Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
DURAGESIC contains fentanyl, an opioid agonist and a
Schedule II controlled substance. As an opioid, DURAGESIC exposes users to the
risks of addiction, abuse, and misuse [see Drug Abuse and Dependence]. As
modified-release products such as DURAGESIC deliver the opioid over an extended
period of time, there is a greater risk for overdose and death due to the
larger amount of fentanyl present.
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed DURAGESIC and in
those who obtain the drug illicitly. Addiction can occur at recommended doses
and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse prior to prescribing DURAGESIC, and monitor all patients receiving
DURAGESIC for the development of these behaviors or conditions. Risks are
increased in patients with a personal or family history of substance abuse
(including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).
The potential for these risks should not, however, prevent the prescribing of DURAGESIC
for the proper management of pain in any given patient. Patients at increased
risk may be prescribed modified-release opioid formulations such as DURAGESIC,
but use in such patients necessitates intensive counseling about the risks and
proper use of DURAGESIC along with intensive monitoring for signs of addiction,
abuse, and misuse.
Abuse or misuse of DURAGESIC by placing it in the mouth,
chewing it, swallowing it, or using it in ways other than indicated may cause
choking, overdose, and death [see OVERDOSAGE].
Opioid agonists such as DURAGESIC are sought by drug
abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing DURAGESIC.
Strategies to reduce these risks include prescribing the drug in the smallest
appropriate quantity and advising the patient on the proper disposal of unused
drug [see PATIENT INFORMATION]. Contact local state
professional licensing board or state controlled substances authority for
information on how to prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory
depression has been reported with the use of opioids, even when used as
recommended. Respiratory depression from opioid use, if not immediately
recognized and treated, may lead to respiratory arrest and death. Management of
respiratory depression may include close observation, supportive measures, and
use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE].
Carbon dioxide (CO2) retention from opioid-induced respiratory depression can
exacerbate the sedating effects of opioids.
DURAGESIC is indicated only in opioid tolerant patients
because of the risk for respiratory depression and death. While serious,
life-threatening, or fatal respiratory depression can occur at any time during
the use of DURAGESIC, the risk is greatest during the initiation of therapy or following
a dose increase. Closely monitor patients for respiratory depression when
initiating therapy with DURAGESIC.
To reduce the risk of respiratory depression, proper
dosing and titration of DURAGESIC are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the DURAGESIC dose when converting patients
from another opioid product can result in fatal overdose with the first dose.
Accidental exposure to DURAGESIC, especially in children,
can result in respiratory depression and death due to an overdose of fentanyl.
A considerable amount of active fentanyl remains in
DURAGESIC even after use as directed. Death and other serious medical problems
have occurred when children and adults were accidentally exposed to DURAGESIC.
Accidental or deliberate application or ingestion by a child or adolescent will
cause respiratory depression that can result in death. Placing DURAGESIC in the
mouth, chewing it, swallowing it, or using it in ways other than indicated may
cause choking or overdose that could result in death. Improper disposal of
DURAGESIC in the trash has resulted in accidental exposures and deaths.
Advise patients about strict adherence to the recommended
handling and disposal instructions in order to prevent accidental exposure to
DURAGESIC [see DOSAGE AND ADMINISTRATION].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of DURAGESIC during pregnancy can result in
withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike
opioid withdrawal syndrome in adults, may be life-threatening if not recognized
and treated, and requires management according to protocols developed by
neonatology experts. If opioid use is required for a prolonged period in a
pregnant woman, advise the patient of the risk of neonatal opioid withdrawal
syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as
irritability, hyperactivity and abnormal sleep pattern, high pitched cry,
tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and
severity of neonatal opioid withdrawal syndrome vary based on the specific
opioid used, duration of use, timing and amount of last maternal use, and rate
of elimination of the drug by the newborn.
