DRUG INTERACTIONS
Benzodiazepines
There have been a number of reports regarding coma and death associated
with the misuse and abuse of the combination of buprenorphine and
benzodiazepines. In many, but not all of these cases, buprenorphine
was misused by self-injection of crushed buprenorphine tablets. Preclinical
studies have shown that the combination of benzodiazepines and buprenorphine
altered the usual ceiling effect on buprenorphine-induced respiratory
depression, making the respiratory effects of buprenorphine appear
similar to those of full opioid agonists. Closely monitor patients
with concurrent use of BUTRANS and 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.
CNS Depressants
The concomitant
use of BUTRANS with other CNS depressants including sedatives, hypnotics,
tranquilizers, general anesthetics, phenothiazines, other opioids,
and alcohol can increase the risk of respiratory depression, profound
sedation, coma and death. Monitor patients receiving CNS depressants
and BUTRANS for signs of respiratory depression, sedation, and hypotension.
When combined therapy with any of the above medications is considered,
the dose of one or both agents should be reduced [see Dosage
and Administration and Warnings
and Precautions].
Drugs Affecting Cytochrome P450 Isoenzymes
Inhibitors of CYP3A4 and 2D6
Because the
CYP3A4 isoenzyme plays a major role in the metabolism of buprenorphine,
drugs that inhibit CYP3A4 activity may cause decreased clearance of
buprenorphine which could lead to an increase in buprenorphine plasma
concentrations and result in increased or prolonged opioid effects.
These effects could be more pronounced with concomitant use of CYP2D6
and 3A4 inhibitors. If co-administration with BUTRANS is necessary,
monitor patients for respiratory depression and sedation at frequent
intervals and consider dose adjustments until stable drug effects
are achieved [see Clinical Pharmacology ].
Inducers of CYP3A4
CYP450
3A4 inducers may induce the metabolism of buprenorphine and, therefore,
may cause increased clearance of the drug which could lead to a decrease
in buprenorphine plasma concentrations, lack of efficacy or, possibly,
development of an abstinence syndrome in a patient who had developed
physical dependence to buprenorphine.
After stopping the treatment of a CYP3A4
inducer, as the effects of the inducer decline, the buprenorphine
plasma concentration will increase which could increase or prolong
both the therapeutic and adverse effects, and may cause serious respiratory
depression. If co-administration or discontinuation of a CYP3A4 inducer
with BUTRANS is necessary, monitor for signs of opioid withdrawal
and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology].
Muscle Relaxants
Buprenorphine
may enhance the neuromuscular blocking action of skeletal muscle relaxants
and produce an increased degree of respiratory depression. Monitor
patients receiving muscle relaxants and BUTRANS for signs of respiratory
depression that may be greater than otherwise expected.
Anticholinergics
Anticholinergics
or other drugs with anticholinergic activity when used concurrently
with opioid analgesics may result in increased risk of urinary retention
and/or severe constipation, which may lead to paralytic ileus. Monitor
patients for signs of urinary retention or reduced gastric motility
when BUTRANS is used concurrently with anticholinergic drugs.
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OVERDOSAGE
Clinical Presentation
Acute overdosage
with BUTRANS is manifested by respiratory depression, somnolence progressing
to stupor or coma, skeletal muscle flaccidity, cold and clammy skin,
constricted pupils, bradycardia, hypotension, partial or complete
airway obstruction, atypical snoring and death. Marked mydriasis
rather than miosis may be seen due to severe hypoxia in overdose situations.
Treatment of Overdose
In case of overdose, priorities are the re-establishment
of a patent and protected airway and institution of assisted or controlled
ventilation if needed. Employ other supportive measures (including
oxygen, vasopressors) in the management of circulatory shock and pulmonary
edema as indicated. Cardiac arrest or arrhythmias will require advanced
life support techniques.
Naloxone
may not be effective in reversing any respiratory depression produced
by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be
of limited value in the management of buprenorphine overdose. The
onset of naloxone effect may be delayed by 30 minutes or more. Doxapram
hydrochloride (a respiratory stimulant) has also been used.
Remove BUTRANS immediately. Because the
duration of reversal would be expected to be less than the duration
of action of buprenorphine from BUTRANS, carefully monitor the patient
until spontaneous respiration is reliably re-established. Even in
the face of improvement, continued medical monitoring is required
because of the possibility of extended effects as buprenorphine continues
to be absorbed from the skin. After removal of BUTRANS, the mean
buprenorphine concentrations decrease approximately 50% in 12 hours
(range 10-24 hours) with an apparent terminal half-life of approximately
26 hours. Due to this long apparent terminal half-life, patients
may require monitoring and treatment for at least 24 hours.
