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Agents for Opioid DependenceAgents for Opioid WithdrawalMixed Opiate Agonist-Antagonist
Buprenorphine is an opioid and therefore has abuse potential and risk of fatal overdose from respiratory failure. Addiction may occur in patients who obtain buprenorphine illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for the development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. The misuse of transdermal buprenorphine by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death. Abuse or misuse of the buccal film may cause choking, overdose, and death. To discourage abuse, the smallest appropriate quantity of buprenorphine should be prescribed, and proper disposal instructions for unused drugs should be given to patients.  For patients being treated for pain, discuss the availability of naloxone with all patients and strongly consider prescribing it in patients who are at increased risk of opioid overdose, such as patients who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental ingestion or opioid overdose.  Strongly consider prescribing naloxone in patients being treated with buprenorphine for OUD because of the potential for relapse. Consider prescribing naloxone in patients using other CNS depressants or if the patient has household members or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu opioid receptor.  Like other opioids, buprenorphine use is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Transdermal and transmucosal buprenorphine are not intended for use on an as-needed basis; use is intended only for patients requiring continuous, around-the-clock opioid analgesia for an extended period of time and requires an experienced clinician who is knowledgeable in the use of long-acting opioids for the management of chronic pain.  When used to treat addiction, sublingual buprenorphine should be initiated only after clear and objective symptoms of narcotic withdrawal are present to avoid precipitating such symptoms due to the antagonist activity of buprenorphine.  Buprenorphine subdermal implants should be initiated only in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product. To minimize implant insertion and removal complications, use of buprenorphine subdermal implants requires an experienced clinician. In the event of buprenorphine implant protrusion or expulsion from the arm, keep the implant away from pediatric patients. Extended-release subcutaneous injectable buprenorphine should be used only in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for at least 7 days, and are transitioning to this injection for maintenance treatment. Prescription use of this product in the treatment of opioid dependence requires an experienced clinician. Clinical data are limited related to the surgical removal of the injection depot.       
As with other opioid agonists, buprenorphine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as coadministration significantly increases the risk for respiratory depression, low blood pressure, and death. The potential risk of serious adverse effects with concomitant use of buprenorphine and other CNS depressants should not preclude medication-assisted treatment (MAT) with buprenorphine for opioid use disorder, since withholding MAT may increase the risk of morbidity and mortality from the opioid use disorder. Discontinuation of other CNS depressants is preferred in most cases; co-therapy may require more intensive counseling and monitoring, possible adjustments to induction procedures, gradual tapering of the CNS depressant to the lowest effective dose, and development of strategies to manage prescribed or illicit CNS depressant use. Educate patients at initiation of buprenorphine treatment about the risk of concurrent use of benzodiazepines, alcohol, and other CNS depressants. In patients receiving MAT with buprenorphine, benzodiazepines are not a preferred treatment for anxiety or insomnia. Prior to co-prescribing benzodiazepines, ensure there is an appropriate diagnosis for use, consider alternatives for insomnia or anxiety, develop a system for alerting other healthcare providers of the patient's buprenorphine treatment, coordinate care to minimize risks, and confirm the proper use of prescribed medication and assess for illicit benzodiazepine use through toxicology screening. There is no evidence to support dose limitations of buprenorphine to address benzodiazepine use in buprenorphine-treated patients; however, in patients who are sedated at the time of buprenorphine dosing, a medically-trained healthcare provider should evaluate the cause of sedation, and delay or omit the buprenorphine dose if needed. If buprenorphine must be administered to patients with pulmonary disease, use extreme caution and initiate treatment at the lowest effective dose. Clinically significant respiratory and CNS depression may occur with therapeutic doses of any form of buprenorphine; patients with pre-existing respiratory or CNS impairment may be at an increased risk of adverse events. Buprenorphine should be used with caution in patients with asthma; use of transdermal buprenorphine or the buccal film is contraindicated in patients with significant respiratory depression and/or acute or severe bronchial asthma (e.g., status asthmaticus) in an unmonitored setting or in the absence of resuscitative equipment. The manufacturer of buprenorphine subdermal implants recommends caution in patients with compromised respiratory function such as occurs with chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, or pre-existing respiratory depression. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Prior to initiation of therapy, it is important to note that naloxone may not be effective in reversing buprenorphine effect. Proper dosing and titration are essential; patients should be monitored for respiratory depression, particularly during initiation or after a dose increase. Caution should be exercised when converting from a different opioid to buprenorphine for pain treatment, as overestimation of the buprenorphine dose may lead to fatal overdose. In patients pulmonary disease such as chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, emphysema, chronic bronchitis, respiratory insufficiency, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to transdermal buprenorphine, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. If sublingual or intravenous buprenorphine are used in patients with compromised respiratory function, it is recommended that the dose be reduced by approximately one-half. Use buprenorphine with caution in patients with: an acute intoxication of CNS depressants (e.g., ethanol intoxication); a history of delirium tremens; heart failure; or obesity. Retention of carbon dioxide from respiratory depression may also aggravate the sedative effects of opioids. Use buprenorphine with caution in patients who have sleep apnea; opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia (hypoxia). Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dose using best practices for opioid tapering. Use buprenorphine with caution in patients who have kyphoscoliosis (a type of scoliosis), as the spine curvature may increase the risk of breathing difficulties. Patients with toxic psychosis may not be good candidates for buprenorphine receipt due to the possible CNS depressive effects. Caution is advised for use of buprenorphine in elderly, cachectic, or debilitated patients, who are more likely to a have a co-morbid disease that affects buprenorphine kinetics and since they may be more sensitive to the respiratory and CNS depressant effects of the drug. Careful monitoring is required, particularly when CYP450 3A4 inhibitors or inducers are used concomitantly; concurrent use of a CYP3A4 inhibitor or discontinuation of a concurrently used CYP3A4 inducer may increase plasma buprenorphine concentrations and potentiate the risk of fatal respiratory depression. Warn all patients that buprenorphine can impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. These effects may persist for varying periods of time after dosing. Impairment of mental or physical abilities may change during dosage adjustments.
