February 10, 2016
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Side Effects


The following serious adverse reactions are described elsewhere in the labeling:

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 5,415 patients were treated with BUTRANS in controlled and open-label chronic pain clinical trials. Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year. The clinical trial population consisted of patients with persistent moderate to severe pain.

The most common serious adverse drug reactions (all < 0.1%) occurring during clinical trials with BUTRANS were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased.

The most common adverse events ( ≥ 2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence.

The most common adverse reactions ( ≥ 5%) reported by patients in clinical trials comparing BUTRANS 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing BUTRANS 20 mcg/hour to BUTRANS 5 mcg/hour are shown in Table 3 below:

Table 2: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Na´ve Patients

MedDRA Preferred Term Open-Label Titration Period
(N = 1024)
Double-Blind Treatment Period
(N = 256)
(N = 283)
Nausea 23% 13% 10%
Dizziness 10% 4% 1%
Headache 9% 5% 5%
Application site pruritus 8% 4% 7%
Somnolence 8% 2% 2%
Vomiting 7% 4% 1%
Constipation 6% 4% 1%

Table 3: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients

MedDRA Preferred Term Open-Label Titration Period
(N = 1160)
Double-Blind Treatment Period
(N = 219)
(N = 221)
Nausea 14% 11% 6%
Application site pruritus 9% 13% 5%
Headache 9% 8% 3%
Somnolence 6% 4% 2%
Dizziness 5% 4% 2%
Constipation 4% 6% 3%
Application site erythema 3% 10% 5%
Application site rash 3% 8% 6%
Application site irritation 2% 6% 2%

The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials.

Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence ≥ 2%

MedDRA Preferred Term BUTRANS
(N = 392)
(N = 261)
Nausea 21% 6%
Application site pruritus 15% 12%
Dizziness 15% 7%
Headache 14% 9%
Somnolence 13% 4%
Constipation 13% 5%
Vomiting 9% 1%
Application site erythema 7% 2%
Application site rash 6% 6%
Dry mouth 6% 2%
Fatigue 5% 1%
Hyperhidrosis 4% 1%
Peripheral edema 3% 1%
Pruritus 3% 0%
Stomach discomfort 2% 0%

The adverse reactions seen in controlled and open-label studies are presented below in the following manner: most common ( ≥ 5%), common ( ≥ 1% to < 5%), and less common ( < 1%).

The most common adverse reactions ( ≥ 5%) reported by patients treated with BUTRANS in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

The common ( ≥ 1% to < 5%) adverse reactions reported by patients treated with BUTRANS in the clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were:

Gastrointestinal disorders: diarrhea, dyspepsia, and upper abdominal pain

General disorders and administration site conditions: fatigue, peripheral edema, application site irritation, pain, pyrexia, chest pain, and asthenia Infections and infestations: urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis

Injury, poisoning and procedural complications: fall

Metabolism and nutrition disorders: anorexia

Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia

Nervous system disorders: hypoesthesia, tremor, migraine, and paresthesia

Psychiatric disorders: insomnia, anxiety, and depression

Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal pain, and cough

Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus

Vascular disorders: hypertension

Other less common adverse reactions, including those known to occur with opioid treatment, that were seen in < 1% of the patients in the BUTRANS trials include the following in alphabetical order:

Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.

Read the Butrans (buprenorphine transdermal system) Side Effects Center for a complete guide to possible side effects



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 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.

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].


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.


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].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 7/20/2015

Side Effects

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