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    Drugs for Opioid Use Disorder
    Mixed Opiate Agonist-Antagonist

    BOXED WARNING

    Accidental exposure, alcoholism, depression, implant insertion and removal complications, potential for overdose or poisoning, requires an experienced clinician, substance abuse

    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 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 drug should be given to patients. 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, subdermal implants requires an experienced clinician who is certified in the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program. 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 who is certified in the Sublocade Risk Evaluation and Mitigation Strategy (REMS) program. Clinical data are limited related to the surgical removal of the injection depot. Buprenorphine products should be kept 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 can cause severe, possibly fatal, respiratory depression, particularly in pediatric patients.

    Acute intoxication of CNS depressants, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), CNS depression, coadministration with other CNS depressants, cor pulmonale, driving or operating machinery, emphysema, ethanol intoxication, heart failure, obesity, psychosis, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    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; obesity or sleep apnea; or kyphoscoliosis. Retention of carbon dioxide from respiratory depression may also aggravate the sedative effects of opioids. Patients with kyphoscoliosis (a type of scoliosis) may be at an increased risk of breathing difficulties due to their spine curvature. 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.

    Labor, neonatal opioid withdrawal syndrome, neonates, obstetric delivery, pregnancy

    There have been no well-controlled studies of buprenorphine in pregnant women. Limited published data on the use of buprenorphine injection in pregnancy have not shown an increased risk of major malformations. However, buprenorphine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus, since opioid dependence in pregnancy is generally associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. 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. 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. The prolonged maternal use of buprenorphine during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Unlike opiate withdrawal in adults, NOWS may be life-threatening if not recognized and treated. Neonates should be observed for signs of NOWS (e.g., irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, failure to gain weight) and managed accordingly. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Onset, duration, and severity of opioid withdrawal in the neonate 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. 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. 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.

    Infection, intramuscular administration

    Intramuscular administration or other routes of deep insertion of 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. 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.

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Semisynthetic mixed opiate agonist-antagonist; partial mu-receptor agonist with a ceiling to its pharmacological effects
    Immediate-release parenteral form used for moderate to severe pain; transdermal and buccal forms used for continuous therapy for chronic severe pain
    Sublingual tablets, dermal implant, and extended-release subcutaneous injection are used for opioid dependence in conjunction with the Drug Addiction Treatment Act (DATA)

    COMMON BRAND NAMES

    Belbuca, Buprenex, Butrans, Probuphine, Sublocade, Subutex

    HOW SUPPLIED

    Belbuca/Buprenorphine/Buprenorphine Hydrochloride Buccal Film: 75mcg, 150mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcg
    Belbuca/Buprenorphine/Buprenorphine Hydrochloride Transmucosal Film: 75mcg, 150mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcg
    Buprenex/Buprenorphine/Buprenorphine Hydrochloride Intramuscular Inj Sol: 0.3mg, 1mL
    Buprenex/Buprenorphine/Buprenorphine Hydrochloride Intravenous Inj Sol: 0.3mg, 1mL
    Buprenorphine/Buprenorphine Hydrochloride/Subutex Sublingual Tablet, SL: 2mg, 8mg
    Buprenorphine/Butrans Transdermal Film ER: 1h, 5mcg, 7.5mcg, 10mcg, 15mcg, 20mcg
    Probuphine Intradermal Imp: 74.2mg
    Sublocade Subcutaneous Inj: 0.5mL, 100mg

    DOSAGE & INDICATIONS

    For the treatment of moderate pain or severe pain.
    For treatment of chronic severe pain in patients who require daily, around-the-clock, long-term opioid treatment.
    NOTE: Transdermal and buccal buprenorphine should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Discontinue all other around-the-clock opioid drugs upon initiation of transdermal buprenorphine.
    NOTE: Transdermal buprenorphine doses of 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, and 20 mcg/hour are for use in opioid-experienced patients only.
    NOTE: Buccal doses of 600 mcg, 750 mcg, and 900 mcg are for use following titration from lower doses of the buccal film.
    Transdermal dosage for use as the first opioid analgesic (Butrans)
    Adults

    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.

    Transdermal dosage for conversion from other opioid agonist analgesics (Butrans)

    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.

    Adults whose daily opioid dose is less than 30 mg oral morphine (or equivalent)

    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.