Keep buprenorphine products out of the reach of pediatric patients and pets, as accidental exposure can cause serious injury or death. Accidental exposure to buprenorphine from any route (including, for example, protrusion or expulsion of an implant from the arm) can cause severe, possibly fatal, respiratory depression, particularly in pediatric patients.
There have been no well-controlled studies of buprenorphine in pregnant women. However, buprenorphine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. The American College of Obstetricians and Gynecologists recommends early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Rely on validated screening tools, such as 4Ps, NIDA Quick Screen, and CRAFFT (for women 26 years or younger). Ensure opioids are appropriately indicated. For women using opioids for chronic pain, consider strategies to avoid or minimize the use of opioids, including alternative pain therapies (i.e., nonpharmacologic) and nonopioid pharmacologic treatments. Take a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids or other high-risk drugs such as benzodiazepines. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for neonatal opioid withdrawal syndrome, and how long-term opioid use may affect care during a future pregnancy. Opioid agonist pharmacotherapy is preferable to medically supervised withdrawal in pregnant women with opioid use disorder. Pregnant women receiving treatment for opioid addiction may require dose adjustments of buprenorphine in order maintain abstinence from illicit drug use; closely monitor patients for withdrawal signs and symptoms and adjust dose as necessary. If the benefit of treatment with the subdermal implant (Probuphine) is determined to outweigh the risks during pregnancy, dosage adjustments cannot be made and the patient should be closely monitored to ensure adequate treatment. Because the implant dose cannot be adjusted, this formulation may not be an appropriate treatment option to initiate in patients who are pregnant. The subcutaneous extended-release injection may also not be the optimal dosage form for use in pregnancy in the opioid dependent patient. Limited published data on the use of buprenorphine injection in pregnancy have not shown an increased risk of major malformations. In published animal reproduction studies with NMP, an excipient in the extended-release subcutaneous injection (Sublocade), preimplantation losses, delayed ossification, reduced fetal weight, developmental delays and reduced cognitive function were reported at doses equivalent to the doses of NMP via the human usual injection dose; inform women of the potential fetal risk. In animal studies, embryofetal death during organogenesis was observed in rats and rabbits treated with oral buprenorphine at doses approximately 53 and 11 times the maximum recommended human dose (MRHD), respectively. Pre- and post-natal development studies in rats demonstrated increased neonatal death after oral, IM, and subcutaneous doses approximately 4, 3, and 0.5 times the times the MRHD, respectively. No teratogenic effects were observed in rats or rabbits given a range of doses more than the MRHD during organogenesis; however, events such as acephalus, omphalocele, and skeletal abnormalities have been reported in a few studies. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Further, prolonged maternal use of opioids, such as buprenorphine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. From postmarketing reports with sublingual use, the time to onset of neonatal withdrawal signs ranged from day 1 to day 8 of life with most cases occurring on day 1. Advise pregnant women receiving treatment for opioid dependence with buprenorphine of the risk of NOWS and ensure that appropriate treatment will be available. The risk for NOWS must be balanced against the risk of untreated opioid addiction in the mother which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. The safety of injectable buprenorphine given during labor and obstetric delivery has not been established. Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. Transdermal and buccal buprenorphine are not for analgesic use during and immediately prior to labor, when shorter acting analgesics or other therapies are more appropriate. Opioids can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. 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. Discuss contraceptive use among all women of reproductive age with a substance use disorder to minimize the risk of unplanned pregnancy.
Intramuscular administration or other routes of deep insertion of the buprenorphine implant may result in rare but serious complications (e.g., neural or vascular injury), difficult localization of the implant, or result in the need for a surgical procedure to remove the implant. Improper placement may lead to local migration, protrusion, and expulsion. The buprenorphine implant should be inserted subdermally only, on the inner side of the upper arm. The implant should be palpable after insertion, and this should be confirmed by palpation immediately after insertion to ensure proper positioning. Complicated removal can occur if the implant is not inserted correctly, is inserted too deeply (intramuscular or in the fascia), is not palpable, or has migrated. Injury to deeper neural or vascular structures in the arm may occur when removing deeply inserted implants. Incomplete insertion or infection may lead to protrusion or expulsion. Infection may occur at the site of the insertion or removal. Excessive palpation shortly after insertion of the implants may increase the chance of infection. Improper removal carries a risk of infection at the implant site. Buprenorphine implants should be used cautiously in patients with a history of recurrent MRSA infections.
Rx, schedule III
Semisynthetic mixed opiate agonist-antagonist; partial mu-receptor agonist with a ceiling to its pharmacological effectsImmediate-release parenteral form used for moderate to severe pain; transdermal and buccal forms used for continuous therapy for chronic severe painSublingual tablets, dermal implant, and extended-release subcutaneous injection are used for opioid dependence in conjunction with the Drug Addiction Treatment Act (DATA)
Belbuca, Buprenex, Butrans, Probuphine, Sublocade, Subutex
Belbuca Buccal Film: 75mcg, 150mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcgBelbuca Transmucosal Film: 75mcg, 150mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcgBuprenex/Buprenorphine/Buprenorphine Hydrochloride Intramuscular Inj Sol: 0.3mg, 1mLBuprenex/Buprenorphine/Buprenorphine Hydrochloride Intravenous Inj Sol: 0.3mg, 1mLBuprenorphine/Buprenorphine Hydrochloride/Subutex Sublingual Tablet, SL: 2mg, 8mgBuprenorphine/Butrans Transdermal Film ER: 1h, 5mcg, 7.5mcg, 10mcg, 15mcg, 20mcgProbuphine Subdermal Imp: 74.2mgSublocade Subcutaneous Inj: 0.5mL, 100mg
5 mcg/hour, applied topically to intact skin, every 7 days; titrate to response and tolerance. While the patch is intended to be worn for 7 days, doses may be titrated after a minimum interval of 72 hours; titrate the dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than 2 patches of the 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour systems. Do not exceed a dose of 20 mcg/hour due to the risk of QT prolongation.