Interactions With Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory
depression, and death may result if DURAGESIC is used concomitantly with
alcohol or other central nervous system (CNS) depressants (e.g., sedatives,
anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of DURAGESIC in a patient taking
a CNS depressant, assess the duration use of the CNS depressant and the
patient's response, including the degree of tolerance that has developed to CNS
depression. Additionally, evaluate the patient's use of alcohol or illicit
drugs that cause CNS depression. If the decision to begin DURAGESIC is made,
reducethe starting dose, monitor patients for signs of sedation and respiratory
depression, and consider using a lower dose of the concomitant CNS depressant [see
Use In Elderly, Cachectic, And Debilitated Patients
Life-threatening respiratory depression is more likely to
occur in elderly, cachectic, or debilitated patients as they may have altered
pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particularly when initiating and titrating DURAGESIC
and when DURAGESIC is given concomitantly with other drugs that depress respiration
[see Life-Threatening Respiratory Depression].
Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and patients having a substantially
decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory
depression for respiratory depression, particularly when initiating therapy with
DURAGESIC, as in these patients, even usual therapeutic doses of DURAGESIC may decrease
respiratory drive to the point of apnea [see Life-Threatening Respiratory Depression]. Consider
the use of alternative non-opioid analgesics in these patients if possible.
Head Injuries And Increased Intracranial Pressure
Avoid use of DURAGESIC 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 [see Life-Threatening Respiratory Depression]. In addition, opioids may obscure
the clinical course of patients with head injury. Monitor patients with brain
tumors who may be susceptible to the intracranial effects of CO2 retention for
signs of sedation and respiratory depression, particularly when initiating
therapy with DURAGESIC, as DURAGESIC may reduce respiratory drive and CO2
retention can further increase intracranial pressure.
DURAGESIC may cause severe hypotension including
orthostatic hypotension and syncope in ambulatory patients. There is an
increased risk in patients whose ability to maintain blood pressure has already
been compromised by a reduced blood volume or concurrent administration of
certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see
DRUG INTERACTIONS]. Monitor these patients for signs of hypotension
after initiating or titrating the dose of DURAGESIC.
Interactions With CYP3A4 Inhibitors And Inducers
Since the CYP3A4 isoenzyme plays a major role in the
metabolism of DURAGESIC, drugs that alter CYP3A4 activity may cause changes in
clearance of fentanyl which could lead to changes in fentanyl plasma
The concomitant use of DURAGESIC with a CYP3A4 inhibitors
(such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin,
nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem,
erythromycin, fluconazole, fosamprenavir, verapamil) may result in an increase
in fentanyl plasma concentrations, which could increase or prolong adverse drug
effects and may cause potentially fatal respiratory depression. Carefully
monitor patients receiving DURAGESIC and any CYP3A4 inhibitor for signs of
sedation and respiratory depression for an extended period of time, and make
dosage adjustments as needed.
CYP450 inducers, such as rifampin, carbamazepine, and
phenytoin, may induce the metabolism of fentanyl and, therefore, may cause
increased clearance of the drug which could lead to a decrease in fentanyl
plasma concentrations, lack of efficacy or, possibly, development of an abstinence
syndrome in a patient who had developed physical dependence to fentanyl.
If co-administration is necessary, caution is advised
when initiating DURAGESIC treatment in patients currently taking, or
discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at
frequent intervals and consider dose adjustments until stable drug effects are
achieved [see DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
Application Of External Heat
Exposure to heat may increase fentanyl absorption and
there have been reports of overdose and death as a result of exposure to heat.
A clinical pharmacology study conducted in healthy adult subjects has shown
that the application of heat over the DURAGESIC system increased fentanyl exposure
[see CLINICAL PHARMACOLOGY].
Warn patients to avoid exposing the DURAGESIC application
site and surrounding area to direct external heat credits [see DOSAGE AND
Patients With Fever
Based on a pharmacokinetic model, serum fentanyl
concentrations could theoretically increase by approximately one-third for
patients with a body temperature of 40°C (104°F) due to temperature-dependent
increases in fentanyl released from the system and increased skin permeability.
