WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse
BUTRANS contains buprenorphine, a Schedule
III controlled substance. As an opioid, BUTRANS exposes users to the
risks of addiction, abuse, and misuse. As modified-release products
such as BUTRANS deliver the opioid over an extended period of time,
there is a greater risk for overdose and death, due to the larger
amount of buprenorphine present.
Although the risk of addiction in
any individual is unknown, it can occur in patients appropriately
prescribed BUTRANS and in those who obtain the drug illicitly. Addiction
can occur at recommended doses and if the drug is misused or abused [see Drug Abuse and Dependence (9)].
Assess each patient’s risk for opioid addiction, abuse, or misuse
prior to prescribing BUTRANS, and monitor all patients receiving BUTRANS
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 abuse or addiction) or mental illness
(e.g., major depression). The potential for these risks should not,
however, prevent the proper management of pain in any given patient.
Patients at increased risk may be prescribed modified-release opioid
formulations such as BUTRANS, but use in such patients necessitates
intensive counseling about the risks and proper use of BUTRANS, along
with intensive monitoring for signs of addiction, abuse, or misuse.
Abuse or
misuse of BUTRANS 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
BUTRANS are sought by drug abusers and people with addiction disorders
and are subject to criminal diversion. Consider these risks when prescribing
or dispensing BUTRANS. 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 Counseling
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-ThreateningRespiratory Depression
Serious, life-threatening, or fatal respiratory depression has been
reported with the use of modified-release 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.
While serious,
life-threatening, or fatal respiratory depression can occur at any
time during the use of BUTRANS, the risk is greatest during the initiation
of therapy or following a dose increase. Closely monitor patients
for respiratory depression when initiating therapy with BUTRANS and
following dose increases.
To reduce the risk of respiratory
depression, proper dosing and titration of BUTRANS are essential [see Dosage and Administration (2)]. Overestimating the BUTRANS dose when converting patients from
another opioid product can result in fatal overdose with the first
dose.
Accidental exposure to BUTRANS, especially in children, can result
in respiratory depression and death due to an overdose of buprenorphine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of BUTRANS 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 BUTRANS is used
concomitantly with alcohol or other (CNS) depressants (e.g., sedatives,
anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of BUTRANS in a patient taking a CNS depressant,
assess the duration of 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
BUTRANS therapy is made, start with BUTRANS 5 mcg/hour patch, monitor
patients for signs of sedation and respiratory depression and consider
using a lower dose of the concomitant CNS depressant [see
Drug Interactions ].
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 BUTRANS and when BUTRANS
is given concomitantly with other drugs that depress respiration [see Warnings and Precautions].
Use in Patients with 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 pre-existing respiratory depression for respiratory depression,
particularly when initiating therapy and titrating with BUTRANS, as
in these patients, even usual therapeutic doses of BUTRANS may decrease
respiratory drive to the point of apnea [see Warnings and
Precautions ]. Consider
the use of alternative non-opioid analgesics in these patients if
possible.
QTc Prolongation
A positive-controlled study
of the effects of BUTRANS on the QTc interval in healthy subjects
demonstrated no clinically meaningful effect at a BUTRANS dose of
10 mcg/hour; however, a BUTRANS dose of 40 mcg/hour (given as two
BUTRANS 20 mcg/hour Transdermal Systems) was observed to prolong the
QTc interval [see Dosage and Administration and Clinical Pharmacology].
Consider these observations
in clinical decisions when prescribing BUTRANS to patients with hypokalemia
or clinically unstable cardiac disease, including: unstable atrial
fibrillation, symptomatic bradycardia, unstable congestive heart failure,
or active myocardial ischemia. Avoid the use of BUTRANS in patients
with a history of Long QT Syndrome or an immediate family member with
this condition, or those taking Class IA antiarrhythmic medications
(e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic
medications (e.g., sotalol, amiodarone, dofetilide).
Hypotensive Effects
BUTRANS 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
BUTRANS.