NOTE: There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. Overestimating dose when converting from another opioid can be fatal with first dose.
5 mcg/hour, applied topically to intact skin, every 7 days. Begin treatment with buprenorphine at the next dosing interval. Use extreme caution when converting patients from methadone as the ratio between methadone and other opioid agonists can vary widely. While the patch is intended to be worn for 7 days, doses may be titrated after a minimum interval of 72 hours; titrate the dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than 2 patches of the 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour systems. Do not exceed a dose of 20 mcg/hour due to the risk of QT prolongation.
Taper the patient's current around-the-clock opioid for up to 7 days to no more than 30 mg of oral morphine or equivalent per day before beginning transdermal buprenorphine. Initiate buprenorphine 10 mcg/hour, applied topically to intact skin, every 7 days. Begin treatment with buprenorphine at the next dosing interval. Use extreme caution when converting patients from methadone as the ratio between methadone and other opioid agonists can vary widely. While the patch is intended to be worn for 7 days, doses may be titrated after a minimum interval of 72 hours; titrate the dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than 2 patches of the 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour systems. Do not exceed a dose of 20 mcg/hour due to the risk of QT prolongation.
Consider the use of an alternate analgesic. The 20 mcg/hour transdermal buprenorphine may not provide adequate analgesia.
75 mcg transmucosally once daily, or every 12 hours if tolerated, placed against the inside of the cheek. After 4 days, increase dosage to 150 mcg every 12 hours. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half.
75 mcg transmucosally once daily, or every 12 hours if tolerated, placed against the inside of the cheek. After 4 days, increase dosage to 150 mcg every 12 hours. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half. Use extreme caution when converting patients from methadone as the potency ratio between methadone and other opioid agonists can vary widely.
Taper the patient's current around-the-clock opioid to no more than 30 mg of oral morphine or equivalent per day before beginning transmucosal buprenorphine. Initiate 150 mcg transmucosally every 12 hours, placed against the inside of the cheek. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half. Use extreme caution when converting patients from methadone as the potency ratio between methadone and other opioid agonists can vary widely.
Taper the patient's current around-the-clock opioid to no more than 30 mg of oral morphine or equivalent per day before beginning transmucosal buprenorphine. Initiate 300 mcg transmucosally every 12 hours, placed against the inside of the cheek. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half. Use extreme caution when converting patients from methadone as the potency ratio between methadone and other opioid agonists can vary widely.
Consider the use of an alternate analgesic. The buccal/transmucosal film may not provide adequate analgesia.
NOTE: Buprenorphine 0.3 mg IM provides analgesia roughly equivalent to morphine 10 mg IM.
0.3 mg IM or slow IV push. The dose may be repeated once if needed 30 to 60 minutes after the initial dose and then every 6 to 8 hours as needed. Depending on the severity of the pain, single doses of up to 0.6 mg IM, may be needed; this dose should only be given IM. Do not exceed 0.6 mg/dose IM or 0.3 mg/dose IV.
0.15 mg IM or slow IV push. The dose may be repeated once if needed 30 to 60 minutes after the initial dose and then every 6 to 8 hours as needed. Extra caution should be exercised with the IV route, particularly with the initial dose.
2 to 6 mcg/kg/dose IM or slow IV push every 4 to 8 hours as needed. Buprenorphine elimination is variable in pediatric patients, and some pediatric patients may not need to be remedicated for 6 to 8 hours. A fixed dosing interval is not recommended until the child's specific needs for analgesia are established. The use of a repeat dose 30 to 60 minutes after the initial dose, as is used in Adult and Adolescent patients, is not recommended in this population.
In a study of post-operative patients, buprenorphine 4 mcg/kg or 2 mcg/kg via epidural injection had a slower onset of analgesia than the same dose given IV. However, the duration of spinal analgesia was significantly longer in patients receiving epidural administration. A greater duration of effect was found with the higher dosage as compared to the lower dosage. The incidence of side effects was not significantly different among the buprenorphine groups.
Administer first dose of buprenorphine when early signs of opioid withdrawal appear and at least 4 hours after the last used short-acting opioid or 24 hours after last used long-acting opioid. To achieve an adequate treatment dose, rapidly titrate dose, in 2 mg to 4 mg increments, until clinical effect is achieved. In some studies, gradual induction over several days resulted in high drop-out rates. Buprenorphine should be used as part of a complete treatment program to include counseling and psychosocial support. Initiate treatment with supervised administration. Use of single-agent buprenorphine during induction may result in fewer withdrawal symptoms than if buprenorphine with naloxone is used.
A target dose of 16 mg sublingually once daily is suggested; however, doses ranging from 4 to 24 mg/day may be required. Titrate dosage in increments of 2 to 4 mg/day to a level that holds the patient in treatment and suppresses opiate withdrawal symptoms. Higher dosages (12 to 16 mg/day) have been associated with reduced opiate craving and fewer opiate-positive urine tests. Doses higher than 24 mg SL once daily have not shown any added benefit. Use as part of a comprehensive treatment plan which includes counseling and psychosocial support. Initiate treatment with supervised administration, and progress to unsupervised administration. When determining prescription quantity for unsupervised administration, consider frequency of visits, patient's stability, and security of home. REDUCING DOSAGE AND STOPPING TREATMENT: Patients may remain on treatment indefinitely as long as the drug is beneficial. If the decision is made to discontinue maintenance therapy, the dose should be tapered to reduce the occurrence of withdrawal signs and symptoms. Additional, patients should be advised of the potential for relapse to illicit drugs use. ALTERNATIVE MAINTENANCE DOSE REGIMEN†: Buprenorphine is indicated for daily administration; however, efficacy has been demonstrated when extending the dosing interval to 3 times per week. In one study, comparable reductions in illicit opioid usage were found with 3 treatments for opioid dependence: buprenorphine, methadone, and levomethadyl. The dosages were individually optimized within a range of 16 to 48 mg 3 times a week for buprenorphine, 60 to 100 mg daily for methadone, and 75 to 161 mg 3 times a week for levomethadyl acetate. Buprenorphine with naloxone is preferred over buprenorphine alone for maintenance treatment, especially when drug administration will not be supervised. Only use single-agent buprenorphine for unsupervised administration in those patients who cannot tolerate buprenorphine with naloxone.
