|indication=moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time
|indication=moderate to severe [[chronic pain]] in patients requiring a continuous, around-the-clock [[opioid]] analgesic for an extended period of time
|blackBoxWarningTitle=WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE
|blackBoxWarningBody=* Proper Patient Selection
* Content
:* 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.
* Potential for Abuse
<!--Adult Indications and Dosage-->
:* 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.
:* 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.
<!--FDA-Labeled Indications and Dosage (Adult)-->
* Limitations of Use
:* Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation.
:* 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.
|fdaLIADAdult=======Indications======
|fdaLIADAdult=======Indications======
* 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.
* 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.
======Dosage======
=====Dosage=====
2.1 General Principles - Selection of patients for treatment with Butrans is governed by the same principles that apply to the use of similar opioid analgesics ...
=====General Principles=====
2.1 General Principles
* 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.
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.
Butrans is for transdermal use (on intact skin) only.
* 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.
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.
* 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.
Each Butrans is intended to be worn for 7 days.
* 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=====
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)].
* 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:
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.
* 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);
If problems with adhesion of Butrans occur, the edges may be taped with first aid tape.
* 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;
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)].
* Concurrent non-opioid analgesic and other medications;
* The type and severity of the patient's pain;
2.2 Initiation of Therapy
* The balance between [[pain]] control and adverse drug experiences;
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:
* 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.
The total daily dose, potency, and specific characteristics of the opioid the patient has been taking previously;
=====Opioid-Naïve Patients=====
The reliability of the relative potency estimate used to calculate the equivalent buprenorphine dose needed (when converting from other opioids or opioid-combination products);
* 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.
The patient’s degree of tolerance to the respiratory-depressant and sedating effects of opioids;
* Conversion from Other Opioids to Butrans
The age, general condition, and medical status of the patient;
* 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.
Concurrent non-opioid analgesic and other medications;
* 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.
The type and severity of the patient's pain;
* Thereafter, individually titrate the dose as described in Section 2.3 Dose Titration.
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.
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.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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.
* 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.
=====Dose Titration=====
2.3 Dose Titration
* 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.
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.
* 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.
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.
=====Maintenance of Therapy and Supplemental Analgesia=====
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.
2.4 Maintenance of Therapy and Supplemental Analgesia
=====Cessation of Therapy=====
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.
* 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=====
During chronic opioid analgesic therapy with Butrans, reassess the continued need for around-the-clock opioid analgesic therapy periodically.
* 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:
2.5 Cessation of Therapy
:* Butrans 5 mcg/hour Transdermal System (dimensions: 45 mm by 45 mm)
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.
:* Butrans 10 mcg/hour Transdermal System (dimensions: 45 mm by 68 mm)
:* Butrans 20 mcg/hour Transdermal System (dimensions: 72 mm by 72 mm)
2.6 Patients with Hepatic Impairment
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
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 ...
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)
|offLabelAdultGuideSupport=
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Non–Guideline-Supported Use (Adult)-->
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport=
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Pediatric Indications and Dosage-->
<!--Pediatric Indications and Dosage-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed=
|fdaLIADPed=There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
<!--Off-Label Use and Dosage (Pediatric)-->
<!--Off-Label Use and Dosage (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport=
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Non–Guideline-Supported Use (Pediatric)-->
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport=
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Contraindications-->
<!--Contraindications-->
|contraindications=* Butrans is contraindicated in: patients who have significant respiratory depression - patients who have severe bronchial asthma - patients who have or are suspected of having ...
|contraindications=* Butrans is contraindicated in:
Butrans is contraindicated in:
:* Patients who have significant [[respiratory depression]].
:* Patients who have severe [[bronchial asthma]].
patients who have significant respiratory depression
:* Patients who have or are suspected of having [[paralytic ileus]].
patients who have severe bronchial asthma
:* Patients who have known [[hypersensitivity]] to any of its components or the active ingredient, buprenorphine
patients who have or are suspected of having paralytic ileus
:* The management of acute pain or in patients who require [[opioid analgesia]] for a short period of time
patients who have known hypersensitivity to any of its components or the active ingredient, buprenorphine
:* The management of post-operative pain, including use after out-patient or day surgeries
the management of acute pain or in patients who require opioid analgesia for a short period of time
:* The management of mild [[pain]]
the management of post-operative pain, including use after out-patient or day surgeries
:* The management of intermittent [[pain]] (e.g., use on an as-needed basis [prn]).
the management of mild pain
|warnings======Respiratory Depression=====
the management of intermittent pain (e.g., use on an as-needed basis [prn])
* [[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.
|warnings=* 5.1 Respiratory Depression - Respiratory depression is the chief hazard of Butrans. Respiratory depression occurs more frequently in elderly or debilitated patients ...