    Adults whose daily opioid dose is 30 to 80 mg oral morphine (or equivalent)

    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.

    Adults whose daily opioid dose is more than 80 mg oral morphine (or equivalent)

    Consider the use of an alternate analgesic. The 20 mcg/hour transdermal buprenorphine may not provide adequate analgesia.

    Transmucosal dosage for use as the first opioid analgesic (Belbuca)
    Adults

    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.

    Transmucosal dosage for conversion from other opioid agonist analgesics (Belbuca)

    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.

    Adults whose daily opioid dose is less than 30 mg oral morphine (or equivalent)

    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.

    Adults whose daily opioid dose is 30 to 89 mg oral morphine (or equivalent)

    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.

    Adults whose daily opioid dose is 90 to 160 mg oral morphine (or equivalent)

    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.

    Adults whose daily opioid dose is more than 160 mg oral morphine (or equivalent)

    Consider the use of an alternate analgesic. The buccal/transmucosal film may not provide adequate analgesia.

    Intramuscular or Intravenous dosage

    NOTE: Buprenorphine 0.3 mg IM provides analgesia roughly equivalent to morphine 10 mg IM.

    Adults and Adolescents

    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.

    Geriatric, Debilitated, and other high-risk Adults or Adolescents, such as those with respiratory disease or on other CNS depressants

    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.

    Children 2 years and older

    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.

    Epidural dosage†
    Adults

    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.

    For the treatment of opiate agonist dependence, including opiate agonist withdrawal symptoms.
    For the prevention of undue symptoms of opiate agonist withdrawal during induction of opiate agonist dependence treatment.
    Sublingual dosage
    Adults

    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. 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 healthcare providers who meet certain qualifying requirements.

    For maintenance treatment of opiate agonist dependence.
    Sublingual dosage
    Adults

    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. 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 healthcare providers who meet certain qualifying requirements.

    Subcutaneous dosage (extended-release once-monthly injection; i.e., Sublocade)
    Adults

    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. May consider an increase in the maintenance dose to 300 mg per month in patients for which the benefits outweigh the risks. Each month, examine injection site for signs of infection or evidence of tampering or attempts to remove the depot. Use as a part of a comprehensive treatment program which includes counseling and psychosocial support. This product is indicated for the treatment of moderate to severe opioid use disorder in patients who have first initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days. 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 healthcare providers who meet certain qualifying requirements.

    For maintenance treatment of opioid agonist dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet equivalent or generic equivalent).
    Subdermal implant dosage
    Adults and Adolescents 16 years and older

    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. 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 healthcare providers who meet certain qualifying requirements.

    For the management of neonatal abstinence syndrome†.
    Sublingual dosage
    Neonates†

    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

    MAXIMUM DOSAGE

    Adults

    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).

    Geriatric

    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).

    Adolescents

    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.

    Children

    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.

    Infants

    Safety and efficacy have not been established.

    Neonates

    60 mcg/kg/day sublingually has been used off-label for neonatal abstinence syndrome.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration
    Oral Solid Formulations

    Sublingual tablets (e.g., Subutex or generic equivalents)
    Buprenorphine tablets are for sublingual use only.
    Do not swallow or chew the tablets. The tablets need to completely dissolve under the tongue. It is important that patients are consistent with tablet administration, since 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 healthcare 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).

    Other Oral Formulations

    Buccal film Administration (i.e., Belbuca buccal film)
    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.
    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. Avoid eating food and drinking liquids until the film has dissolved.
    To dispose of unused films, remove all films from their foil packages. Flush the films down the toilet and discard foil packaging in the trash.
    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 healthcare 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).

    Extemporaneous Compounding-Oral

    Extemporaneous 0.075 mg/mL buprenorphine oral suspension:
    Open one 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).
     
    Administration
    Using 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 greater than 0.5 mL, divide into 2 administrations separated by at least 2 minutes.

    Injectable Administration
    Intravenous Administration

    Immediate-release injection solution (e.g., Buprenex or generic equivalent):
    No dilution is necessary. Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit.
    Give buprenorphine 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.

    Intramuscular Administration

    Immediate-release injection solution (e.g., Buprenex or generic equivalent)
    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.