FOR TREATMENT FOLLOWING INDUCTION: Initially, 300 mg subcutaneously once monthly in the abdominal region for the first 2 months, then 100 mg once monthly given subcutaneously in the abdominal region as a maintenance dose. Administer monthly with a minimum of 26 days between doses. For patients on an established regimen of 100 mg monthly, a 2-month dosing interval may be considered in certain situations (e.g., extended travel); in these instances, a single 300 mg dose may be given to cover the 2-month period. Thereafter, the 100 mg monthly regimen would resume. May consider an increase in the maintenance dose to 300 mg per month in patients for which the benefits outweigh the risks. There should be a minimum of 26 days between doses. This product is indicated for the treatment of moderate to severe opioid use disorder in patients who have first initiated treatment with a buprenorphine-containing product, delivering the equivalent of 8 to 24 mg/day of transmucosal buprenorphine for a minimum of 7 days [e.g., one buprenorphine and naloxone 8 mg/2 mg sublingual tablet provides equivalent buprenorphine exposure to 1 buprenorphine 8 mg sublingual tablet, 1 buprenorphine and naloxone 4.2 mg/0.7 mg buccal film, or 1 buprenorphine and naloxone 5.7 mg/1.4 mg sublingual tablet]. FOR TRANSITION FROM LONG-TERM, ESTABLISHED TRANSMUCOSAL TREATMENT: For patients receiving transmucosal buprenorphine doses of 8 to 18 mg/day, give 300 mg subcutaneously once for the first month, followed by 100 mg subcutaneously once monthly. May consider giving 300 mg as the second dose in patients who experience craving or withdrawal symptoms after the initial 300 mg dose. For patients receiving transmucosal buprenorphine doses of 20 to 24 mg/day, give 300 mg subcutaneously once monthly for the first 2 months, then 100 mg subcutaneously once monthly. Administer monthly with a minimum of 26 days between doses.
Each dose consists of 4 implants inserted subdermally in the inner side of the upper arm. The implants are intended to be in place for 6 months. New implants may be inserted subdermally in an area of the inner side of either upper arm that has not been previously used at the time of removal, if continued treatment is desired. If new implants are not inserted on the same day as the removal of old implants, maintain patients on their previous dose of transmucosal buprenorphine prior to insert of the implant. Following 1 insertion in each arm, most patients should be transitioned back to a transmucosal buprenorphine-containing product for continued treatment. There is no experience with a second insertion into a previously-used administration site, other site on the arm, or a site other than the upper arm. Although some patients may require occasional supplemental dosing with buprenorphine, patients should not be provided with prescriptions for as-needed transmucosal buprenorphine. Patients who feel the need for supplemental dosing should be seen and evaluated promptly. Ongoing use of supplemental dosing with transmucosal buprenorphine indicates that the amount of buprenorphine delivered by the buprenorphine implant is not adequate for stable maintenance. In these cases, consider use of alternate buprenorphine products for maintenance of treatment. Buprenorphine should be used as part of a complete treatment program to include counseling and psychosocial support.
Initially, 13.2 to 15.9 mcg/kg/day sublingually divided every 8 hours. Titration schedules vary, but may be titrated by either 0.8 mcg/kg increments or by 25% per day based on targeted NAS scores (Max: 60 mcg/kg/day sublingually). Phenobarbital may be added when a maximum buprenorphine dose has been achieved or if unable to wean after 24 to 48 hours. Once symptoms are controlled, taper dosage. After infant symptoms have been stable for at least 24 to 48 hours, dosage may be decreased by 0.8 mcg/kg increments back down to 4.4 mcg/kg/dose every 8 hours for 3 doses, with additional fixed incremental reductions in dose and interval (2.6 mcg/kg/dose every 8 hours for 3 doses, 1.7 mcg/kg/dose every 8 hours for 3 doses, 1.7 mcg/kg/dose every 12 hours for 2 doses, and 1.7 mcg/kg/dose every 24 hours for 1 dose) or 10% per day until within 10% of starting dose. Dosage, interval, length of treatment, and taper schedule are variable and must be individualized to control symptoms of withdrawal. Weaning may take several weeks to months.
†Indicates off-label use
0.6 mg/dose IM, 0.3 mg/dose IV, 20 mcg/hour transdermally, or 900 mcg transmucosal every 12 hours for pain; 24 mg/day SL, 300 mg/month extended-release subcutaneous injection, or 4 implants/6 months subdermally for opioid dependence (each implant contains 74.2 mg of buprenorphine).
16 to 17 years: 0.6 mg/dose IM and 0.3 mg/dose IV for pain. Four implants/6 months subdermally for opioid dependence (each implant contains 74.2 mg of buprenorphine). Safety and efficacy of the buprenorphine patch and buprenorphine buccal film for pain have not been established; safety and efficacy of buprenorphine SL and extended-release SQ injection for opioid dependence have not been established.13 to 15 years: 0.6 mg/dose IM and 0.3 mg/dose IV for pain. Safety and efficacy of other dosage forms have not been established.
2 years and older: 6 mcg/kg/dose IV/IM every 4 to 8 hours for pain. Safety and efficacy of other dosage forms have not been established.Younger than 2 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
60 mcg/kg/day sublingually has been used off-label for neonatal abstinence syndrome.
