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These highlights do not include all the information needed to use Butrans safely and effectively. See full prescribing information for Butrans. Butrans (buprenorphine) Transdermal System for transdermal administration CIII Initial U.S. A | Butrans

05:10 EDT 27th August 2014 | BioPortfolio
Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Proper Patient Selection Butrans is a transdermal formulation of buprenorphine indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. (1)

Potential for Abuse Butrans contains buprenorphine which is a mu opioid partial agonist and a Schedule III controlled substance. Butrans can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the abuse potential when prescribing or dispensing Butrans in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. (9)

Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction. (2.2)

Limitations of Use Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation. (2.3)

Avoid exposing the Butrans application site and surrounding area to direct external heat sources. Temperature-dependent increases in buprenorphine release from the system may result in overdose and death. (5.11)

Butrans is indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time.

Selection of patients for treatment with Butrans is governed by the same principles that apply to the use of similar opioid analgesics. Physicians should individualize treatment in every case, using non-opioid analgesics, opioids on an as-needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society, and Federation of State Medical Boards Model Policy.

Butrans is for transdermal use (on intact skin) only.

Do not use Butrans if the pouch seal is broken or the patch is cut, damaged, or changed in any way. Do not cut Butrans.

Each Butrans is intended to be worn for 7 days.

Apply Butrans to the upper outer arm, upper chest, upper back or the side of the chest. These 4 sites (each present on both sides of the body) provide 8 possible application sites. Rotate Butrans among the 8 described skin sites. After Butrans removal, wait a minimum of 21 days before reapplying to the same skin site [see Clinical Pharmacology (12.3)] .

Apply Butrans to a hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Do not apply Butrans to irritated skin. If the application site must be cleaned, clean the site with water only. Do not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before applying Butrans.

If problems with adhesion of Butrans occur, the edges may be taped with first aid tape.

If Butrans falls off during the 7 days dosing interval, dispose of the transdermal system properly and place a new Butrans on at a different skin site [see How Supplied/Storage and Handling (16)] .

It is critical to initiate the dosing regimen individually for each patient. Overestimating the Butrans dose when converting patients from another opioid medication can result in fatal overdose with the first dose [see Overdosage (10)] . Consider the following when selecting the initial dose of Butrans:

The following dosing recommendations, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Opioid-Naïve Patients For opioid-naïve patients, initiate treatment with Butrans 5 mcg/hour. Thereafter, individually titrate the dose as described in Section 2.3 Dose Titration to a level that provides adequate analgesia and minimizes side effects. Dose may be titrated to the next higher level after a minimum of 72 hours.

Conversion from Other Opioids to Butrans There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. For conversion from other opioids to Butrans (see Table 1), taper the patient’s current around-the-clock opioids for up to 7 days to no more than 30 mg of morphine or equivalent per day before beginning treatment with Butrans. Patients may use short-acting analgesics as needed until analgesic efficacy with Butrans is attained.

For patients whose daily dose was less than 30 mg of oral morphine or equivalent, initiate treatment with Butrans 5 mcg/hour. For patients whose daily dose was between 30 and 80 mg morphine equivalents, initiate treatment with Butrans 10 mcg/hour (see Table 1). Thereafter, individually titrate the dose as described in Section 2.3 Dose Titration.

Use caution when prescribing Butrans to opioid-experienced patients requiring high doses of opioids (more than 80 mg/day of oral morphine equivalents). Butrans 20 mcg/hour may not provide adequate analgesia for patients requiring greater than 80 mg/day oral morphine equivalents.

Table 1: Dose Estimation for Conversion of Oral Morphine Equivalents to Butrans
Current Opioid Analgesic Current Daily Dose
Oral Morphine Equivalent <30 mg 30-80 mg
 
Recommended Butrans Starting Dose 5 mcg/hour 10 mcg/hour

Based on the patient’s requirement for supplemental short-acting analgesics, upward titration may be instituted with a minimum Butrans titration interval of 72 hours, based on the pharmacokinetic profile and time to reach steady state levels [see Clinical Pharmacology (12.3)] . Individually titrate the dose, under close supervision, to a level that provides adequate analgesia with tolerable side effects.

The maximum Butrans dose is 20 mcg/hour. Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation. In a clinical trial, Butrans 40 mcg/hour (given as two Butrans 20 mcg/hour systems) resulted in prolongation of the QTc interval [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)] .

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between the prescriber, other members of the healthcare team, the patient, and the caregiver/family. Advise patients and caregivers/family members of the potential side effects.