    Subcutaneous Administration

    Extended-release once-monthly subcutaneous injection (i.e., Sublocade)
    -General Information for use:
    Only a healthcare professional should prepare and administer this injection.
    Healthcare settings and pharmacies that order and dispense this injection must be certified in the Sublocade REMS program and comply with the REMS requirements.
    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 healthcare 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).
     
    -Subcutaneous Administration of extended-release injection (Sublocade):
    Only for subcutaneous injection in the abdominal region. DO NOT administer intramuscularly or intravenously. 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.

    Other Injectable Administration

    Epidural Administration
    NOTE: Buprenorphine is not approved by the FDA 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.

    Topical Administration
    Transdermal Patch Formulations

    Transdermal patch system (Butrans transdermal system)
    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.
    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.

    Other Administration Route(s)

    Subdermal Implant Administration
    Probuphine (buprenorphine) implant
    All prescribing healthcare 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 healthcare providers who meet certain qualifying requirements.
    In the Case of Spontaneous Expulsion of the Probuphine implant:
    The patient should contact the prescribing healthcare 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 healthcare provider office to determine whether the full implant has been expelled.
    The prescribing healthcare 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.

    STORAGE

    Belbuca:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Buprenex:
    - 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 F
    Probuphine:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Sublocade:
    - 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 F
    Subutex:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Opiate agonist hypersensitivity

    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.

    Accidental exposure, alcoholism, depression, implant insertion and removal complications, potential for overdose or poisoning, requires an experienced clinician, substance abuse

    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 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 drug should be given to patients. 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, subdermal implants requires an experienced clinician who is certified in the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program. 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 who is certified in the Sublocade Risk Evaluation and Mitigation Strategy (REMS) program. Clinical data are limited related to the surgical removal of the injection depot. Buprenorphine products should be kept 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 can cause severe, possibly fatal, respiratory depression, particularly in pediatric patients.

    Abrupt discontinuation

    Patients receiving sublingual buprenorphine for opioid dependence may still experience withdrawal effects, especially during the induction phase. Abrupt discontinuation of buprenorphine may also result in symptoms of withdrawal, such as restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis, vomiting, and diarrhea; however, because buprenorphine is a partial opiate agonist, the withdrawal syndrome is generally milder than that seen with full agonists, and may be delayed in onset. The best method for sublingual buprenorphine discontinuation has not been determined; both abrupt discontinuation and tapering have been used. When a buprenorphine transdermal system or buprenorphine buccal film is no longer required by the patient, the dose should be tapered as part of a comprehensive treatment plan. If buprenorphine subdermal implants are not to be immediately replaced upon removal, maintain patients on their previous dosage of sublingual buprenorphine until buprenorphine implant treatment is resumed. If discontinuing buprenorphine implants without resumption of therapy, monitor patients for withdrawal with consideration given to use of a tapering dose of transmucosal buprenorphine. After reaching steady-state of extended-release buprenorphine injection (Sublocade) in 4 to 6 months, patients who discontinue use of the injection will have detectable levels of buprenorphine for 12 months or longer and should be monitored for several months for signs and symptoms of withdrawal and treated appropriately. The correlation between plasma concentrations of buprenorphine and those detectable in urine are unknown.

    Dental work, surgery

    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.

    Anxiety

    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.

    Acute abdomen, constipation, diarrhea, GI obstruction, ileus, inflammatory bowel disease, toxic megacolon, ulcerative colitis

    Buprenorphine should not be used in patients with GI obstruction. Buprenorphine buccal film is contraindicated for use in known or suspected GI obstruction, including paralytic ileus. Buprenorphine transdermal system is contraindicated for use in patients with paralytic ileus. Use buprenorphine cautiously in patients with toxic megacolon, recent gastrointestinal tract surgery, infectious diarrhea, and ulcerative colitis. Patients with ulcerative colitis or other inflammatory bowel disease may be more sensitive to constipation caused by opiate agonists. Use in patients with an acute abdomen condition may obscure the diagnosis or clinical course.Although opiate agonists are usually contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, buprenorphine should not be given until the toxic substance has been eliminated.

    Children, infants

    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..