Monitor patients wearing DURAGESIC systems who develop fever closely for opioid
side effects and reduce the DURAGESIC dose if necessary. Warn patients to avoid
strenuous exertion that leads to increased core body temperature while wearing
DURAGESIC to avoid the risk of potential overdose and death.
DURAGESIC may produce bradycardia. Monitor patients with
bradyarrhythmias closely for changes in heart rate, particularly when
initiating therapy with DURAGESIC.
A clinical pharmacology study with DURAGESIC in patients
with cirrhosis has shown that systemic fentanyl exposure increased in these
patients. Because of the long half-life of fentanyl when administered as
DURAGESIC and hepatic metabolism of fentanyl, avoid use of DURAGESIC in
patients with severe hepatic impairment. Insufficient information exists to
make precise dosing recommendations regarding the use of DURAGESIC in patients
with impaired hepatic function. Therefore, to avoid starting patients with mild
to moderate hepatic impairment on too high of a dose, start with one half of
the usual dosage of DURAGESIC. Closely monitor for signs of sedation and
respiratory depression, including at each dosage increase. [see DOSING AND
ADMINISTRATION, Use In Specific Populations and CLINICAL
A clinical pharmacology study with intravenous fentanyl
in patients undergoing kidney transplantation has shown that patients with high
blood urea nitrogen level had low fentanyl clearance. Because of the long
half-life of fentanyl when administered as DURAGESIC, avoid the use of
DURAGESIC in patients with severe renal impairment. Insufficient information
exists to make precise dosing recommendations regarding the use of DURAGESIC in
patients with impaired renal function. Therefore, to avoid starting patients
with mild to moderate renal impairment on too high of a dose, start with one
half of the usual dosage of DURAGESIC. Closely monitor for signs of sedation
and respiratory depression, including at each dosage increase [see DOSING
AND ADMINISTRATION, Use In Specific Populations and CLINICAL PHARMACOLOGY].
Use In Pancreatic/Biliary Tract Disease
DURAGESIC may cause spasm of the sphincter of Oddi.
Monitor patients with biliary tract disease, including acute pancreatitis for
worsened symptoms. DURAGESIC may cause increases in the serum amylase
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine)
analgesics in patients who have received or are receiving a course of therapy
with an opioid agonist analgesic, including DURAGESIC. In these patients, mixed
agonist/antagonist and partial agonist analgesics may reduce the analgesic
effect and/or may precipitate withdrawal symptoms.
Driving And Operating Machinery
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. Warn patients not to drive or operate
dangerous machinery unless they are tolerant to the effects of the DURAGESIC.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Addiction, Abuse, And Misuse
Inform patients that the use of DURAGESIC, even when
taken as recommended, can result in addiction, abuse, and misuse, which can
lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct
patients not to share DURAGESIC with others and to take steps to protect
DURAGESIC from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression, including information that the risk is greatest when
starting DURAGESIC or when the dose is increased, and that it can occur even at
recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how to
recognize respiratory depression and to seek medical attention if breathing
Inform patients to keep DURAGESIC in a secure place out
of the reach of children due to the high risk of respiratory depression or
death. [see WARNINGS AND PRECAUTIONS].
DURAGESIC can be accidentally transferred to children.
Instruct patients to take special precautions to avoid accidental contact when
holding or caring for children.
Instruct patients that, if the patch dislodges and
accidentally sticks to the skin of another person, to immediately take the
patch off, wash the exposed area with water and seek medical attention for the
accidentally exposed individual as accidental exposure may lead to death or
other serious medical problems.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of DURAGESIC during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and
treated [see WARNINGS AND PRECAUTIONS].
Interactions With Alcohol And Other CNS Depressants
Inform patients that potentially serious additive effects
may occur if DURAGESIC is used with alcohol or other CNS depressants, and not
to use such drugs unless supervised by a healthcare provider.
Important Administration Instructions
Advise patients never to change the dose of DURAGESIC or
the number of patches applied to the skin unless instructed to do so by the
prescribing healthcare professional.