The intent of the titration period is to establish a patient-specific weekly Butrans dose that will maintain adequate analgesia with tolerable side effects for as long as pain management is necessary. Immediate-release opioid and non-opioid medications can be used as supplemental analgesia during Butrans therapy.

During chronic opioid analgesic therapy with Butrans, reassess the continued need for around-the-clock opioid analgesic therapy periodically.

When the patient no longer requires therapy with Butrans, taper the dose gradually to prevent signs and symptoms of withdrawal in the physically dependent patient; consider introduction of an appropriate immediate-release opioid medication. Undertake discontinuation of therapy as part of a comprehensive treatment plan.

Start patients with mild to moderate hepatic impairment with the Butrans 5 mcg/hour dose. Thereafter, individually titrate the dose to a level that provides adequate analgesia and tolerable side effects, under the close supervision of the prescriber. Butrans has not been evaluated in patients with severe hepatic impairment. As Butrans is only intended for 7-day application, consider use of an alternate analgesic that may permit more flexibility with the dosing in patients with severe hepatic impairment [see Warnings and Precautions (5.1), Use In Specific Populations (8.6), and Clinical Pharmacology (12.3)] .

Butrans is available as:

Butrans is contraindicated in:

Respiratory depression is the chief hazard of Butrans. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids, including Butrans, are given in conjunction with other agents that depress respiration.

Profound sedation, unresponsiveness, infrequent deep (“sighing”) breaths or atypical snoring frequently accompany opioid-induced respiratory depression.

Use Butrans with extreme caution in patients with any of the following:

Butrans may cause somnolence, dizziness, alterations in judgment and alterations in levels of consciousness, including coma.

Hypotension, profound sedation, coma or respiratory depression may result if Butrans is added to a regimen that includes other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids). Therefore, use caution when deciding to initiate therapy with Butrans in patients who are taking other CNS depressants. Take into account the types of other medications being taken, the duration of therapy with them, and the patient’s response to those medicines, including the degree of tolerance that has developed to CNS depression. Consider the patient’s use, if any, of alcohol and/or illicit drugs that cause CNS depression. If the decision to begin Butrans is made, start with a lower Butrans dose than usual.

Consider using a lower initial dose of a CNS depressant when given to a patient currently taking Butrans due to the potential of additive CNS depressant effects.

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 Clinical Pharmacology (12.2)] .

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).

The respiratory depressant effects of opioids, including Butrans, include carbon dioxide retention, which can lead to an elevation of cerebrospinal fluid pressure. This effect may be exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Butrans may produce miosis that is independent of ambient light, and altered consciousness, either of which may obscure neurologic signs associated with increased intracranial pressure in persons with head injuries.

Butrans may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Buprenorphine may produce orthostatic hypotension in ambulatory patients. Administer Butrans with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Butrans contains buprenorphine, a partial agonist at the mu opioid receptor and a Schedule III controlled substance. Opioid agonists have potential for being abused, are sought by drug abusers and people with addiction disorders, and are subject to criminal diversion.

Butrans can be abused in a manner similar to other opioid agonists, legal or illicit. Consider this potential for abuse when prescribing or dispensing Butrans in situations where the prescriber or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, assess patients for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients; however, they will require intensive monitoring for signs of abuse.

Notwithstanding concerns about abuse, addiction, and diversion, provide proper management of pain. However, all patients treated with opioid agonists require careful monitoring for signs of abuse and addiction, since use of opioid agonist analgesic products carries the risk of addiction even under appropriate medical use [see Drug Abuse and Dependence (9.2)] . Data are not available to establish the true incidence of addiction in patients with chronic pain treated with opioids.

Abuse of Butrans poses a significant risk to the abuser that could potentially result in overdose or death [see Drug Abuse and Dependence (9)] .

Contact your state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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 through 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. In other cases, insufficient data were available to determine the etiology of the abnormality. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), baseline and periodic monitoring of liver function during treatment with Butrans is recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected.

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.

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, etc., while wearing the system because an increase in absorption of buprenorphine may occur [see Clinical Pharmacology (12.3)] . 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 wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the Butrans dose should be adjusted if necessary [see Dosage and Administration (2.4)] .

Butrans may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly.

Butrans, as with other opioids, may aggravate seizure disorders, may lower seizure threshold, and therefore, may induce seizures in some clinical settings. Use Butrans with caution in patients with a history of seizure disorders.