Immediate-release parenteral dosage forms (e.g., Buprenex or generic equivalent):Specific guidelines for dosage adjustments in hepatic impairment are not available; however, dosage adjustments may be necessary. Adjust based on clinical response. Extended-release subcutaneous injection (e.g., Sublocade or generic equivalent):Moderate to severe hepatic impairment (e.g., Child Pugh B or C): Use is not recommended.Mild hepatic impairment (e.g., Child Pugh A): No dosage adjustments are needed. Sublingual dosage form (e.g., Subutex or generic equivalents):Severe hepatic impairment: Consider reducing the starting and titration incremental dose by half, and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.Moderate hepatic impairment: No dosage adjustment is needed; however, patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.Mild hepatic impairment: No dosage adjustment or specific monitoring is required. Transdermal patch (e.g., Butrans):In patients with mild to moderate hepatic impairment where the patch is the first opioid analgesic, initiate patients on 5 mcg/hour transdermally. Otherwise, cautiously select a dose that corresponds to the patient's oral morphine equivalents per day and other factors that influence initial patch selection (see manufacturer's literature). In some patients, alternate therapy should be considered. Closely monitor the patient for the first 24 to 72 hours of treatment with the patch for respiratory depression. Individually titrate the dose thereafter to a level that provides adequate analgesia and tolerable side effects. The buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment and is only intended for 7-day application. Consider the use of an alternate analgesic with more flexibility of dosing in patients with severe hepatic impairment. Buccal film (e.g., Belbuca):Severe hepatic impairment (Child-Pugh C): Reduce starting dose and titration dose by half that of patients with normal liver function, from 150 mcg to 75 mcg.Mild to moderate hepatic impairment: No dose adjustment necessary. Subdermal implant (i.e., Probuphine):Moderate to severe hepatic impairment: Do not use as dose titration cannot be performed. Patients who develop moderate or severe hepatic impairment during treatment should be monitored for sedation and respiratory depression; implant removal may be necessary.Mild hepatic impairment: No dose adjustment necessary.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed. Some manufacturers recommend cautious use in severe renal impairment.
For storage information, see specific product information within the How Supplied section.
Sublingual tablets (e.g., Subutex)Completely dissolve under the tongue. Do not swallow or chew the tablets; swallowing the tablet will reduce the bioavailability of the drug.For doses requiring more than 2 tablets, patients are advised to either place all the tablets at once under the tongue or, if they cannot fit more than 2 tablets comfortably, place 2 tablets at a time under the tongue. With either option, patients should hold the tablets under the tongue until they completely dissolve.Prior to induction, determine the type of opioid dependence (i.e., long- or short-acting opioids).Induction: To avoid precipitating withdrawal, induction with buprenorphine should be undertaken only after objective and clear signs of withdrawal are present.Short-acting opioid: Administer first dose at least 4 hours or longer after the patient last used heroin or other short-acting opioid.Longer-acting opioid (e.g., methadone): Administer first dose at least 24 hours or longer after the patient last long-acting opioid use.Maintenance: Buprenorphine; naloxone combination tablets are preferred to buprenorphine single-ingredient tablets for maintenance treatment.Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to health care providers who meet certain qualifying requirements.Pharmacists who wish to verify whether a physician is qualified under DATA to prescribe buprenorphine sublingual tablets may contact 1-866-BUP-CSAT(1-866-287-2728).Storage: Keep buprenorphine secured in a location not accessible by others.Disposal: Flush unused buprenorphine down the toilet when it is no longer needed if a drug take-back option is not readily available.
Buccal film (e.g., Belbuca)Do not use if the package seal is broken or the film is cut, damaged, or changed in any way.Use the tongue to wet the inside of the check or rinse the mouth with water to wet the area for placement.Avoid applying the film to areas of the mouth with open sores or lesions.Apply the film immediately after removal from the package.Place the yellow side of the film against the inside of the cheek. Hold the film in place with clean, dry fingers for 5 seconds. Leave the film in place until it fully dissolves, usually within 30 minutes.Do not manipulate the film with the tongue or fingers after it is in place. Avoid eating food and drinking liquids until the film has dissolved. Do not chew or swallow the film.Abuse or misuse of the film by swallowing may cause choking, overdose, and death.Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to health care providers who meet certain qualifying requirements.Pharmacists who wish to verify whether a physician is qualified under DATA to prescribe buprenorphine may contact 1-866-BUP-CSAT(1-866-287-2728).Storage: Keep buprenorphine secured in a location not accessible by others.Disposal: Remove film from the foil packaging and flush unused medication down the toilet if a drug take-back option is not readily available.
Extemporaneous 0.075 mg/mL oral suspensionOpen a 0.3 mg/mL ampule of buprenorphine.Add 1.26 mL of 95% ethanol to 0.3 mg buprenorphine (obtained from the 0.3 mg/mL ampule).Add simple syrup to obtain a final total volume of 4 mL.Storage: The solution is stable in amber glass bottles (for 30 days) and oral dispensing syringes (for 7 days) when stored at room temperature at 68 to 77 degrees F (20 to 25 degrees C). AdministrationUsing a syringe, place under the tongue for sublingual administration.A pacifier may be placed in the neonate's mouth to maximize contact with the sublingual mucosa.If the volume is more than 0.5 mL, divide into 2 administrations separated by at least 2 minutes.
Immediate-release injection solution (e.g., Buprenex)No dilution is necessary. Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit.Give by slow IV injection over 2 minutes directly into a vein or into the tubing of a freely flowing, compatible IV solution. Rapid IV injection may result in an increased frequency of adverse effects.Do not exceed maximum of 0.3 mg/dose IV; if an adult patient (not in a high-risk category) requires a single dose more than 0.3 mg, then administer via the intramuscular route only.
Immediate-release injection solution (e.g., Buprenex)No dilution is necessary. Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit.May give the immediate-release injection solution of buprenorphine by deep IM injection.
