose and titrate patients upwards (no
more frequently than every 3 days after the initial dose or than every 6 days
thereafter) until analgesic efficacy is attained. For delivery rates in excess
of 100 mcgm/h, multiple systems may be used.
TABLE B
EQUIANALGESIC POTENCY CONVERSION
--------------------------------------------------------------------------------------------------------------------------------------------------
EQUIANALGESIC DOSE (MG)
NAME IMa PO
--------------------------------------------------------------------------------------------------------------------------------------------------
morphine 10 60 (30)b
hydromorphone 1.5 7.5
(Dilaudid(R))
methadone 10 20
(Dolophine(R))
oxycodone 15 30
(Percocet(R))
levorphanol 2 4
(Levo-Dromoran(R))
oxymorphone 1 10 (PR)
(Numorphan(R))
heroin 5 60
meperidine 75 --
(Demerol(R))
codeine 130 200
--------------------------------------------------------------------------------------------------------------------------------------------------
Note: All IM and PO doses in this chart are considered equivalent to 10 mg of
IM morphine in analgesic effect. IM denotes intramuscular, PO oral, and PR
rectal.
a Based on single-dose studies in which an intramuscular dose of each drug
listed was compared with morphine to establish the relative potency. Oral
doses are those recommended when changing from parenteral to an oral
route.
b The conversion ratio of 10 mg parenteral morphine=30 mg oral morphine is
based on clinical experience in patients with chronic pain.
Reference:
a Foley, K.M. (1985) The treatment of cancer pain. NEJM 313(2):84-95.
b Ashburn and Lipman (1993) Management of pain in the cancer patient. Anesth
Analg 76: 402-416.
TABLE C
RECOMMENDED FENT DOSE BASED UPON
DAILY ORAL MORPHINE DOSE
------------------------------------------------
ORAL 24-HOUR FENT
MORPHINE DOSE
(MG/DAY) (MCGM/HR)
------------------------------------------------
45-134 25
135-224 50
225-314 75
315-404 100
405-494 125
495-584 150
585-674 175
675-764 200
765-854 225
855-944 250
945-1034 275
1035-1124 300
NOTE: In clinical trials these ranges of daily oral morphine doses were used as
a basis for conversion to FENT.
Although controlled studies are not available, in clinical practice it is
customary to consider the doses of opioid given IM, IV or subcutaneously to be
equivalent. There may be some differences in pharmacokinetic parameters such as
Cmax and Tmax.
The majority of patients are adequately maintained with FENT 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 FENT dose should be
evaluated before changing dosing intervals in order to maintain patients on a
72-hour regimen.
Because of the increase in serum fentanyl concentration over the first 24 hours
following initial system application, the initial evaluation of the maximum
analgesic effect of FENT cannot be made before 24 hours of wearing. The
initial FENT dosage may be increased after 3 days (see Dose Titration).
During the initial application of FENT, patients should use short-acting
analgesics for the first 24 hours as needed until analgesic efficacy with
FENT is attained. Thereafter, some patients still may require periodic
supplemental doses of other short-acting analgesics for 'breakthrough' pain.
DOSE TITRATION
The conversion ratio from oral morphine to FENT is conservative, and 50% of
patients are likely to require a dose increase after initial application of
FENT. The initial FENT 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 FENT for the patient to reach equilibrium on the new dose (see graph in
ACTIONS/CLINICAL PHARMACOLOGY). Therefore, patients should wear a higher dose
through two 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 90 mg/24 hours of oral morphine to a 25 mcgm/h
increase in FENT dose.
DISCONTINUATION OF FENT
To convert patients to another opioid, remove FENT and titrate the dose of
the new analgesic based upon the patient's report of pain until adequate
analgesia has been attained. Upon system removal, 17 hours or more are required
for a 50% decrease in serum fentanyl concentrations. For patients requiring
discontinuation of opioids, a gradual downward titration is recommended since it
is not known what dose level the opioid may be discontinued without producing
the signs and symptoms of abrupt withdrawal.
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