* Profound [[sedation]], unresponsiveness, infrequent deep (“sighing”) breaths or atypical snoring frequently accompany opioid-induced [[respiratory depression]].
5.1 Respiratory Depression
* Use Butrans with extreme caution in patients with any of the following:
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.
other risk of substantially decreased respiratory reserve such as [[asthma]], severe [[obesity]], [[sleep apnea]], [[myxedema]], clinically-significant [[kyphoscoliosis]], and [[central nervous system]] (CNS) [[depression]]
Profound sedation, unresponsiveness, infrequent deep (“sighing”) breaths or atypical snoring frequently accompany opioid-induced respiratory depression.
:* [[Hypoxia]]
:* [[Hypercapnia]]
Use Butrans with extreme caution in patients with any of the following:
:* Pre-existing [[respiratory depression]]
=====CNS Depression=====
significant chronic obstructive pulmonary disease or cor pulmonale
* Butrans may cause [[somnolence]], [[dizziness]], alterations in judgment and alterations in levels of consciousness, including [[coma]].
other risk of substantially decreased respiratory reserve such as asthma, severe obesity, sleep apnea, myxedema, clinically-significant kyphoscoliosis, and central nervous system (CNS) depression
* Interactions with Alcohol, [[Central Nervous System Depressants]], and Illicit Drugs
hypoxia
* [[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.
hypercapnia
* 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.
pre-existing respiratory depression
=====QTc Prolongation=====
5.2 CNS Depression
* 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.
Butrans may cause somnolence, dizziness, alterations in judgment and alterations in levels of consciousness, including coma.
* 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]]).
=====Head Injury=====
5.3 Interactions with Alcohol, Central Nervous System Depressants, and Illicit Drugs
* 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.
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.
=====Hypotensive Effects=====
* 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]].
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.
=====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.
5.4 QTc Prolongation
* 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]]).
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)].
* 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.
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).
* 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.
5.5 Head Injury
=====Hepatotoxicity=====
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.
* 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=====
5.6 Hypotensive Effects
* 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.
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.
=====Anaphylactic/Allergic Reactions=====
* 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.
5.7 Misuse, Abuse, and Diversion of Opioids
=====Application of External Heat=====
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.
* 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=====
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.
* 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=====
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.
* 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.
=====Seizures=====
Abuse of Butrans poses a significant risk to the abuser that could potentially result in overdose or death [see Drug Abuse and Dependence (9)].
* 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=====
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.
* 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
5.8 Hepatotoxicity
:* 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.
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.
:* 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=====
5.9 Application Site Skin Reactions
* Butrans has not been studied and is not approved for use in the management of addictive disorders.
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.
=====MAO Inhibitors=====
* 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]].
5.10 Anaphylactic/Allergic Reactions
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.
5.11 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 [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.
5.12 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 [see Dosage and Administration (2.4)].
5.13 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.
5.14 Seizures
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.
5.15 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.
5.16 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.
5.17 Use in Addiction Treatment
Butrans has not been studied and is not approved for use in the management of addictive disorders.
5.18 MAO Inhibitors
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.
|clinicalTrials=The following adverse reactions described elsewhere in the labeling include: Respiratory Depression [see Warnings and Precautions (5.1)] CNS Depression [see Warnings and ...
The following adverse reactions described elsewhere in the labeling include:
Respiratory Depression [see Warnings and Precautions (5.1)]
CNS Depression [see Warnings and Precautions (5.2)]
QTc Prolongation [see Warnings and Precautions (5.4)]
Hypotensive Effects [see Warnings and Precautions (5.6)]
Application Site Skin Reactions [see Warnings and Precautions (5.9)]
Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.10)]
Seizures [see Warnings and Precautions (5.14)]
6.1 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 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:
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
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:
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
|drugInteractions=* =====Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers=====
* Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when buprenorphine sublingual tablets is given concurrently with agents that affect CYP3A4 activity. The concomitant use of buprenorphine sublingual tablet with CYP3A4 inhibitors (e.g., [[azole antifungals]] such as [[ketoconazole]], [[macrolide]] antibiotics such as [[erythromycin]], and [[HIV protease inhibitors]]) should be monitored and may require dose-reduction of one or both agents.