Extended-release once-monthly subcutaneous injection (e.g., Sublocade)Only a health care professional should prepare and administer this injection.Approved for use in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for at least 7 days, and are transitioning to this injection for maintenance treatment. This product should be used as part of a comprehensive treatment program that includes counseling and psychosocial support.Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to health care providers who meet certain qualifying requirements.Pharmacists who wish to verify whether a physician is qualified under DATA to prescribe buprenorphine may contact 1-866-BUP-CSAT(1-866-287-2728). AdministrationOnly for subcutaneous injection in the abdominal region. DO NOT administer intramuscularly, intravenously, or intradermally. Serious harm or death could result if administered intravenously.Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit. Each dose is a clear, colorless to yellow to amber solution.Administer monthly with a minimum of 26 days between doses.Only use the syringe and safety needle included with the product for administration. Do not attach the needle until the time of administration.Choose an injection site in the abdominal region. Do not inject into an area where the skin is irritated, reddened, bruised, infected, or scarred in any way.Do not rub the injection area after the injection. If bleeding occurs, use a gauze pad or bandage but only use minimal pressure.Advise the patient that there may be a lump for several weeks after the injection that will decrease in size over time.To avoid irritation, rotate the injection site with each monthly injection.The injection site should be examined for infection, evidence of tampering, or attempts to remove the depot.Storage: Store the unopened prefilled syringes in the refrigerator in the original packaging; do not freeze. Once outside the refrigerator this product may be stored in its original packaging at room temperature, 15 to 30 degrees C (59 to 86 degrees F), for up to 7 days prior to administration. Discard the injection if left at room temperature for longer than 7 days.
Epidural AdministrationNOTE: Buprenorphine is not FDA-approved for epidural administration.This route of administration should only be used by specially trained health care professionals.Placement of epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. For example, for thoracic surgery placement at T2 to T8, upper abdominal surgery, T4 to L1, lower abdominal surgery, T10 to L3, upper extremity surgery, C2 to C8 and lower extremity surgery, T12 to L3.After ensuring proper placement of the needle or catheter, inject appropriate dose into the epidural space.
Transdermal patch system (e.g., Butrans)Apply to intact skin only.Do not use if the pouch seal is broken or the patch is cut, damaged, or changed in any way. Do not cut the buprenorphine transdermal system.Instruct patients to apply immediately after removal from the individually sealed pouch.Each buprenorphine transdermal system is intended to be worn for 7 days.Apply to the upper outer arm, upper chest, upper back, or the side of the chest. Rotate buprenorphine transdermal system application among the 8 described sites (each present on both sides of the body). After removal of the patch, wait a minimum of 21 days before reapplying to the same skin site.Apply to a hairless or nearly hairless skin site. If necessary, hair should be clipped, not shaven. Do not apply to irritated skin.If necessary, clean site with water only and allow to dry completely before application. Do not use soaps, alcohol, oils, lotions, or abrasive devices.The patch may be worn while bathing or showering.Avoid exposing the patch application site and surrounding areas to external heat sources (e.g., heating pads, electric blankets, heated water beds, hair dryers, tanning beds, hot baths or saunas, excessive sun exposure, or hot climate).If the adhesive matrix (which contains buprenorphine) of the patch accidentally touches skin, wash the area with water. Do not use soap, alcohol, or other solvents to remove the adhesive; doing so may enhance drug absorption.If problems arise with the adherence of the patch, the edges of the patch may be taped with first aid tape. If problems with the patch not sticking continue, cover the patch with special see-through adhesive dressings (e.g., Bioclusive or Tegaderm).If the buprenorphine transdermal system falls off during the 7 day dosing interval, dispose of the patch properly and place a new patch at a different skin site.Storage: Keep buprenorphine secured in a location not accessible by others.Disposal: Dispose of damaged, used, and unneeded buprenorphine patches right away by folding patch in half so that the adhesive side is inward and immediately flush down the toilet. Alternatively, buprenorphine patches may be sealed in the Patch-Disposal Unit provided and then disposed of in the trash. Never dispose of a buprenorphine patch in the trash without sealing it in the Patch-Disposal Unit.
Subdermal Implant AdministrationSubdermal implant (Probuphine)All prescribing health care providers performing implant insertions and/or removals must successfully complete a live training program on insertion and removal procedures, including demonstrating competency in Probuphine procedures, and become certified in the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program.Patients eligible for the implant must currently be on a maintenance dose of 8 mg/day or less of a buprenorphine or buprenorphine/naloxone sublingual tablet or its transmucosal buprenorphine product equivalent (the dose of transmucosal buprenorphine providing blood levels comparable or lower than the level provided by buprenorphine subdermal implants) and have been stable on this dose without any need for supplemental dosing for 3 months or longer. Additionally, patients should be clinically stable as well as a suitable candidate for treatment (social support system, stable living environment, etc.).For details on insertion and removal of the inserts, see prescribing information.Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to health care providers who meet certain qualifying requirements.In the Case of Spontaneous Expulsion of the Probuphine implant:The patient should contact the prescribing health care provider as soon as possible.Instruct the patient to place the implant in a plastic bag, store it safely out of reach of children, and to bring it to the health care provider office to determine whether the full implant has been expelled.The prescribing health care provider must carefully monitor patient until the implant is replaced to evaluate for withdrawal or other clinical indicators that supplemental transmucosal buprenorphine may be needed.
Belbuca:- Store at 77 degrees F; excursions permitted to 59-86 degrees FBuprenex:- Discard product if it contains particulate matter, is cloudy, or discolored- Protect from light- Store at controlled room temperature (between 68 and 77 degrees F)Butrans:- Store at 77 degrees F; excursions permitted to 59-86 degrees FProbuphine:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FSublocade:- Discard product if it contains particulate matter, is cloudy, or discolored- Discard product that has been exposed to conditions other than those recommended- Discard unused portion. Do not store for later use.- Discard unused product 7 days after first opening the pouch- May be stored at room temperature for up to 1 week- Refrigerated product should reach room temperature before administration- Store between 35 to 46 degrees FSubutex:- Store at controlled room temperature (between 68 and 77 degrees F)
Although true hypersensitivity reactions are rare, caution is advised in patients with known or suspected opiate agonist hypersensitivity. Buprenorphine use is contraindicated in patients with buprenorphine hypersensitivity. Buprenorphine subdermal implant is also contraindicated in patients with a history of hypersensitivity to ethylene vinyl acetate.