Use Butrans with caution in the following conditions, due to increased risk of adverse reactions: alcoholism; delirium tremens; adrenocortical insufficiency; CNS depression; debilitation; kyphoscoliosis associated with respiratory compromise; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis.

Butrans may cause spasm of the sphincter of Oddi. Use with caution in patients with biliary tract disease, including acute pancreatitis. Opioids, including Butrans, may cause increased serum amylase.

The administration of Butrans may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use Butrans with caution in patients who are at risk of developing ileus.

Butrans has not been studied and is not approved for use in the management of addictive disorders.

Butrans is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

The following adverse reactions described elsewhere in the labeling include:

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 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:

 

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

The adverse events 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 events (≥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 events 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 events, 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, dysmenorrhea, 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.

Table 2: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients
  Open-Label Titration Period Double-Blind Treatment Period
  Butrans Butrans Placebo
MedDRA Preferred Term (N = 1024) (N = 256) (N = 283)
Nausea 23% 13% 11%
Dizziness 10% 4% 1%
Headache 10% 5% 5%
Application site pruritus 8% 4% 7%
Somnolence 8% 2% 2%
Vomiting 8% 4% 2%
Constipation 7% 4% 1%
Table 3: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients
  Open-Label Titration Period Double-Blind Treatment Period
  Butrans Butrans 20 Butrans 5
MedDRA Preferred Term (N = 1160) (N = 219) (N = 221)
Nausea 15% 12% 8%
Headache 11% 11% 5%
Application site pruritus 9% 13% 5%
Somnolence 6% 5% 2%
Vomiting 5% 5% 2%
Dizziness 5% 5% 2%
Constipation 4% 6% 3%
Application site erythema 3% 10% 5%
Application site rash 3% 9% 6%
Application site irritation 2% 5% 3%
Table 4: Adverse Events Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence ≥2%
MedDRA Preferred Term
 
Butrans
(N = 392)
Placebo
(N = 261)
Nausea 23% 8%
Dizziness 16% 8%
Headache 16% 11%
Application site pruritus 15% 12%
Constipation 14% 5%
Somnolence 14% 5%
Vomiting 11% 2%
Peripheral edema 7% 3%
Dry mouth 7% 2%
Application site erythema 7% 2%
Application site rash 6% 6%
Fatigue 5% 1%
Hyperhidrosis 4% 1%
Pruritus 4% 1%
Fall 4% 2%
Diarrhea 3% 2%
Pain in extremity 3% 2%
Insomnia 3% 2%
Dyspnea 3% 1%
Dyspepsia 3% 3%
Urinary tract infection 3% 2%
Back pain 3% 2%
Joint swelling 3% 1%
Hypoesthesia 2% 1%
Arthralgia 2% 2%
Stomach discomfort 2% 1%
Rash 2% 1%
Anorexia 2% 1%
Paraesthesia 2% 1%
Tremor 2% <1%
Confusional State 2% 3%

Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with Butrans, did not have any effect on C and AUC of buprenorphine. Based on this observation, pharmacokinetics of Butrans is not expected to be affected by co-administration 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. It should be noted that 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 (12.3)] .

The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied; therefore it is recommended that patients receiving Butrans be closely monitored for reduced efficacy if inducers of CYP3A4 (e.g. phenobarbital, carbamazepine, phenytoin, rifampin) are co-administered [see Clinical Pharmacology (12.3)] .

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. Prescribe Butrans with caution to patients taking benzodiazepines or other drugs that act on the central nervous system regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking Butrans, and caution patients to use benzodiazepines concurrently with Butrans only as directed by their physician.

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

There are no adequate and well-controlled studies with Butrans in pregnant women. Butrans should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and 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. Area under the curve (AUC) values for buprenorphine with Butrans application and SC injection were approximately 140 and 110 times that of human subjects who received the MRHD of one Butrans 20 mcg/hour.

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.

The safety of Butrans given during labor and delivery has not been established.

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Butrans is not recommended for use in women immediately prior to and during labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which 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.

Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. Have a specific opioid antagonist, such as naloxone or nalmefene, available for reversal of opioid-induced respiratory depression in the neonate.

Neonates whose mothers have been taking opioids chronically may also exhibit withdrawal signs, either at birth and/or in the nursery, because they have developed physical dependence. This is not, however, synonymous with addiction. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

Buprenorphine has been detected in low concentrations in human milk. Breast-feeding is not advised in mothers treated with Butrans.

The safety and efficacy of Butrans in patients under 18 years of age has not been established. Butrans is not recommended for use in pediatric patients.