* The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is recommended that patients receiving buprenorphine sublingual tablets be monitored for signs and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g., [[efavirenz]], [[phenobarbital]], [[carbamazepine]], [[phenytoin]], [[rifampicin]]) are co-administered [see Clinical Pharmacology]
=====Antiretrovirals=====
* Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with [[buprenorphine]]. [[Nucleoside reverse transcriptase inhibitors]] (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. [[Non-nucleoside reverse transcriptase inhibitors]] (NNRTIs) are metabolized principally by CYP3A4. [[Efavirenz]], [[nevirapine]] and [[etravirine]] are known CYP3A inducers whereas [[delaviridine]] is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., [[efavirenz]] and [[delavirdine]]) and [[buprenorphine]] have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine treatment have their dose monitored if NNRTIs are added to their treatment regimen. Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity ([[nelfinavir]], [[lopinavir]]/[[ritonavir]], [[ritonavir]]) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity ([[atazanavir]] and [[atazanavir]]/[[ritonavir]]) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is recommended, and dose reduction of buprenorphine may be warranted.
=====[[Benzodiazepines]]=====
* There have been a number of post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection. 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. Buprenorphine sublingual tablets should be prescribed with caution to patients taking benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the advice of a physician or are being abused/misused. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking buprenorphine sublingual tablets, and should also be cautioned to use benzodiazepines concurrently with buprenorphine sublingual tablets only as directed by their physician.
:* Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine maintenance treatment. Observe newborns for [[poor feeding]], [[diarrhea]], [[irritability]], [[tremor]], [[rigidity]], and [[seizures]], and manage accordingly. [See Warnings and Precautions]
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=* As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
===== Data=====
:* Human Data
::* Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.
:* Animal Data
::* 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.
::* Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human sublingual dose). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human sublingual dose). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human sublingual dose). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human sublingual dose), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human sublingual dose), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human sublingual dose) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human sublingual dose). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human sublingual dose), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human sublingual dose) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human sublingual dose) were not statistically significant.
::* In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human sublingual dose).
::* Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human sublingual dose). Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human sublingual dose), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human sublingual dose), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human sublingual dose). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human sublingual dose).
|useInNursing======Risk Summary=====
* Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants . There are no data on the combination product buprenorphine/naloxone in breastfeeding , however oral absorption of naloxone is minimal. Caution should be exercised when Zubsolv is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Zubsolv and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
=====Clinical Considerations=====
* Advise the nursing mother taking Zubsolv to monitor the infant for increased drowsiness and breathing difficulties.
* Data
:* Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.
:* Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.
:* No adverse reactions were observed in the infants in these two studies.
|useInPed=* The safety and effectiveness of buprenorphine sublingual tablets have not been established in pediatric patients. This product is not appropriate for the treatment of [[neonatal abstinence syndrome]] in neonates, because it contains naloxone, an opioid antagonist.
|useInGeri=* Clinical studies of buprenorphine/naloxone sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=* No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.
|useInHepaticImpair=* The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both drugs are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. However, it is not known whether both drugs are affected to the same degree. Therefore, dosage should be adjusted and patients should be watched for signs and symptoms of precipitated opioid withdrawal.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
<!--Administration and Monitoring-->
|administration=* Transdermal
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
|overdose=* The manifestations of acute overdose include [[pinpoint pupils]], [[sedation]], [[hypotension]], [[respiratory depression]], and death.
* In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.
* In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of ZUBSOLV should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.
|mechAction=* Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist at mu-opioid receptors and produces opioid withdrawal signs and symptoms, if administered parenterally, in individuals physically dependent on full opioid agonists.
|nonClinToxic======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.
<!--Structure-->
=====Carcinogenicity=====
|structure=* 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 ...
* 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.
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:
* 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).
[[File:Buprenorphine structure 2.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]
|PD=Central Nervous System Effects
=====Mutagenicity=====
* 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.
Buprenorphine binds to and dissociates from the mu opioid receptor slowly.
=====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.