Buprenorphine should not be used in patients with impaired consciousness or coma. Decreased respiratory function and an unusually slow heart rate can produce cerebral hypoxia and produce increased intracranial pressure due to carbon dioxide retention. Buprenorphine may itself elevate cerebrospinal fluid pressure and cause a decrease in heart rate, and should be used with caution in patients with head trauma, hypoxemia, hypercapnia, intracranial mass, intracranial hypertension, and other circumstances associated with increased intracranial pressure. Additionally, buprenorphine may cause sedation and pupillary changes such as miosis that may obscure the clinical evaluation and course of head injury or coma.
Buprenorphine, as used in the treatment of opiate dependent patients, does not have antianxiety effects. Patients who are maintained on buprenorphine will react to life problems and stress with the same anxiety symptoms as other individuals. Avoid confusing such symptoms with those of opiate abstinence and do not treat anxiety by increasing the dosage of buprenorphine. The action of buprenorphine in maintenance treatment is limited to the control of opiate withdrawal symptoms and is not effective in the treatment of anxiety.
Buprenorphine products used in the treatment of opioid dependence are not appropriate for use as an analgesic for pain management. These products are not appropriate for use in patients who are opiate-naive. There have been deaths reported in opioid-naive patients who received a 2-mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine subdermal implants (Probuphine) are not appropriate for opioid-naive patients or patients who have not achieved and sustained prolonged clinical stability while being maintained on buprenorphine 8 mg/day or less of a Subutex or Suboxone sublingual tablet or generic equivalent. The extended-release subcutaneous buprenorphine injection (Sublocade) is not appropriate for use in opioid-naive patients; this injection is only indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustments of the transmucosal product for a minimum of 7 days, and who are transitioning to this injection for maintenance therapy.
While opiate agonists are usually contraindicated for use in patients with infectious diarrhea or diarrhea secondary to poisoning, antimotility agents have been used successfully in these patients. If possible, buprenorphine should not be given until the toxic substance has been eliminated.
Abrupt discontinuation of buprenorphine in physically dependent patients has resulted in serious withdrawal symptoms, uncontrolled pain, suicide, and drug-seeking behavior. Buprenorphine is a partial opioid agonist; hence, the withdrawal syndrome is generally milder than that seen with full agonists and may be delayed in onset. Consider the opioid dose, duration of therapy, type of pain being treated, and physical and psychological attributes of the patient prior to decreasing the dose or discontinuing therapy. Ensure ongoing care of the physically dependent patient, including a multimodal approach to pain management, and devise an appropriate tapering schedule and follow-up plan so that patient and provider goals are clear and realistic. When discontinuing therapy due to suspected substance abuse, evaluate and treat the patient or refer for evaluation and treatment of the substance abuse disorder. Opioid tapering schedules must be individualized. For physically dependent patients being treated for pain, decrease by no more than 10% to 25% of the total daily dose every 2 to 4 weeks. Patients who have been taking opioids for shorter periods of time may tolerate a more rapid taper. If buprenorphine subdermal implants are not to be immediately replaced upon removal, maintain patients on their previous dosage of sublingual buprenorphine until treatment is resumed. Monitor those who elect to discontinue implantable treatment for withdrawal with consideration given to use of a tapering dose of transmucosal buprenorphine. Monitor patients for signs and symptoms of withdrawal for several months after discontinuation of extended-release buprenorphine injection; at steady state (achieved in 4 to 6 months), patients who discontinue use will have detectable buprenorphine concentrations for 12 months or longer. Reassess patients frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur. If withdrawal symptoms arise, pause the taper or increase the opioid dose to the previous dose, then proceed with a slow taper. Monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. Withdrawal may also be precipitated through administration of drugs with opioid antagonist activity (e.g., naloxone) or mixed agonist/antagonist analgesics (e.g., nalbuphine). The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the opioid antagonist. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, avoid the use of buprenorphine in patients who are receiving a full opioid agonist analgesic as it may reduce the analgesic effect and/or precipitate withdrawal symptoms.
Tolerance can develop during chronic opioid therapy; patients receiving opioid dependence therapy may be under treated or denied pain treatment. Prior to surgery or dental work, assess and discuss pain management with patients receiving treatment for opioid dependence. Patients who require treatment for acute pain management or require anesthesia while on buprenorphine should receive a non-opioid analgesic if possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with careful monitoring of respiratory function. Because of the partial agonist activity of buprenorphine, higher doses of the full opiate agonist may be required for analgesic effect during concurrent use. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anesthesia, the manufacturer of buprenorphine subdermal implants recommends that patients be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy must be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.
Buprenorphine should not be used in patients with GI obstruction. The buccal film and transdermal system are contraindicated for use in patients with paralytic ileus; the buccal film is contraindicated for use in known or suspected GI obstruction. Use buprenorphine cautiously in patients with: ulcerative colitis or other inflammatory bowel disease, as they may be more sensitive to opiate agonist-induced constipation; toxic megacolon; recent gastrointestinal tract surgery; or infectious diarrhea. Use in patients with an acute abdomen condition may obscure the diagnosis or clinical course.
The safety and efficacy of the buprenorphine transdermal system, buprenorphine buccal film, and extended-release subcutaneous buprenorphine injection have not been established in infants, children, or adolescents, nor has sublingual buprenorphine or buprenorphine subdermal implants in pediatric patients less than 16 years of age. There is insufficient experience to recommend parenteral immediate-release buprenorphine injection solution in infants or children below the age of 2 years. Due to greater variation in buprenorphine clearance in children between the ages of 2 to 12 as compared to adults, a fixed dosing interval of buprenorphine is not recommended until the child's needs for analgesia are established. Whenever possible analgesia should be administered to a pediatric patient through a noninvasive route (i.e., orally or through an existing IV line). The administration of analgesic medications intramuscularly to children sends them the message that to achieve pain relief more pain must be given; this can lead to denial of pain by fearful children. Buprenorphine can cause severe, possibly fatal, respiratory depression in children; dosage forms should be kept out of the reach of children, including any implant protrusions or expulsions.