Use in Patientswith Head Injury or Increased Intracranial Pressure
Monitor patients
taking BUTRANS who may be susceptible to the intracranial effects
of CO2 retention (e.g., those with evidence
of increased intracranial pressure or brain tumors) for signs of sedation
and respiratory depression, particularly when initiating therapy with
BUTRANS. BUTRANS may reduce respiratory drive, and the resultant
CO2 retention can further increase intracranial
pressure. Opioids may also obscure the clinical course in a patient
with a head injury.
Avoid the
use of BUTRANS in patients with impaired consciousness or coma.
Hepatotoxicity
Although not observed in BUTRANS chronic pain
clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice
have been observed in individuals receiving sublingual buprenorphine
for the treatment of opioid dependence, both in clinical trials and
in post-marketing adverse event reports. The spectrum of abnormalities
ranges from transient asymptomatic elevations in hepatic transaminases
to case reports of hepatic failure, hepatic necrosis, hepatorenal
syndrome, and hepatic encephalopathy. In many cases, the presence
of pre-existing liver enzyme abnormalities, infection with hepatitis B
or hepatitis C virus, concomitant usage of other potentially hepatotoxic
drugs, and ongoing injection drug abuse may have played a causative
or contributory role. For patients at increased risk of hepatotoxicity
(e.g., patients with a history of excessive alcohol intake, intravenous
drug abuse or liver disease), obtain baseline liver enzyme levels
and monitor periodically and during treatment with BUTRANS.
Application SiteSkin Reactions
In rare cases,
severe application site skin reactions with signs of marked inflammation
including “burn,” “discharge,” and “vesicles” have occurred. Time
of onset varies, ranging from days to months following the initiation
of BUTRANS treatment. Instruct patients to promptly report the development
of severe application site reactions and discontinue therapy.
Anaphylactic/AllergicReactions
Cases of acute and
chronic hypersensitivity to buprenorphine have been reported both
in clinical trials and in the post-marketing experience. The most
common signs and symptoms include rashes, hives, and pruritus. Cases
of bronchospasm, angioneurotic edema, and anaphylactic shock have
been reported. A history of hypersensitivity to buprenorphine is
a contraindication to the use of BUTRANS.
Application ofExternal Heat
Advise patients
and their caregivers to avoid exposing the BUTRANS application site
and surrounding area to direct external heat sources, such as heating
pads or electric blankets, heat or tanning lamps, saunas, hot tubs,
and heated water beds while wearing the system because an increase
in absorption of buprenorphine may occur [see Clinical Pharmacology]. Advise patients
against exposure of the BUTRANS application site and surrounding area
to hot water or prolonged exposure to direct sunlight. There is a
potential for temperature-dependent increases in buprenorphine released
from the system resulting in possible overdose and death.
Patients with Fever
Monitor patients wearing BUTRANS systems who
develop fever or increased core body temperature due to strenuous
exertion for opioid side effects and adjust the BUTRANS dose if signs
of respiratory or central nervous system depression occur.
Use in Patientswith Gastrointestinal Conditions
BUTRANS is contraindicated in patients with paralytic ileus. Avoid
the use of BUTRANS in patients with other GI obstruction.
The buprenorphine in BUTRANS may cause
spasm of the sphincter of Oddi. Monitor patients with biliary tract
disease, including acute pancreatitis, for worsening symptoms. Opioids
may cause increases in the serum amylase.
Use in Patientswith Convulsive or Seizure Disorders
The buprenorphine in BUTRANS
may aggravate convulsions in patients with convulsive disorders, and
may induce or aggravate seizures in some clinical settings. Monitor
patients with a history of seizure disorders for worsened seizure
control during BUTRANS therapy.
Driving and Operating Machinery
BUTRANS may impair the mental and physical abilities needed
to perform potentially hazardous activities 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 BUTRANS and know
how they will react to the medication.
Use in Addiction Treatment
BUTRANS has not been studied and is not approved for use in the management
of addictive disorders.
USE IN SPECIFIC POPULATIONS
Pregnancy
Clinical Considerations
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 ].
Teratogenic Effects - Pregnancy Category
C
There are no adequate and well-controlled
studies in pregnant women. BUTRANS should be used during pregnancy
only if the potential benefit justifies the potential risk to the
fetus.