In an individual physically dependent on
opioids, administration of an opioid receptor antagonist may precipitate
an acute withdrawal. The severity of the withdrawal produced will
depend on the degree of physical dependence and the dose of the antagonist
administered. If a decision is made to treat serious respiratory
depression in the physically dependent patient with an opioid antagonist,
administration of the antagonist should be begun with care and by
titration with smaller than usual doses of the antagonist.
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DRUG ABUSE AND DEPENDENCE
Controlled Substance
BUTRANS contains buprenorphine, a Schedule III
controlled substance with an abuse potential similar to other Schedule
III opioids. BUTRANS can be abused and is subject to misuse, addiction
and criminal diversion [see Warnings and Precautions ].
Abuse
All patients treated with opioids require
careful monitoring for signs of abuse and addiction, since use of
opioid analgesic products carries the risk of addiction even under
appropriate medical use.
Drug
abuse is the intentional non-therapeutic use of an over-the-counter
or prescription drug, even once, for its rewarding psychological or
physiological effects. Drug abuse includes, but is not limited to
the following examples: the use of a prescription or over-the-counter
drug to get “high”, or the use of steroids for performance enhancement
and muscle build up.
Drug addiction
is a cluster of behavioral, cognitive, and physiological phenomena
that develop after repeated substance use and includes: a strong desire
to take the drug, difficulties in controlling its use, persisting
in its use despite harmful consequences, a higher priority given to
drug use than to other activities and obligations, increased tolerance,
and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common to addicts and
drug abusers. Drug-seeking tactics include emergency calls or visits
near the end of office hours, refusal to undergo appropriate examination,
testing or referral, repeated claims of loss of prescriptions, tampering
with prescriptions and reluctance to provide prior medical records
or contact information for other treating physician(s). “Doctor shopping”
(visiting multiple prescribers) to obtain additional prescriptions
is common among drug abusers and people suffering from untreated addiction.
Preoccupation with achieving adequate pain relief can be appropriate
behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from
physical dependence and tolerance. Physicians should be aware that
addiction may not be accompanied by concurrent tolerance and symptoms
of physical dependence in all addicts. In addition, abuse of opioids
can occur in the absence of true addiction.
BUTRANS, like other opioids, can be diverted for non-medical
use into illicit channels of distribution. Careful record-keeping
of prescribing information, including quantity, frequency, and renewal
requests, as required by state law, is strongly advised.
Proper assessment of the patient, proper
prescribing practices, periodic re-evaluation of therapy, and proper
dispensing and storage are appropriate measures that help to reduce
abuse of opioid drugs.
Risks Specific to the Abuse of BUTRANS
BUTRANS is intended for transdermal use only. Abuse
of BUTRANS poses a risk of overdose and death. This risk is increased
with concurrent abuse of BUTRANS with alcohol and other substances
including other opioids and benzodiazepines [see Warnings
and Precautions and Drug Interactions]. Intentional compromise
of the transdermal delivery system will result in the uncontrolled
delivery of buprenorphine and pose a significant risk to the abuser
that could result in overdose and death [see Warnings and
Precautions ]. Abuse
may occur by applying the transdermal system in the absence of legitimate
purpose, or by swallowing, snorting, or injecting buprenorphine extracted
from the transdermal system.
Dependence
Both tolerance and physical dependence
can develop during chronic opioid therapy. Tolerance is the need for
increasing doses of opioids to maintain a defined effect such as analgesia
(in the absence of disease progression or other external factors).
Tolerance may occur to both the desired and undesired effects of
drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal
symptoms after abrupt discontinuation or a significant dose reduction
of a drug. Withdrawal also may be precipitated through the administration
of drugs with opioid antagonist activity, e.g., naloxone, nalmefene,
or mixed agonist/antagonist analgesics (pentazocine, butorphanol,
nalbuphine). Physical dependence may not occur to a clinically significant
degree until after several days to weeks of continued opioid usage.
BUTRANS should not be abruptly discontinued [see Dosage and Administration]. If BUTRANS is abruptly discontinued in a physically-dependent
patient, an abstinence syndrome may occur. Some or all of the following
can characterize this syndrome: restlessness, lacrimation, rhinorrhea,
yawning, perspiration, chills, myalgia, and mydriasis. Other signs
and symptoms also may develop, including: irritability, anxiety, backache,
joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia,
vomiting, diarrhea, or increased blood pressure, respiratory rate,
or heart rate.
Infants born to
mothers physically dependent on opioids will also be physically dependent
and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations].
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