Cardiovascular Effects
|packLabel=[[File:Butran 01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Buttran 02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Buprenorphine may cause a reduction in blood pressure
[[File:Butran 03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:DailyMed BUTRANS buprenorphine patch extended release.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Electrophysiology
|fdaPatientInfo=[[File:But patient councelling information.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|alcohol=Alcohol-Buprenorphine (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
The effect of Butrans 10 mcg/hour and 2 x Butrans 20 mcg/hour on QTc interval was evaluated in a double-blind (Butrans vs. placebo), randomized, placebo and active-controlled (moxifloxacin 400 mg, open label), parallel-group, dose-escalating, single-dose study in 132 healthy male and female subjects aged 18 to 55 years. The dose escalation sequence for Butrans during the titration period was: Butrans 5 mcg/hour for 3 days, then Butrans 10 mcg/hour for 3 days, then Butrans 20 mcg/hour for 3 days, then 2 x Butrans 20 mcg/hour for 4 days. The QTc evaluation was performed during the third day of Butrans 10 mcg/hour and the fourth day of 2 x Butrans 20 mcg/hour when the plasma levels of buprenorphine were at steady state for the corresponding doses [see Warnings and Precautions (5.4)].
There was no clinically meaningful effect on mean QTc with a Butrans dose of 10 mcg/hour. A Butrans dose of 40 mcg/hour (given as two 20 mcg/hour Butrans Transdermal Systems) prolonged mean QTc by a maximum of 9.2 (90% CI: 5.2-13.3) msec across the 13 assessment time points.
Endocrine Effects
Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.
Other Effects
Buprenorphine causes dose-related miosis and produces urinary retention in some patients.
In-vitro and animal studies indicate various effects of naturally occurring opioids, such as morphine, on components of the immune system. The clinical significance of these findings is unknown. Whether buprenorphine, a semi-synthetic opioid, has immunological effects similar to morphine is unknown.
[[File:Buprenorphine structure 2.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]
|PK=[[File:Buprenorphine structure 2.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]
Absorption
Transdermal delivery studies showed that intact human skin is permeable to buprenorphine. In clinical pharmacology studies, the median time for Butrans 10 mcg/hour to deliver quantifiable buprenorphine concentrations (≥25 pg/mL) was approximately 17 hours. The absolute bioavailability of Butrans relative to IV administration, following a 7-day application, is approximately 15% for all doses (Butrans 5, 10, and 20 mcg/hour).
Distribution
Buprenorphine is approximately 96% bound to plasma proteins, mainly to alpha- and beta-globulin.
Studies of IV buprenorphine have shown a large volume of distribution (approximately 430 L), implying extensive distribution of buprenorphine.
Following IV administration, buprenorphine and its metabolites are secreted into bile and excreted in urine. CSF buprenorphine concentrations appear to be approximately 15-25% of concurrent plasma concentrations.
Metabolism
Buprenorphine metabolism in the skin following Butrans application is negligible. Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites.
Buprenorphine primarily undergoes N-dealkylation by CYP3A4 to norbuprenorphine and glucuronidation by UGT-isoenzymes (mainly UGT1A1 and 2B7) to buprenorphine 3-O-glucuronide. Norbuprenorphine, the major metabolite, is also glucuronidated (mainly UGT1A3) prior to excretion.
Norbuprenorphine is the only known active metabolite of buprenorphine. It has been shown to be a respiratory depressant in rats, but only at concentrations at least 50-fold greater than those observed following application to humans of Butrans 20 mcg/hour.
Since metabolism and excretion of buprenorphine occur mainly via hepatic elimination, reductions in hepatic blood flow induced by some general anesthetics (e.g., halothane) and other drugs may result in a decreased rate of hepatic elimination of the drug, resulting in increased plasma concentrations.
Excretion
Following intramuscular administration of 2 mcg/kg dose of buprenorphine, approximately 70% of the dose was excreted in feces within 7 days. Approximately 27% was excreted in urine. The total clearance of buprenorphine is approximately 55 L/hour in postoperative patients.
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis - Buprenorphine administered daily by skin painting to Sprague ...