In animal studies, buprenorphine
caused an increase in the number of stillborn offspring, reduced litter
size, and reduced offspring growth in rats at maternal exposure levels
that were approximately 10 times that of human subjects who received
one BUTRANS 20 mcg/hour, the maximum recommended human dose (MRHD).
Studies in rats and rabbits demonstrated
no evidence of teratogenicity following BUTRANS or subcutaneous (SC)
administration of buprenorphine during the period of major organogenesis.
Rats were administered up to one BUTRANS 20 mcg/hour every 3 days
(gestation days 6, 9, 12, & 15) or received daily SC buprenorphine
up to 5 mg/kg (gestation days 6-17). Rabbits were administered four
BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18,
& 19) or received daily SC buprenorphine up to 5 mg/kg (gestation
days 6-19). No teratogenicity was observed at any dose. AUC values
for buprenorphine with BUTRANS application and SC injection were approximately
110 and 140 times, respectively, that of human subjects who received
the MRHD of one BUTRANS 20 mcg/hour.
Non-Teratogenic Effects
In a peri- and post-natal study conducted in
pregnant and lactating rats, administration of buprenorphine either
as BUTRANS or SC buprenorphine was associated with toxicity to offspring.
Buprenorphine was present in maternal milk. Pregnant rats were administered
1/4 of one BUTRANS 5 mcg/hour every 3 days or received daily SC buprenorphine
at doses of 0.05, 0.5, or 5 mg/kg from gestation day 6 to lactation
day 21 (weaning). Administration of BUTRANS or SC buprenorphine at
0.5 or 5 mg/kg caused maternal toxicity and an increase in the number
of stillborns, reduced litter size, and reduced offspring growth at
maternal exposure levels that were approximately 10 times that of
human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Maternal
toxicity was also observed at the no observed adverse effect level
(NOAEL) for offspring.
Labor and Delivery
Opioids cross the placenta and may produce respiratory
depression in neonates. BUTRANS 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.
Nursing Mothers
Buprenorphine is excreted in breast milk. The
amount of buprenorphine received by the infant varies depending on
the maternal plasma concentration, the amount of milk ingested by
the infant, and the extent of first pass metabolism.
Withdrawal symptoms can occur in breast-feeding infants
when maternal administration of buprenorphine is stopped.
Because of the potential for adverse reactions
in nursing infants from BUTRANS, a decision should be made whether
to discontinue nursing or discontinue the drug, taking into account
the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of BUTRANS in patients
under 18 years of age has not been established.
Geriatric Use
Of the total number of subjects in the clinical
trials (5,415), BUTRANS was administered to 1,377 patients aged 65
years and older. Of those, 457 patients were 75 years of age and
older. In the clinical program, the incidences of selected BUTRANS-related
AEs were higher in older subjects. The incidences of application site
AEs were slightly higher among subjects < 65 years of age than
those ≥ 65 years of age for both BUTRANS and placebo treatment groups.
In a single-dose study of healthy elderly
and healthy young subjects treated with BUTRANS 10 mcg/hour, the pharmacokinetics
were similar. In a separate dose-escalation safety study, the pharmacokinetics
in the healthy elderly and hypertensive elderly subjects taking thiazide
diuretics were similar to those in the healthy young adults. In the
elderly groups evaluated, adverse event rates were similar to or lower
than rates in healthy young adult subjects, except for constipation
and urinary retention, which were more common in the elderly. Although
specific dose adjustments on the basis of advanced age are not required
for pharmacokinetic reasons, use caution in the elderly population
to ensure safe use [see Clinical Pharmacology].
Hepatic Impairment
In a study utilizing intravenous buprenorphine,
peak plasma levels (Cmax) and exposure (AUC)
of buprenorphine in patients with mild and moderate hepatic impairment
did not increase as compared to those observed in subjects with normal
hepatic function. BUTRANS has not been evaluated in patients with
severe hepatic impairment. As BUTRANS is intended for 7-day dosing,
consider the use of alternate analgesic therapy in patients with severe
hepatic impairment [see Dosage and Administration and Clinical Pharmacology].
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