    Acute intoxication of CNS depressants, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), CNS depression, coadministration with other CNS depressants, cor pulmonale, driving or operating machinery, emphysema, ethanol intoxication, heart failure, obesity, psychosis, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    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; obesity or sleep apnea; or kyphoscoliosis. Retention of carbon dioxide from respiratory depression may also aggravate the sedative effects of opioids. Patients with kyphoscoliosis (a type of scoliosis) may be at an increased risk of breathing difficulties due to their spine curvature. 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.

    Coma, head trauma, hypoxemia, increased intracranial pressure, intracranial mass

    Buprenorphine should not be used in patients with impaired consciousness or coma. Decreased respiratory function and bradycardia can produce cerebral hypoxia and produce increased intracranial pressure due to carbon dioxide retention. Buprenorphine may itself elevate cerebrospinal fluid pressure and cause bradycardia 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.

    Labor, neonatal opioid withdrawal syndrome, neonates, obstetric delivery, pregnancy

    There have been no well-controlled studies of buprenorphine in pregnant women. Limited published data on the use of buprenorphine injection in pregnancy have not shown an increased risk of major malformations. However, buprenorphine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus, since opioid dependence in pregnancy is generally associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. 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. 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. The prolonged maternal use of buprenorphine during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Unlike opiate withdrawal in adults, NOWS may be life-threatening if not recognized and treated. Neonates should be observed for signs of NOWS (e.g., irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, failure to gain weight) and managed accordingly. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Onset, duration, and severity of opioid withdrawal in the neonate 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. 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. 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.

    Breast-feeding

    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.

    Hepatic disease, hepatic encephalopathy, hepatitis, jaundice

    Dosage adjustments and/or close monitoring of buprenorphine are recommended based upon the severity of hepatic disease/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). The dosage of subdermal implants (Probuphine) cannot be titrated and patients with pre-existing moderate to severe hepatic impairment (e.g., Child Pugh B or C) are not candidates for treatment. Conditions associated with hepatic impairment include hepatic encephalopathy, liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, jaundice, concomitant usage of other potentially hepatotoxic drugs, or ongoing intravenous drug use; such patients may be at an increased risk for the development of further hepatic damage when treated with buprenorphine. In both clinical trials and postmarketing experience, cytolytic hepatitis and hepatitis with jaundice have been reported during buprenorphine therapy. 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.  Patients who develop moderate to severe hepatic impairment while being treated with buprenorphine should be monitored for toxicity or symptoms of excessive dosage  caused by increased levels of buprenorphine; in patients using the subdermal implants, some patients may require removal of the implants.

    Bladder obstruction, oliguria, prostatic hypertrophy, renal failure, renal impairment, urethral stricture, urinary retention, urinary tract obstruction

    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 if this medication is prescribed to patients with severe renal impairment or renal failure, as many dosage forms have not been studied in these patients. 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.

    Biliary cirrhosis, biliary obstruction, biliary tract disease, gallbladder disease, pancreatitis

    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.

    Acute heart failure, acute myocardial infarction, atrial fibrillation, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    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 the buprenorphine transdermal system in healthy subjects, a buprenorphine dose of 40 mcg/hour (given as two 20 mcg/hour systems) was observed to cause QT prolongation. In contrast, buprenorphine 10 mcg/hour did not demonstrate a clinically meaningful effect on the QT interval. Many manufacturers buprenorphine recommend avoiding use in patients with a history of long QT syndrome, family history of long QT syndrome, and in patients taking Class IA or Class III antiarrhythmic medications, or taking 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, acute heart failure, or active myocardial ischemia (acute myocardial infarction)). Consider the risk for QT prolongation in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or liver disease may also be at increased risk for QT prolongation.

    Fever, heating pad, sunlight (UV) exposure

    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.

    Hypotension, hypovolemia, orthostatic hypotension

    As with other opiate agonists, buprenorphine use 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 worsen or occur during buprenorphine therapy.

    Seizure disorder, seizures

    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.

    Opioid-naive patients, pain

    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.