When no longer needed, advise patients how to safely
taper DURAGESIC and not to stop it abruptly to avoid the risk of precipitating
Warnings About Heat
Warn patients of the potential for temperature-dependent
increases in fentanyl release from the patch that could result in an overdose
of fentanyl. Instruct patients to contact their healthcare provider if they
develop a high fever. Instruct patients to:
- avoid strenuous exertion that can increase body
temperature while wearing the patch
- avoid exposing the DURAGESIC application site and
surrounding area to direct external heat credits including heating pads,
electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot
baths, and heated water beds.
Driving Or Operating Heavy Machinery
DURAGESIC may impair mental and/or physical ability
required for the performance of potentially hazardous tasks (e.g., driving,
operating machinery). Instruct patients to refrain from any potentially
dangerous activity when starting on DURAGESIC or when their dose is being adjusted,
until it is established that they have not been adversely affected.
Advise women of childbearing potential who become, or are
planning to become pregnant, to consult a healthcare provider prior to
initiating or continuing therapy with DURAGESIC.
Additive Effects Of Alcohol And Other CNS Depressants
Instruct patients not to use alcohol or other CNS
depressants (e.g. sleep medications, tranquilizers) while using DURAGESIC
because dangerous additive effects may occur, resulting in serious injury or
Advise patients of the potential for severe constipation.
Instruct patients to refer to the Instructions for Use
for proper disposal of DURAGESIC. To properly dispose of a used patch, instruct
patients to remove it, fold so that the adhesive side of the patch adheres to
itself, and immediately f lush down the toilet. Unused patches should be removed
from their pouches, the protective liners removed, the patches folded so that
theadhesive side of the patch adheres to itself, and immediately flushed down
Instruct patients to dispose of any patches remaining
from a prescription as soon as they are no longer needed.
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
In a two-year carcinogenicity study conducted in rats,
fentanyl was not associated with an increased incidence of tumors at
subcutaneous doses up to 33 μg/kg/day in males or 100 μg/kg/day in
females (0.16 and 0.39 times the human daily exposure obtained via the 100
mcg/h patch based on AUC0-24h comparison).
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.
Impairment Of Fertility
The potential effects of fentanyl on male and female
fertility were examined in the rat model via two separate experiments. In the
male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or
0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating;
female rats were not treated. In the female fertility study, female rats were
treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous
intravenous infusion for 14 days prior to mating until day 16 of pregnancy;
male rats were not treated. Analysis of fertility parameters in both studies
indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either
the male or the female alone produced no effects on fertility (this dose is
approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch
on a mg/m² basis). In a separate study, a single daily bolus dose of fentanyl
was shown to impair fertility in rats when given in intravenous doses of 0.3
times the human dose for a period of 12 days.
Use In Specific Populations
Fetal/neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for
medical or nonmedical purposes can result in physical dependence in the neonate
and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns
for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding,
diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see
WARNINGS AND PRECAUTIONS].
Pregnancy C: There are no adequate and
well-controlled studies in pregnant women. DURAGESIC should be used during
pregnancy only if the potential benefit justifies the potential risk to the
The potential effects of fentanyl on embryo-fetal
development were studied in the rat, mouse, and rabbit models. Published
literature reports that administration of fentanyl (0, 10, 100, or 500 μg/kg/day)
to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted micro osmotic
minipumps did not produce any evidence of teratogenicity (the high dose is approximately
2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis).
In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03
mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of
embryo-toxicity and a slight increase in mean delivery time in the 0.03
mg/kg/day group. There was no clear evidence of teratogenicity noted.
Pregnant female New Zealand White rabbits were treated
with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to
day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of
the live fetuses at the high dose, which may be attributed to maternal toxicity.
Under the conditions of the assay, there was no evidence for fentanyl induced
adverse effects on embryo-fetal development at doses up to 0.4 mg/kg
(approximately 3 times the daily human dose administered by a 100 mcg/hr patch
on a mg/m² basis).
Chronic maternal treatment with fentanyl during pregnancy
has been associated with transient respiratory depression, behavioral changes,
or seizures characteristic of neonatal abstinence syndrome in newborn infants.