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 and safety outcomes 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 Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

In a study utilizing intravenous buprenorphine, peak plasma levels (C) 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 and should be administered with caution [see Dosage and Administration (2.6), and Clinical Pharmacology (12.3)] .

The pharmacokinetics of buprenorphine is not altered during the course of renal failure [see Clinical Pharmacology (12.3)] .

There was no significant gender effect observed for Butrans with respect to either the incidence of adverse events or pharmacokinetics [see Clinical Pharmacology (12.3)] .

Butrans contains buprenorphine, a mu opioid partial agonist and Schedule III controlled substance. Butrans can be abused and is subject to misuse, abuse, addiction and criminal diversion.

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.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Opioid drugs are sought by people with substance use disorders (abuse or addiction, the latter of which is also called “substance dependence”) and criminals who supply them by diverting medicines out of legitimate distribution channels. Butrans is a target for theft and diversion.

“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, altering or forging of prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among people with untreated substance use disorders, and criminals who divert controlled substances.

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 and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since Butrans may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests 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.

Butrans is intended for transdermal use only. 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 (5.1)] . The risk of fatal overdose is further increased when buprenorphine is abused concurrently with alcohol or other CNS depressants, including other opioids and benzodiazepines [see Warnings and Precautions (5.3)] . 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.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, proper dispensing and correct storage and handling are appropriate measures that help to limit misuse and abuse of opioid drugs. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence to an opioid is manifested by characteristic withdrawal signs and symptoms after abrupt discontinuation of a drug, significant dose reduction, or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid analgesic therapy.

The opioid abstinence or withdrawal syndrome in adults is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate [see Use In Specific Populations (8.2)]

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.

In general, opioids should not be abruptly discontinued [see Dosage and Administration (2.5)] .

Acute overdosage with Butrans can be 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.

Deaths due to overdose have been reported with abuse and misuse of buprenorphine. Review of case reports has indicated that the risk of fatal overdose is further increased when Butrans is abused concurrently with alcohol or other CNS depressants, including other opioids.

In cases of overdose, remove Butrans immediately. It is important to take the pharmacokinetic profile of Butrans into account when treating overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as opioid 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 the treatment of Butrans overdosage, primary attention should be given to the maintenance of a patent airway, and of effective ventilation (clearance of CO2) and oxygenation, whether by spontaneous, assisted or controlled respiration. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

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. Since the duration of action of Butrans may exceed that of the antagonist, keep the patient under continued surveillance and administer repeated doses of the antagonist according to the antagonist labeling as needed to maintain adequate respiration. Maintenance of adequate ventilation is essential when managing Butrans overdose and more important than specific antidote treatment with an opioid antagonist such as naloxone.

Do not administer opioid antagonists in the absence of clinically significant respiratory or circulatory depression secondary to buprenorphine overdose. In patients who are physically dependent on any opioid agonist including Butrans, an abrupt partial or complete reversal of opioid effects may precipitate an acute abstinence or withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. See the prescribing information for the specific opioid antagonist for details of its proper use.

Butrans is a transdermal system providing systemic delivery of buprenorphine, a mu opioid partial agonist analgesic, continuously for 7 days. The chemical name of buprenorphine is 6,14-ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- α-(1,1-dimethylethyl)-4, 5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy-α-methyl-, [5α, 7α, (S)]. The structural formula is:

The molecular weight of buprenorphine is 467.6; the empirical formula is CHNO. Buprenorphine occurs as a white or almost white powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol and ether, and slightly soluble in cyclohexane. The pKa is 8.5 and the melting point is about 217°C.

IMAGE Bup structure.jpg

Three different strengths of Butrans are available: 5, 10, and 20 mcg/hour (Table 5). The active component of the system is buprenorphine. The remaining components are pharmacologically inactive. The proportion of buprenorphine mixed in the adhesive matrix is the same in each of the 3 strengths. The amount of buprenorphine released from each system per hour is proportional to the active surface area of the system. The skin is the limiting barrier to diffusion from the system into the bloodstream.

Butrans is a rectangular or square, beige-colored system consisting of a protective liner and functional layers. Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a beige-colored web backing layer; (2) an adhesive rim without buprenorphine; (3) a separating layer over the buprenorphine-containing adhesive matrix; (4) the buprenorphine-containing adhesive matrix; and (5) a peel-off release liner. Before use, the release liner covering the adhesive layer is removed and discarded.

The active ingredient in Butrans is buprenorphine. The inactive ingredients in each system are:

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Purdue Pharma L.P.

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