    Geriatric

    Caution is advised for 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. According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of pain management due to recent fractures or joint replacement, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Individuals receiving palliative care or those in hospice settings are excluded from the Beers Criteria; the balance of benefits and harms of medication management for these patients may differ from those of the general population of older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The Guidelines caution that opioids may cause constipation, nausea, vomiting, sedation, lethargy, weakness, confusion, dysphoria, physical and psychological dependency, hallucinations, and unintended respiratory depression, especially in individuals with compromised pulmonary function. These adverse effects can lead to other consequences such as falls. In addition, the initiation of longer-acting opioids is not recommended unless shorter-acting opioids have been unsuccessful, or titration of shorter-acting doses has established a clear daily dose of opioid analgesic that can be provided by using a long-acting form.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use buprenorphine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. 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 hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of 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 patients for 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 undergo laboratory evaluation.

    Infection, intramuscular administration

    Intramuscular administration or other routes of deep insertion of 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. 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.

    Scleroderma

    Because buprenorphine implants are administered subdermally, caution is recommended when using the implants in patients with a history of keloid formation or connective tissue disease (e.g., scleroderma).

    Infertility, reproductive risk

    Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk to males or females. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible.

    Intravenous administration

    Do not administer the extended-release buprenorphine formulation (Sublocade) intravenously or intramuscularly. Intravenous administration of the extended-release buprenorphine formulation for subcutaneous injection presents significant risk of serious harm or death because the injection solution forms a solid mass upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic, including life threatening pulmonary emboli, could result if administered intravenously. The injection is available only through a restricted program called the SUBLOCADE REMS Program because of the risk of serious harm or death that could result from intravenous self-administration. The goal of the program is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense this injection directly to a healthcare provider for administration by a healthcare provider.

    ADVERSE REACTIONS

    Severe

    coma / Early / 0-1.0
    AV block / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    ileus / Delayed / 0-1.0
    cyanosis / Early / 0-1.0
    apnea / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    angioedema / Rapid / 0-1.0
    bronchospasm / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    visual impairment / Early / 0-1.0
    atrial fibrillation / Early / 0-0.2
    cholecystitis / Delayed / 0-0.2
    stroke / Early / 0-0.2
    seizures / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    SIADH / Delayed / Incidence not known
    neonatal respiratory depression / Rapid / Incidence not known
    neonatal opioid withdrawal syndrome / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    withdrawal / Early / 0-24.0
    constipation / Delayed / 0-13.0
    depression / Delayed / 0-11.0
    erythema / Early / 3.0-10.0
    hematoma / Early / 7.0-7.0
    migraine / Early / 0-5.0
    angina / Early / 0-5.0
    hypotension / Rapid / 0-5.0
    hypertension / Early / 0-5.0
    dyspnea / Early / 0-5.0
    edema / Delayed / 5.0-5.0
    elevated hepatic enzymes / Delayed / 0-5.0
    epiphora / Early / 5.0-5.0
    anemia / Delayed / 1.0-4.9
    peripheral edema / Delayed / 1.0-4.9
    peripheral vasodilation / Rapid / 0-3.9
    dysphoria / Early / 0-1.0
    psychosis / Early / 0-1.0
    hallucinations / Early / 0-1.0
    dysarthria / Delayed / 0-1.0
    confusion / Early / 0-1.0
    memory impairment / Delayed / 0-1.0
    palpitations / Early / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    QT prolongation / Rapid / 0-1.0
    dehydration / Delayed / 0-1.0
    dysphagia / Delayed / 0-1.0
    wheezing / Rapid / 0-1.0
    hypoventilation / Rapid / 0-1.0
    respiratory depression / Rapid / 0-1.0
    urinary incontinence / Early / 0-1.0
    urinary retention / Early / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    amblyopia / Delayed / 0-1.0
    blurred vision / Early / 0-1.0
    euphoria / Early / 0-1.0
    chest pain (unspecified) / Early / 0-0.2
    impaired cognition / Early / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known