Symptoms of neonatal respiratory or neurological depression were no more
frequent than expected in most studies of infants born to women treated acutely
during labor with intravenous or epidural fentanyl. Transient neonatal muscular
rigidity has been observed in infants whose mothers were treated with
The potential effects of fentanyl on prenatal and
postnatal development were examined in the rat model. Female Wistar rats were treated
with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day
6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day)
significantly decreased body weight in male and female pups and also decreased survival
in pups at day 4. Both the mid-dose and high-dose of fentanyl animals
demonstrated alterations in some physical landmarks of development (delayed
incisor eruption and eye opening) and transient behavioral development
(decreased locomotor activity at day 28 which recovered by day 50). The
mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose
administered by a 100 mcg/hr patch on a mg/m² basis.
Labor And Delivery
Opioids cross the placenta and may produce respiratory
depression in neonates. DURAGESIC is not for use in women during and
immediately prior to labor, when shorter acting analgesics or other analgesic
techniques are more appropriate. Opioid analgesics can prolong labor through actions
that temporarily reduce the strength, duration, and frequency of uterine
contractions. However, this effect is not consistent and may be offset by an
increased rate of cervical dilatation, which tends to shorten labor.
Fentanyl is excreted in human milk; therefore, DURAGESIC
is not recommended for use in nursing women because of the possibility of
effects in their infants.
The safety of DURAGESIC was evaluated in three open-label
trials in 289 pediatric patients with chronic pain, 2 years of age through 18
years of age. Starting doses of 25 mcg/h and higher were used by 181 patients
who had been on prior daily opioid doses of at least 45 mg/day of oral morphine
or an equianalgesic dose of another opioid. Initiation of DURAGESIC therapy in pediatric
patients taking less than 60 mg/day of oral morphine or an equianalgesic dose
of another opioid has not been evaluated in controlled clinical trials.
The safety and effectiveness of DURAGESIC in children
under 2 years of age have not been established.
To guard against excessive exposure to DURAGESIC by young
children, advise caregivers to strictly adhere to recommended DURAGESIC
application and disposal instructions [see DOSAGE AND ADMINISTRATION and
WARNINGS AND PRECAUTIONS].
Clinical studies of DURAGESIC did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
Data from intravenous studies with fentanyl suggest that
the elderly patients may have reduced clearance and a prolonged half-life.
Moreover, elderly patients may be more sensitive to the active substance than
younger patients. A study conducted with the DURAGESIC patch in elderly
patients demonstrated that fentanyl pharmacokinetics did not differ
significantly from young adult subjects, although peak serum concentrations
tended to be lower and mean half-life values were prolonged to approximately 34
hours [see CLINICAL PHARMACOLOGY].
Monitor geriatric patients closely for signs of sedation
and respiratory depression, particularly when initiating therapy with DURAGESIC
and when given in conjunction with other drugs that depress respiration [see WARNINGS
The effect of hepatic impairment on the pharmacokinetics
of DURAGESIC has not been fully evaluated. A clinical pharmacology study with
DURAGESIC in patients with cirrhosis has shown that systemic fentanyl exposure
increased in these patients. Because there is in-vitro and in-vivo evidence of
extensive hepatic contribution to the elimination of DURAGESIC, hepatic impairment
would be expected to have significant effects on the pharmacokinetics of DURAGESIC.
Avoid use of DURAGESIC in patients with severe hepatic impairment [see DOSING
AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL
The effect of renal impairment on the pharmacokinetics of
DURAGESIC has not been fully evaluated. A clinical pharmacology study with
intravenous fentanyl in patients undergoing kidney transplantation has shown
that patients with high blood urea nitrogen level had low fentanyl clearance.
Because there is in-vivo evidence of renal contribution to the elimination of DURAGESIC,
renal impairment would be expected to have significant effects on the pharmacokinetics
of DURAGESIC. Avoid the use of DURAGESIC in patients with severe renal impairment
[see DOSING AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL