Included as part of the "PRECAUTIONS" Section
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 [see Drug Abuse And Dependence]. Because extended-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. 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 BUTRANS,
and monitor all patients receiving BUTRANS for the development of these behaviors and
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 opioids 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 OVERDOSE].
Opioids 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 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, 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 OVERDOSE]. 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 dosage
increase. Monitor patients closely for respiratory depression, especially within the first 24-72
hours of initiating therapy with and following dosage increases of BUTRANS.
To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are
essential [see DOSAGE AND ADMINISTRATION]. Overestimating the BUTRANS dosage 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 in the neonate. Neonatal
opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be lifethreatening
if not recognized and treated, and requires management according to protocols
developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal
syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged
period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment
will be available [see Use In Specific Populations , PATIENT INFORMATION].
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use
of BUTRANS with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine
sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics
alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with
the concomitant use of other CNS depressant drugs with opioid analgesics [see DRUG INTERACTIONS].
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly
with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of
concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose
of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and
titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a
benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic,
and titrate based on clinical response. Follow patients closely for signs and symptoms of
respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when
BUTRANS is used with benzodiazepines or other CNS depressants (including alcohol and illicit
drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant
use of the benzodiazepine or other CNS depressant have been determined. Screen patients for
risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for
overdose and death associated with the use of additional CNS depressants including alcohol and
illicit drugs [see DRUG INTERACTIONS , PATIENT INFORMATION].
Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease
Or In Elderly, Cachectic, Or Debilitated Patients
The use of BUTRANS in patients with acute or severe bronchial asthma in an unmonitored
setting or in the absence of resuscitative equipment is contraindicated.
Patients With Chronic Pulmonary Disease
BUTRANS-treated patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased
respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased
risk of decreased respiratory drive including apnea, even at recommended dosages of BUTRANS
[see Life-Threatening Respiratory Depression].
Elderly, Cachectic, Or Debilitated Patients
Life-threatening respiratory depression is more likely
to occur in elderly, cachectic, or debilitated patients because they may have altered
pharmacokinetics or altered clearance compared to younger, healthier patients [see Life-Threatening Respiratory Depression].
Monitor such patients closely, particularly when initiating and titrating BUTRANS and when
BUTRANS is given concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression, Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants]. Alternatively, consider the use of non-opioid analgesics in these
Cases of adrenal insufficiency have been reported with opioid use, more often following greater
than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms
and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as
soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses
of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and
continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as
some cases reported use of a different opioid without recurrence of adrenal insufficiency. The
information available does not identify any particular opioids as being more likely to be
associated with adrenal insufficiency.
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.
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), or other medications that prolong the QTc interval [see DOSAGE AND ADMINISTRATION , ADVERSE REACTIONS , CLINICAL PHARMACOLOGY].
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
dosage of BUTRANS. In patients with circulatory shock, BUTRANS may cause vasodilation
that can further reduce cardiac output and blood pressure. Avoid the use of BUTRANS in
patients with circulatory shock.
Risks Of Use In Patients With Increased Intracranial Pressure, Brain Tumors, Head
Injury Or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with
evidence of increased intracranial pressure or brain tumors), BUTRANS may reduce respiratory
drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such
patients for signs of sedation and respiratory depression, particularly when initiating therapy with
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.
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 Site Skin 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.
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.
Risks Of Use With Application Of External 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 [see PATIENT INFORMATION].
Risk Of Use In 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.
Risks Of Use In Patients With Gastrointestinal Conditions
BUTRANS is contraindicated in patients with known or suspected gastrointestinal obstruction,
including paralytic ileus.
The buprenorphine in BUTRANS may cause spasm of the sphincter of Oddi. Opioids may cause
increases in the serum amylase. Monitor patients with biliary tract disease, including acute
pancreatitis, for worsening symptoms.
Increased Risk Of Seizures In Patients With Seizure Disorders
The buprenorphine in BUTRANS may increase the frequency of seizures in patients with seizure
disorders, and may increase the risk of seizures in other clinical settings associated with seizures.
Monitor patients with a history of seizure disorders for worsened seizure control during
Risks Of 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 [see PATIENT INFORMATION].
Use In Addiction Treatment
BUTRANS has not been studied and is not approved for use in the management of addictive
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions
Addiction, Abuse, And Misuse
Inform patients that the use of BUTRANS, even when taken as recommended, can result in
addiction, abuse, and misuse, which could lead to overdose and death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share BUTRANS with others and to take steps to
protect BUTRANS 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 BUTRANS or when the dosage 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 difficulties
Inform patients that accidental exposure, especially in children, may result in respiratory
depression or death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store
BUTRANS securely and to dispose of unused BUTRANS by folding the patch in half and
flushing it down the toilet [see DOSAGE AND ADMINISTRATION] .
Interaction With Benzodiazepines And Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if BUTRANS is
used with benzodiazepines or other CNS depressants, including alcohol, and not to use these
concomitantly unless supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS].
Interaction With Benzodiazepines
Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking
BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as
directed by their physician [see DRUG INTERACTIONS].
Inform patients that OPIOIDS could cause a rare but potentially life-threatening condition
resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms
of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct
patients to inform their physicians if they are taking, or plan to take serotonergic medications
[see DRUG INTERACTIONS].
Inform patients to avoid taking BUTRANS while using any drugs that inhibit monoamine
oxidase. Patients should not start MAOIs while taking BUTRANS [see DRUG INTERACTIONS].
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening
condition. Adrenal insufficiency may present with non-specific symptoms and signs such as
nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise
patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS AND PRECAUTIONS].
Important Administration Instructions
Instruct patients how to properly use BUTRANS, including the following:
To carefully follow instructions for the application, removal, and disposal of BUTRANS.
Each week, apply BUTRANS to a different site based on the 8 described skin sites, with a
minimum of 3 weeks between applications to a previously used site [see DOSAGE AND ADMINISTRATION].
To apply BUTRANS to a hairless or nearly hairless skin site. If none are available, instruct
patients to clip the hair at the site and not to shave the area. Instruct patients not to apply to
irritated skin. If the application site must be cleaned, use clear water only. Soaps, alcohol,
oils, lotions, or abrasive devices should not be used. Allow the skin to dry before applying
BUTRANS [see DOSAGE AND ADMINISTRATION].
To avoid exposing the BUTRANS application site to external heat sources, hot water, or
prolonged direct sunlight [see WARNINGS AND PRECAUTIONS].
Do not discontinue BUTRANS without first discussing the need for a tapering regimen with
the prescriber [see DOSAGE AND ADMINISTRATION].
Inform patients that BUTRANS may cause orthostatic hypotension and syncope. Instruct
patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious
consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or
lying position) [see WARNINGS AND PRECAUTIONS].
Inform patients that anaphylaxis has been reported with ingredients contained in BUTRANS.
Advise patients how to recognize such a reaction and when to seek medical attention [see WARNINGS AND PRECAUTIONS ,CONTRAINDICATIONS , ADVERSE REACTIONS].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of BUTRANS during
pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening
if not recognized and treated [see WARNINGS AND PRECAUTIONS , Use In Specific Populations .
Inform female patients of reproductive potential that BUTRANS can cause fetal harm and to
inform their healthcare provider of a known or suspected pregnancy [see Use In Specific Populations].
Advise patients that breastfeeding is not recommended during treatment with BUTRANS [see Use In Specific Populations]
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether
these effects on fertility are reversible [see Use In Specific Populations].
Driving Or Operating Heavy Machinery
Inform patients that BUTRANS may impair the ability to perform potentially hazardous
activities such as driving a car or operating heavy machinery. Advise patients not to perform
such tasks until they know how they will react to the medication [see WARNINGS AND PRECAUTIONS].
Advise patients of the potential for severe constipation, including management instructions and
when to seek medical attention [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY].
Instruct patients to refer to the Instructions for Use for proper disposal of BUTRANS. Patients
can dispose of used or unused BUTRANS patches in the trash by sealing them in the Patch-
Disposal Unit, following the instructions on the unit.
Alternatively, instruct patients to dispose of used patches by folding the adhesive side of the
patch to itself, then flushing the patch down the toilet immediately upon removal. Unused
patches should be removed from their pouches, the protective liners removed, the patches folded
so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.
Instruct patients to dispose of any patches remaining from a prescription as soon as they are no
longer needed [see DOSAGE AND ADMINISTRATION].
Healthcare professionals can telephone Purdue Pharma’s Medical Services Department
(1-888-726-7535) for information on this product.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Buprenorphine administered daily by skin painting to Sprague Dawley rats for 100 weeks at
dosages (20, 60, or 200 mg/kg) produced systemic exposures (based on AUC) that ranged from
approximately 130 to 350 times that of human subjects administered the maximum
recommended human dose (MRHD) of BUTRANS 20 mcg/hour.An increased incidence of
benign testicular interstitial cell tumors, considered buprenorphine treatment-related, was
observed in male rats compared with concurrent controls. The tumor incidence was also above
the highest incidence in the historical control database of the testing facility. These tumors were
noted at 60 mg/kg/day and higher at approximately 220 times the proposed MRHD based on
AUC. The no observed effect level (NOEL) was 20 mg/kg/day (approximately 140 times the
proposed MRHD based on AUC). The mechanism leading to the tumor findings and the
relevance to humans is unknown.
Buprenorphine was administered by skin painting to hemizygous Tg.AC mice over a 6-month
study period. At the dosages administered daily (18.75, 37.5, 150, or 600 mg/kg/day),
buprenorphine was not carcinogenic or tumorigenic at systemic exposure to buprenorphine,
based on AUC, of up to approximately 1000 times that of human subjects administered
BUTRANS 20 mcg/hour, the MRHD.
Buprenorphine was not genotoxic in three in vitro genetic toxicology studies (bacterial
mutagenicity test, mouse lymphoma assay, chromosomal aberration assay in human peripheral
blood lymphocytes), and in one in vivo mouse micronucleus test.
Impairment Of Fertility
BUTRANS (1/4 of a BUTRANS 5 mcg/hour, one BUTRANS 5 mcg/hour, or one BUTRANS 20
mcg/hour every 3 days in males for 4 weeks prior to mating for a total of 10 weeks and in
females for 2 weeks prior to mating through Gestation Day 7) had no effect on fertility or general
reproductive performance of rats at AUC-based exposure levels as high as approximately 65
times (females) and 100 times (males) that for human subjects who received BUTRANS 20
mcg/hour, the MRHD.
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal
syndrome [see WARNINGS AND PRECAUTIONS]. Available data with BUTRANS in pregnant
women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction 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) [see Data]. Based on animal data,
advise pregnant women of the potential risk to a fetus. The estimated background risk of major
birth defects and miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
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. 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. Observe newborns for symptoms of neonatal opioid
withdrawal syndrome and manage accordingly [see WARNINGS AND PRECAUTIONS].
Labor and Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. An opioid
antagonist such as naloxone must be available for reversal of opioid-induced respiratory
depression in the neonate. BUTRANS is not recommended for use in women immediately prior
to labor, when shorter acting analgesics or other analgesic techniques are more appropriate.
Opioid analgesics, including BUTRANS, 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
Studies in rats and rabbits demonstrated no evidence of teratogenicity following BUTRANS or
subcutaneous (SC) administration of buprenorphine during the period of 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 to 17). Rabbits were
administered four BUTRANS 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, 15, 18, and
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.
In a pre- 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.
Because of the potential for serious adverse reactions, including excess sedation and respiratory
depression in a breastfed infant, advise patients that breastfeeding is not recommended during
treatment with BUTRANS.
Monitor infants exposed to BUTRANS through breast milk for excess sedation and respiratory
depression. Withdrawal symptoms can occur in breastfed infants when maternal administration
of buprenorphine is stopped or when breast-feeding is stopped.
Females And Males Of Reproductive Potential
Chronic use of opioids may cause reduced fertility in females and males of reproductive
potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS
, Preclinical Pharmacology , Nonclinical Toxicology].
The safety and efficacy of BUTRANS in patients under 18 years of age has not been established.
BUTRANS has been evaluated in an open-label clinical trial in pediatric patients. However,
definitive conclusions are not possible because of the small sample size.
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].
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred
after large initial doses were administered to patients who were not opioid-tolerant or when
opioids were co-administered with other agents that depress respiration. Titrate the dosage of
BUTRANS slowly in geriatric patients and monitor closely for signs of central nervous system
and respiratory depression [see WARNINGS AND PRECAUTIONS].
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].