    Mild

    nausea / Early / 5.0-33.0
    headache / Early / 1.0-29.1
    insomnia / Early / 0-21.4
    dizziness / Early / 1.5-15.0
    weakness / Early / 0-14.0
    asthenia / Delayed / 0-14.0
    back pain / Delayed / 1.0-14.0
    drowsiness / Early / 0-13.0
    diaphoresis / Early / 1.0-12.6
    anxiety / Delayed / 1.0-12.0
    pruritus / Rapid / 0-12.0
    abdominal pain / Early / 1.0-11.7
    infection / Delayed / 1.0-11.7
    rhinitis / Early / 0-11.0
    vertigo / Early / 0-10.0
    vomiting / Early / 1.0-9.0
    chills / Rapid / 0-7.8
    skin irritation / Early / 1.0-6.0
    hypoesthesia / Delayed / 0-5.0
    tremor / Early / 0-5.0
    paresthesias / Delayed / 0-5.0
    anorexia / Delayed / 0-5.0
    dyspepsia / Early / 0-5.0
    cough / Delayed / 0-5.0
    rash / Early / 0-5.0
    musculoskeletal pain / Early / 0-5.0
    miosis / Early / 0-5.0
    arthralgia / Delayed / 1.0-4.9
    myalgia / Early / 1.0-4.9
    pharyngitis / Delayed / 1.0-4.9
    hyperhidrosis / Delayed / 1.0-4.9
    lethargy / Early / 1.0-4.9
    sinusitis / Delayed / 0-4.9
    flushing / Rapid / 0-4.9
    fever / Early / 1.0-4.9
    dysgeusia / Early / 0-1.0
    nightmares / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    syncope / Early / 0-1.0
    emotional lability / Early / 0-1.0
    agitation / Early / 0-1.0
    restlessness / Early / 0-1.0
    pallor / Early / 0-1.0
    flatulence / Early / 0-1.0
    hiccups / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    hyperventilation / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    injection site reaction / Rapid / 0-1.0
    rhinorrhea / Early / 0-1.0
    malaise / Early / 0-1.0
    diplopia / Early / 0-1.0
    xerophthalmia / Early / 0-1.0
    ecchymosis / Delayed / 0-0.7
    diarrhea / Early / 5.0
    xerostomia / Early / 5.0
    fatigue / Early / 3.9
    amenorrhea / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as dihydrocodeine. Dihydrocodeine is found in several combination cough products. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression if buprenorphine is used with dihydrocodeine. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) If concurrent use of doxylamine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Diphenhydramine: (Moderate) If concurrent use of diphenhydramine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Hydrocodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Oxycodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as oxycodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Pentazocine: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Propoxyphene: (Major) Buprenorphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists due to the fact that buprenorphine is a partial mu-receptor agonist that has greater receptor affinity than many full agonists. Buprenorphine may also be used concurrently with some opioid agonists, and additive CNS depressive effects are possible. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. Any effect of buprenorphine may last for several days, since buprenorphine dissociates from the mu-receptor very slowly. Due to the mu-receptor high affinity binding, buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. The additive or antagonistic effects are dependent upon the dose of pure opiate agonist used; antagonistic effects are more common at low to moderate doses of the pure opioid agonist.
    Acetaminophen; Tramadol: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as tramadol. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Additionally, concurrent use of opiates with other drugs that modulate serotonergic function, such as tramadol, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. There is also a potential for increased risk of seizures if tramadol is given with other opiates.
    Acrivastine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Albuterol: (Minor) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, fluticasone; vilanterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Albuterol; Ipratropium: (Minor) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, fluticasone; vilanterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Alfentanil: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as alfentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Alfuzosin: (Major) Buprenorphine should be used cautiously and with close monitoring with should be used cautiously and with alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Almotriptan: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as selective serotonin-receptor agonists ('triptans'), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and a triptan is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Alosetron: (Moderate) Concurrent use of buprenorphine and antidiarrheals can lead to severe constipation and possibly additive CNS depression.
    Alprazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amiodarone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Antiarrhythmics with an established risk for QT prolongation and TdP include disopyramide, flecainide, propafenone, quinidine (including dextromethorphan; quinidine), procainamide, amiodarone, ibutilide, and sotalol. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as amiodarone may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Amitriptyline: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tricyclic antidepressants (TCAs) and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation. (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tricyclic antidepressants (TCAs) and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Amoxapine: (Major) If concurrent use of amoxapine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as amoxapine, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Amprenavir: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of strong CYP3A4 inhibitors such as anti-retroviral protease inhibitors (e.g., amprenavir, fosamprenavir, indinavir, nelfinavir) may result in increased systemic exposure to buprenorphine, with the potential for excessive buprenorphine-related side effects; however, studies have shown that nelfinavir has little effect on buprenorphine pharmacokinetics and no significant pharmacodynamic effects. In general, if a protease inhibitor and buprenorphine are used concurrently, monitor accordingly for sedation and respiratory depression and adjust the buprenorphine dosage if needed. Consider conservative buprenorphine therapy in patients already on a CYP3A4 inhibitor. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Anagrelide: (Major) Buprenorphine should be used cautiously and with close monitoring with anagrelide. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of buprenorphine and anagrelide for cardiovascular effects and evaluate as necessary.