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Buprenorphine administered daily by skin painting to Sprague Dawley rats for 100 weeks at dosages (20, 60, or 200 mg/kg) produced systemic exposures (based on area under the curve, AUC) that ranged from approximately 130 to 350 times that of human subjects administered the maximum recommended human dose (MRHD) of Butrans 20 mcg/hour. An increased incidence of benign testicular interstitial cell tumors, considered buprenorphine treatment-related, was observed in male rats compared with concurrent controls. The tumor incidence was also above the highest incidence in the historical control database of the testing facility. These tumors were noted at 60 mg/kg/day and higher at approximately 220 times the proposed MRHD based on AUC). The no observed effect level (NOEL) was 20 mg/kg/day (approximately 140 times the proposed MRHD based on AUC). The mechanism leading to the tumor findings and relevance to humans is unknown.
Buprenorphine was administered by skin painting to hemizygous Tg.AC mice over a 6-month study period. At the dosages administered daily (18.75, 37.5, 150, or 600 mg/kg/day), buprenorphine was not carcinogenic or tumorigenic at systemic exposure to buprenorphine, based on AUC, of up to approximately 1000 times that of human subjects administered Butrans 20 mcg/hour, the MRHD.
Mutagenesis
Buprenorphine was not genotoxic in 3 in-vitro genetic toxicology studies (bacterial mutagenicity test, mouse lymphoma assay, chromosomal aberration assay in human peripheral blood lymphocytes), and in one in vivo mouse micronucleus test).
Impairment of Fertility
Butrans (1/4 of a Butrans 5 mcg/hour, one Butrans 5 mcg/hour, or one Butrans 20 mcg/hour) every 3 days in males for 4 weeks prior to mating for a total of 10 weeks and in females for 2 weeks prior to mating through gestation day 7) had no effect on fertility or general reproductive performance of rats at AUC-based exposure levels as high as approximately 65 times (females) and 100 times (males) that for human subjects who received Butrans 20 mcg/hour, the MRHD.
|clinicalStudies=The efficacy of Butrans has been evaluated in four 12-week double-blind, controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate to severe chronic low back pain or osteoarthritis using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain failed to show efficacy. One study in osteoarthritis, that included an active comparator, failed to show efficacy for Butrans and the active comparator.
12-Week Study in Opioid-Naïve Patients with Chronic Low Back Pain
A total of 1,024 patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered an open-label, dose-titration period for up to four weeks. Patients initiated therapy with three days of treatment with Butrans 5 mcg/hour. After three days, if adverse events were tolerated but the pain persisted (≥5 on an 11-point, 0 to 10 Numerical Rating Scale), the dose was increased to Butrans 10 mcg/hour. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to Butrans 20 mcg/hour for an additional 10-12 days. Patients who achieved adequate analgesia and tolerable adverse effects on Butrans were then randomized to remain on their titrated dose of Butrans or matching placebo. Fifty-three percent of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Twenty three percent of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. The remaining 10% of patients were dropped due to various administrative reasons.
During the first seven days of double-blind treatment patients were allowed up to two tablets per day of immediate-release oxycodone 5 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to either acetaminophen 500 mg or ibuprofen 200 mg at a maximum of four tablets per day. Sixty-six percent of the patients treated with Butrans completed the 12-week treatment compared to 70% of the patients treated with placebo. Of the 256 patients randomized to Butrans, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 283 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events.
Of the patients who were randomized, the mean pain (SE) NRS scores were 7.2 (0.08) and 7.2 (0.07) at screening and 2.6 (0.08) and 2.6 (0.07) at pre-randomization (beginning of double-blind phase) for the Butrans and placebo groups, respectively.
The score for average pain over the last 24 hours at the end of the study (Week 12/Early Termination) was statistically significantly lower for patients treated with Butrans compared with patients treated with placebo. The proportion of patients with various degrees of improvement, from screening to study endpoint, is shown in Figure 3 below.
[[File:Buprenorphine structure 2.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]
12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain
One thousand one hundred and sixty (1,160) patients on chronic opioid therapy (total daily dose 30-80 mg morphine equivalent) entered an open-label, dose-titration period with Butrans for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with Butrans 10 mcg/hour for three days. After three days, if the patient tolerated the adverse effects, the dose was increased to Butrans 20 mcg/hour for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on Butrans 20 mcg/hour were randomized to remain on Butrans 20 mcg/hour or were switched to a low-dose control (Butrans 5 mcg/hour) or an active control. Fifty-seven percent of the patients who entered the open-label titration period were able to titrate to and tolerate the adverse effects of Butrans 20 mcg/hour and were randomized into a 12-week double-blind treatment phase. Twelve percent of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period.
