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Black Box Warning
WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE
See full prescribing information for complete Boxed Warning.
* Proper Patient Selection
Buprenorphine (transdermal) is an analgesic that is FDA approved for the treatment of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritis, nausea, vomiting, constipation, xerostomia, headache, and dizziness.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- 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.
- 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.
Initiation of Therapy
- 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. Consider the following when selecting the initial dose of Butrans:
- The total daily dose, potency, and specific characteristics of the opioid the patient has been taking previously;
- The reliability of the relative potency estimate used to calculate the equivalent buprenorphine dose needed (when converting from other opioids or opioid-combination products);
- The patient’s degree of tolerance to the respiratory-depressant and sedating effects of opioids;
- The age, general condition, and medical status of the patient;
- Concurrent non-opioid analgesic and other medications;
- The type and severity of the patient's pain;
- The balance between pain control and adverse drug experiences;
- Risk factors for abuse, addiction, or diversion, including a prior history of abuse, addiction, or diversion.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Maintenance of Therapy and Supplemental Analgesia
- 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.
Cessation of Therapy
- 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.
Patients with Hepatic Impairment
- 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.
- Butrans is available as:
- Butrans 5 mcg/hour Transdermal System (dimensions: 45 mm by 45 mm)
- Butrans 10 mcg/hour Transdermal System (dimensions: 45 mm by 68 mm)
- Butrans 20 mcg/hour Transdermal System (dimensions: 72 mm by 72 mm)
Off-Label Use and Dosage (Adult)
There is limited information regarding Off-Label Guideline-Supported Use of Buprenorphine (transdermal) in adult patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Buprenorphine (transdermal) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Buprenorphine (transdermal) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
There is limited information regarding Off-Label Guideline-Supported Use of Buprenorphine (transdermal) in pediatric patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Buprenorphine (transdermal) in pediatric patients.
- Butrans is contraindicated in:
- Patients who have significant respiratory depression.
- Patients who have severe bronchial asthma.
- Patients who have or are suspected of having paralytic ileus.
- Patients who have known hypersensitivity to any of its components or the active ingredient, buprenorphine
- The management of acute pain or in patients who require opioid analgesia for a short period of time
- The management of post-operative pain, including use after out-patient or day surgeries
- The management of mild pain
- The management of intermittent pain (e.g., use on an as-needed basis [prn]).
WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE
See full prescribing information for complete Boxed Warning.
* Proper Patient Selection
- 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.
- Interactions with Alcohol, Central Nervous System Depressants, and Illicit Drugs
- 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.
- 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 activemyocardial 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.
Misuse, Abuse, and Diversion of Opioids
- 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. * 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.
- 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.
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.
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, etc., while wearing the system because an increase in absorption of buprenorphine may occur. 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 with Fever
- 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.
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. 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.
Special Risk Groups
- 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.
- Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions
- 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.
Use in Addiction Treatment
- 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.
Clinical Trials Experience
There is limited information regarding Buprenorphine (transdermal) Clinical Trials Experience in the drug label.
There is limited information regarding Buprenorphine (transdermal) Postmarketing Experience in the drug label.
There is limited information regarding Buprenorphine (transdermal) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy Category (FDA):
There is no FDA guidance on usage of Buprenorphine (transdermal) in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Buprenorphine (transdermal) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Buprenorphine (transdermal) during labor and delivery.
There is no FDA guidance on the use of Buprenorphine (transdermal) in women who are nursing.
There is no FDA guidance on the use of Buprenorphine (transdermal) in pediatric settings.
There is no FDA guidance on the use of Buprenorphine (transdermal) in geriatric settings.
There is no FDA guidance on the use of Buprenorphine (transdermal) with respect to specific gender populations.
There is no FDA guidance on the use of Buprenorphine (transdermal) with respect to specific racial populations.
There is no FDA guidance on the use of Buprenorphine (transdermal) in patients with renal impairment.
There is no FDA guidance on the use of Buprenorphine (transdermal) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Buprenorphine (transdermal) in women of reproductive potentials and males.
There is no FDA guidance one the use of Buprenorphine (transdermal) in patients who are immunocompromised.
Administration and Monitoring
There is limited information regarding Buprenorphine (transdermal) Administration in the drug label.
There is limited information regarding Buprenorphine (transdermal) Monitoring in the drug label.
There is limited information regarding the compatibility of Buprenorphine (transdermal) and IV administrations.
There is limited information regarding Buprenorphine (transdermal) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Mechanism of Action
There is limited information regarding Buprenorphine (transdermal) Mechanism of Action in the drug label.
There is limited information regarding Buprenorphine (transdermal) Structure in the drug label.
There is limited information regarding Buprenorphine (transdermal) Pharmacodynamics in the drug label.
There is limited information regarding Buprenorphine (transdermal) Pharmacokinetics in the drug label.
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Buprenorphine has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via ZUBSOLV.
- A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in Alderley Park rats. Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the recommended human sublingual dose based on buprenorphine AUC comparisons). A statistically significant increase in Leydig cell adenomas was observed in all dose groups. No other drug-related tumors were noted.
- Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately 0.4, 3, and 35 times the recommended human sublingual dose) for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rat, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30 times the recommended human sublingual dose).
- The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay (Ames test) using four strains of S. typhimurium and two strains of E. coli. The combination was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the rat.
- Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis "rec" assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.
- Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.
Impairment of Fertility
- Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended human sublingual dose) produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (equivalent to approximately 10 mg/kg/day; estimated exposure approximately 6 times the recommended human sublingual dose) had no adverse effect on fertility.
There is limited information regarding Buprenorphine (transdermal) Clinical Studies in the drug label.
There is limited information regarding Buprenorphine (transdermal) How Supplied in the drug label.
There is limited information regarding Buprenorphine (transdermal) Storage in the drug label.
Package and Label Display Panel
Patient Counseling Information
Precautions with Alcohol
Alcohol-Buprenorphine (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Look-Alike Drug Names
There is limited information regarding Buprenorphine (transdermal) Look-Alike Drug Names in the drug label.
The contents of this FDA label are provided by the National Library of Medicine.