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apalutamide: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with apalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If apalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Apomorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with apomorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as apomorphine. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if buprenorphine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in buprenorphine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Buprenorphine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of buprenorphine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e.arformoterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Aripiprazole: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of aripiprazole and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of aripiprazole and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation, such as buprenorphine. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concomitant drug use is unavoidable, frequently monitor electrocardiograms.
    Artemether; Lumefantrine: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If coadministration is necessary, consider ECG monitoring.
    Asenapine: (Major) Buprenorphine should be avoided in combination with asenapine. Asenapine has been associated with QT prolongation. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). The manufacturer of asenapine recommends avoiding coadministration with with other agents also known to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as dihydrocodeine. Dihydrocodeine is found in several combination cough products. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression if buprenorphine is used with dihydrocodeine. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Carisoprodol: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Aspirin, ASA; Oxycodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as oxycodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Atazanavir: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir.
    Atazanavir; Cobicistat: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir. (Moderate) The plasma concentrations of buprenorphine and its metabolite, norbuprenorphine, are elevated when administered concurrently cobicistat. Dose adjustments are not required; however clinical monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Atomoxetine: (Major) Buprenorphine should be used cautiously and with close monitoring with atomoxetine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as atomoxetine. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as methylene blue, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Atropine; Difenoxin: (Moderate) Buprenorphine is an opioid analgesic. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of buprenorphine and antidiarrheals, such as atropine; diphenoxylate, can lead to severe constipation and possibly additive CNS depression.
    Atropine; Diphenoxylate: (Moderate) Buprenorphine is an opioid analgesic. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of buprenorphine and antidiarrheals, such as atropine; diphenoxylate, can lead to severe constipation and possibly additive CNS depression.
    Azithromycin: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of azithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). There have been case reports of QT prolongation and torsade de pointes (TdP) with the use of azithromycin in post-marketing reports. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as azithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Baclofen: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants, like baclofen. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Barbiturates: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bedaquiline: (Major) Buprenorphine should be used cautiously and with close monitoring with bedaquiline. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Bedaquiline has also been reported to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
    Belladonna; Opium: (Moderate) Buprenorphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists due to the fact that buprenorphine is a partial mu receptor agonist that has greater receptor affinity than many full agonists. Additive CNS, respiratory, and hypotensive effects are possible with this combination.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as methylene blue, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Buprenorphine should be used cautiously and with close monitoring with metronidazole. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Buprenorphine should be used cautiously and with close monitoring with metronidazole. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Boceprevir: (Moderate) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as boceprevir. During co-administration, use the lowest buprenorphine starting dose and slowly titrate to desired effect. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is advisable. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including buprenorphine.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including buprenorphine or buprenorphine; naloxone.
    Brigatinib: (Moderate) Monitor for decreased efficacy of buprenorphine as well as signs and symptoms of opioid withdrawal if coadministration with brigatinib is necessary. Buprenorphine is a CYP3A substrate and brigatinib induces CYP3A in vitro. The interaction of buprenorphine with many CYP3A4 inducers has not been studied; plasma concentrations of buprenorphine may decrease.
    Brompheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Budesonide; Formoterol: (Moderate) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Buprenorphine; Naloxone: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving mixed opiate agonists/antagonists. Naltrexone will antagonize the therapeutic benefits of mixed opiate agonists/antagonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects (respiratory insufficiency or arrest or circulatory collapse) with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Buspirone: (Moderate) If concurrent use of buspirone and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Butorphanol: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Capsaicin; Metaxalone: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants, such as metaxalone. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbamazepine: (Moderate) Inducers of CYP3A4 such as carbamazepine, may induce the hepatic metabolism of buprenorphine or opiate agonists, which may lead to opiate withdrawal or inadequate pain control.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of diphenhydramine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Carbinoxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate ago