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Butrans

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Butrans

Butrans

SIDE EFFECTS

The following adverse reactions described elsewhere in the labeling include:

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 BUTRANS
(N = 1024)
Double-Blind Treatment Period
BUTRANS
(N = 256)
Placebo
(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 BUTRANS
(N = 1160)
Double-Blind Treatment Period
BUTRANS 20
(N = 219)
BUTRANS 5
(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)
Placebo
(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

DRUG INTERACTIONS

Hepatic Enzyme Inhibitors and Inducers

CYP3A4 Inhibitors

Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with BUTRANS, did not have any effect on Cmax (maximum concentration) and AUC (area under the curve) of buprenorphine. Based on this observation, the pharmacokinetics of BUTRANS are not expected to be affected by coadministration of CYP3A4 inhibitors.

However, certain protease inhibitors (PIs) with CYP3A4 inhibitory activity such as atazanavir and atazanavir/ritonavir resulted in elevated levels of buprenorphine and norbuprenorphine following sublingual administration of buprenorphine and naloxone. Patients in this study reported increased sedation, and symptoms of opiate excess have been found in post-marketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly. Atazanavir is both a CYP3A4 and UGT1A1 inhibitor. As such, the drug-drug interaction potential for buprenorphine with CYP3A4 inhibitors is likely to be dependent on the route of administration as well as the specificity of enzyme inhibition [see CLINICAL PHARMACOLOGY].

CYP3A4 Inducers

The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Monitor patients receiving concurrent therapy with BUTRANS and CYP3A4 inducers (e.g., phenobarbital, carbamazepine, phenytoin, rifampin) closely for reduced efficacy or signs of withdrawal [see CLINICAL PHARMACOLOGY].

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

Concurrent use of BUTRANS and other central nervous system (CNS) depressants (e.g., sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, and alcohol) can increase the risk of respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and BUTRANS for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents.

Skeletal Muscle Relaxants

BUTRANS, like other opioids, may interact with skeletal muscle relaxants to enhance neuromuscular blocking action and increase respiratory depression.

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.

Drug Abuse And Dependence

Controlled Substance

BUTRANS contains buprenorphine, a mu opioid partial agonist and Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BUTRANS can be abused and is subject to misuse, abuse, addiction and criminal diversion.

Abuse

Abuse of BUTRANS poses a hazard of overdose and death. This risk is increased with compromise of the BUTRANS Transdermal System and with concurrent abuse of alcohol or other substances. BUTRANS has been diverted for non-medical use.

All patients treated with opioids, including BUTRANS, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

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 in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “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 may 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.

The risks of misuse and abuse should be considered when prescribing or dispensing BUTRANS. Concerns about abuse and addiction, should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient.

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]. Compromising 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].

Last reviewed on RxList: 7/19/2012
This monograph has been modified to include the generic and brand name in many instances.

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