The developmental and health benefits of breast-feeding for the infant should be considered along with the clinical need of buprenorphine for the mother and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. Due to low concentrations of buprenorphine in breast milk and infant serum, as well as poor oral bioavailability in the nursing infant, use may be acceptable during breast-feeding. Available data have not demonstrated adverse reactions in breast-fed infants; however, there is potential for serious adverse reactions such as sedation, respiratory depression, or withdrawal symptoms when the drug or breast-feeding is discontinued. Monitor the infant for drowsiness, adequate weight gain, and developmental milestones if buprenorphine must be used in the lactating mother. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties. Based on 2 studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low concentrations in human milk and infant urine. In a study of 7 lactating women taking a median oral dose of buprenorphine 7 mg/day, an exclusively breast-fed infant with milk consumption of 150 mL/kg/day would receive an estimated mean buprenorphine dose of 0.38% and a mean norbuprenorphine dose of 0.18% of the maternal weight-adjusted dose. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Buprenorphine dosage adjustments and close monitoring are recommended based upon the severity of hepatic disease or impairment and the buprenorphine formulation used. The extended-release subcutaneous injection is not recommended for use in patients with moderate to severe hepatic impairment (e.g., Child Pugh B or C). Patients with pre-existing moderate to severe hepatic impairment (e.g., Child Pugh B or C) are not candidates for the subdermal implant (Probuphine) because the dosage cannot be titrated. There may be an increased risk for further hepatic damage when buprenorphine is used in patients who have conditions associated with hepatic impairment, including hepatic encephalopathy, liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, jaundice, concomitant use of other potentially hepatotoxic drugs, or ongoing intravenous drug use. Cytolytic hepatitis and hepatitis with jaundice have been reported with buprenorphine in both clinical trials and postmarketing experience. Many, though not all, cases involved patients with such co-morbid conditions. Baseline liver function tests (LFTs) and periodic monitoring, particularly in patients at increased risk, are recommended with buprenorphine use for chronic pain or opioid dependence. Monitor for toxicity or symptoms of excessive dosage in patients who develop moderate to severe hepatic impairment during treatment; some patients using the subdermal implants may require implant removal.
Patients with impaired renal function, including patients receiving dialysis, have demonstrated similar buprenorphine plasma concentrations following the use of parenteral buprenorphine to those patients with normal renal function. However, caution is still advised in severe renal impairment or renal failure, as many dosage forms have not been studied patients with these conditions. Use buprenorphine with caution in patients with pre-existing urinary retention or conditions that may lead to such as this medicine has been associated with urinary retention and oliguria due to drug-induced increases in the tension of the detrusor muscle. Patients more prone to urinary retention include those with bladder obstruction, prostatic hypertrophy, urinary tract obstruction, urethral stricture, or recent urinary tract surgery.
Buprenorphine has been shown to increase intracholedochal pressure to a similar degree as other opiate agonists and thus, should be administered with caution to patients with biliary tract disease such as those with acute pancreatitis, gallbladder disease, gallstones, biliary obstruction, or biliary cirrhosis.
Use buprenorphine with caution in patients who have adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema, as there may be an increased risk of adverse events (e.g., hypothyroidism may increase the risk for prolonged QT interval). Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH), and may stimulate or inhibit the thyroid stimulating hormone. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, administer physiologic replacement doses of corticosteroids and, if appropriate, wean the patient off of opioid therapy. If the opioid can be discontinued, perform a follow-up assessment of adrenal function to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases report using a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should be evaluated.
Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Due to the risk of QT prolongation, do not exceed doses of one 20 mcg/hour buprenorphine transdermal system or 900 mcg every 12 hours of the buccal film for the treatment of pain. In a controlled study of healthy subjects, a transdermal system dosage of 40 mcg/hour (given as two 20 mcg/hour systems) was observed to cause QT prolongation. In contrast, 10 mcg/hour did not demonstrate a clinically meaningful effect on the QT interval. Many manufacturers recommend avoiding use in patients with a personal or family history of long QT syndrome, and in patients taking Class IA or Class III antiarrhythmic medications or other medications that prolong the QT interval. The manufacturer of the buccal film further recommends avoiding use with other drugs that prolong the QT interval and recommends performing periodic electrocardiograms (ECGs) in patients at risk, such as those with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease (e.g., unstable atrial fibrillation, symptomatic bradycardia, active myocardial ischemia (acute myocardial infarction), or acute heart failure). Use buprenorphine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, pyrexia or elevated body temperature, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Patients wearing the buprenorphine transdermal system should avoid exposing the application site and surrounding area to direct external heat sources. A heating pad or electric blanket, heat lamps, saunas, hot tubs, heated water beds, etc. should be avoided while wearing the system because an increase in the absorption of buprenorphine may occur. Patients should not expose the application site to hot water or have prolonged direct sunlight (UV) exposure. Temperature dependent increases in buprenorphine release from the system may occur and result in possible overdose or death. In addition, patients wearing the system should be monitored for opioid side effects if they develop a fever while wearing the system or if they develop an increased core body temperature due to exercise. A dose adjustment may be necessary. Fever may also increase the risk for QT prolongation; monitor appropriately.
Buprenorphine, like other opiate agonists, may lower blood pressure and cause orthostatic hypotension. Use with caution in patients with pre-existing hypotension from any cause including hypovolemia and concurrent administration of other medications which may compromise vasomotor tone. Advise ambulatory patients that orthostatic hypotension may occur or worsen during buprenorphine therapy.
Opiate analgesics, especially in high doses, can lower seizure threshold and precipitate convulsions, particularly in patients with a preexisting seizure disorder or a history of seizures. Use buprenorphine with caution in such patients and monitor for loss of seizure control.
Caution is advised for the use of buprenorphine in geriatric, cachectic, or debilitated patients, who are more likely to a have a co-morbid condition that affects buprenorphine kinetics; the geriatric patient may also be more sensitive to the respiratory and CNS depressant effects of the drug.       The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in re