During the double-blind period, patients were permitted to take ibuprofen (200 mg tablets) or acetaminophen (500 mg tablets) every 4 hours as needed for supplemental analgesia (up to 3200 mg of ibuprofen and 4 grams of acetaminophen daily). Sixty seven percent of patients treated with Butrans 20 mcg/hour and 58% of patients treated with Butrans 5 mcg/hour completed the 12-week treatment. Of the 219 patients randomized to Butrans 20 mcg/hour, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to Butrans 5 mcg/hour, 24% discontinued due to lack of efficacy and 6% due to adverse events.
Of the patients who were able to be randomized in the double-blind period, the mean pain (SE) NRS scores were 6.4 (0.08) and 6.5 (0.08) at screening and were 2.8 (0.08) and 2.9 (0.08) at pre-randomization (beginning of Double-Blind Period) for the Butrans 5 mcg/hour and Butrans 20 mcg/hour, respectively.
The score for average pain over the last 24 hours at Week 12 was statistically significantly lower for subjects treated with Butrans 20 mcg/hour compared to subjects treated with Butrans 5 mcg/hour. A higher proportion of Butrans 20 mcg/hour patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to Butrans 5 mcg/hour patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 4 below.
[[File:Buprenorphine structure 2.jpg|thumb|none|400px|left|This image is provided by the National Library of Medicine.]]
|howSupplied=* Butrans (buprenorphine) Transdermal System is supplied in cartons containing 4 individually-packaged systems and a pouch containing 4 Patch-Disposal Units. Butrans 5 mcg/hour ...
Butrans (buprenorphine) Transdermal System is supplied in cartons containing 4 individually-packaged systems and a pouch containing 4 Patch-Disposal Units.
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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
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.
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.
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.
Limitations of Use
Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation.
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.
Overview
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)
Indications
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.
Dosage
General Principles
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.
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.
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.
Dose Titration
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)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Buprenorphine (transdermal) in adult patients.
Non–Guideline-Supported Use
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)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Buprenorphine (transdermal) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Buprenorphine (transdermal) in pediatric patients.
The management of intermittent pain (e.g., use on an as-needed basis [prn]).
Warnings
WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE
See full prescribing information for complete Boxed Warning.
* 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.
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.
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.
Limitations of Use
Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation.
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.
Respiratory Depression
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:
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.
QTc Prolongation
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.
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 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.
Hepatotoxicity
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.
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.
Seizures
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.
MAO Inhibitors
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.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Buprenorphine (transdermal) Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Buprenorphine (transdermal) Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Buprenorphine (transdermal) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
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.
Nursing Mothers
There is no FDA guidance on the use of Buprenorphine (transdermal) in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Buprenorphine (transdermal) in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Buprenorphine (transdermal) in geriatric settings.
Gender
There is no FDA guidance on the use of Buprenorphine (transdermal) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Buprenorphine (transdermal) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Buprenorphine (transdermal) in patients with renal impairment.
Hepatic 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.
Immunocompromised Patients
There is no FDA guidance one the use of Buprenorphine (transdermal) in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Buprenorphine (transdermal) Administration in the drug label.
Monitoring
There is limited information regarding Buprenorphine (transdermal) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Buprenorphine (transdermal) and IV administrations.
Overdosage
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.
There is limited information regarding Buprenorphine (transdermal) Mechanism of Action in the drug label.
Structure
There is limited information regarding Buprenorphine (transdermal) Structure in the drug label.
Pharmacodynamics
There is limited information regarding Buprenorphine (transdermal) Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Buprenorphine (transdermal) Pharmacokinetics in the drug label.
Nonclinical Toxicology
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.
Carcinogenicity
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).
Mutagenicity
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.
Clinical Studies
There is limited information regarding Buprenorphine (transdermal) Clinical Studies in the drug label.
How Supplied
There is limited information regarding Buprenorphine (transdermal) How Supplied in the drug label.
Storage
There is limited information regarding Buprenorphine (transdermal) Storage in the drug label.
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|?Pill Ingred
|?Pill Imprint
|?Pill Dosage
|?Pill Color
|?Pill Shape
|?Pill Size (mm)
|?Pill Scoring
|?NDC
|?Drug Author
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Package and Label Display Panel
This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
Precautions with Alcohol
Alcohol-Buprenorphine (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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