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Buprenorphine: Drug information

Buprenorphine: Drug information
(For additional information see "Buprenorphine: Patient drug information" and see "Buprenorphine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
Buprenorphine Safety Alert January 2022

The FDA is warning about the risks of dental problems associated with transmucosal (buccal, sublingual) buprenorphine-containing medicines. Dental adverse events, including tooth decay, cavities, dental abscesses/infection, tooth erosion, and in some cases total tooth loss, have been reported even in patients with no history of dental issues. The FDA will require that a new warning about the risk of dental problems be added to the prescribing information and the patient Medication Guide for all transmucosal buprenorphine-containing medicines. Prescribers should advise patients to see a dentist soon after starting the medicine and during treatment.

Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-dental-problems-buprenorphine-medicines-dissolved-mouth-treat-opioid-use-disorder.

REMS Drugs COVID-19 Safety Alert March 2020

Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.

Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.

ALERT: US Boxed Warning
Accidental exposure (buccal film, transdermal patch):

Accidental exposure to even one dose of buprenorphine, especially by children, can result in a fatal overdose of buprenorphine.

Addiction, abuse, and misuse (buccal film, immediate-release injection, transdermal patch):

Buprenorphine exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing buprenorphine and monitor all patients regularly for the development of these behaviors or conditions.

Opioid analgesic risk evaluation and mitigation strategy (REMS):

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression (buccal film, immediate-release injection, transdermal patch):

Serious, life-threatening, or fatal respiratory depression may occur with use of buprenorphine. Monitor for respiratory depression, especially during initiation of buprenorphine or following a dose increase. Misuse or abuse of buprenorphine by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film or transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death.

Neonatal opioid withdrawal syndrome (buccal film, immediate-release injection, transdermal patch):

Prolonged use of buprenorphine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk associated with insertion and removal (subdermal implant):

Insertion and removal of buprenorphine implant are associated with the risk of implant migration, protrusion, and expulsion resulting from the procedure. Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion of drug implants inserted in the upper arm. Additional complications may include local migration, protrusion, and expulsion. Incomplete insertions or infections may lead to protrusion or expulsion.

Because of the risks associated with insertion and removal, buprenorphine implant is available only through a restricted program called the Probuphine REMS Program. All healthcare providers must successfully complete a live training program on the insertion and removal procedures and become certified, prior to performing insertions or prescribing buprenorphine implants. Patients must be monitored to ensure that the implant is removed by a healthcare provider certified to perform insertions.

Risks from concomitant use with benzodiazepines or other CNS depressants (buccal film, immediate-release injection, transdermal patch):

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of buprenorphine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Risk of serious harm or death with intravenous administration (extended-release injection):

Serious harm or death could result if extended-release injection is administered intravenously. The injection forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thromboembolic events, including life-threatening pulmonary emboli if administered intravenously.

Because of the risk of serious harm or death that could result from intravenous self-administration, buprenorphine extended-release injection is only available through a restricted program called the Sublocade REMS Program. Healthcare settings and pharmacies that order and dispense buprenorphine extended-release injection must be certified in this program and comply with the REMS requirements.

Brand Names: US
  • Belbuca;
  • Buprenex;
  • Butrans;
  • Probuphine Implant Kit [DSC];
  • Sublocade
Brand Names: Canada
  • Belbuca [DSC];
  • BuTrans 10;
  • BuTrans 15;
  • BuTrans 20;
  • BuTrans 5;
  • Probuphine;
  • Sublocade;
  • Subutex
Pharmacologic Category
  • Analgesic, Opioid;
  • Analgesic, Opioid Partial Agonist
Dosing: Adult

Note: Buprenorphine 8 mg sublingual tablet = buprenorphine/naloxone 8 mg/2 mg sublingual film = buprenorphine/naloxone 4.2 mg/0.7 mg buccal film = buprenorphine/naloxone 5.7 mg/1.4 mg sublingual tablet.

Acute pain

Acute pain (moderate to severe):

Note: Long-term use is not recommended. The following recommendations are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.

IR injection: IM or slow IV: Initial: 0.3 mg every 6 to 8 hours as needed; initial dose (up to 0.3 mg) may be repeated once 30 to 60 minutes after the initial dose.

Chronic pain

Chronic pain (moderate to severe):

Buccal film:

Note: Buprenorphine buccal film doses of 600, 750, and 900 mcg are only for use following titration from lower doses (maximum dose: 900 mcg every 12 hours). For patients with oral mucositis, reduce the starting dose and titration incremental dose by 50%.

Opioid-naive patients and opioid-non-tolerant patients: Initial: Buccal: 75 mcg once daily or, if tolerated, every 12 hours for ≥4 days, then increase to 150 mcg every 12 hours.

Opioid-experienced patients (conversion from other opioids to buprenorphine): Discontinue all other around-the-clock opioids when buprenorphine is initiated. Taper patient's current opioid to no more than 30 mg oral morphine sulfate equivalents daily before initiating buprenorphine. Following analgesic taper, base the initial buprenorphine dose on the patient's daily opioid dose prior to taper. Patients may require additional short-acting analgesics during the taper period.

Patients who were receiving daily dose of <30 mg of oral morphine equivalents: Initial: Buccal: Buprenorphine 75 mcg once daily or every 12 hours.

Patients who were receiving daily dose of 30 to 89 mg of oral morphine equivalents: Initial: Buccal: Buprenorphine 150 mcg every 12 hours.

Patients who were receiving daily dose of 90 to 160 mg of oral morphine equivalents: Initial: Buccal: Buprenorphine 300 mcg every 12 hours.

Patients who were receiving daily dose of >160 mg of oral morphine equivalents: Buprenorphine buccal film may not provide adequate analgesia; consider the use of an alternate analgesic.

Conversion from methadone: Close monitoring is required when converting methadone to another opioid. Ratio between methadone and other opioid agonists varies widely according to previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Dose titration (opioid-naive or opioid-experienced patients): Individually titrate in increments of 150 mcg every 12 hours, no more frequently than every 4 days, to a dose that provides adequate analgesia and minimizes adverse reactions (maximum dose: 900 mcg every 12 hours; doses up to 450 mcg every 12 hours were studied in opioid naive patients). Patients may require additional short-acting analgesics during titration.

Discontinuation of therapy: When discontinuing buccal film, use a gradual downward titration, such as decreasing the dose by no more than 10% to 25% in a physically dependent patient and continue downward titration every 2 to 4 weeks. If patient displays withdrawal symptoms, temporarily interrupt the taper or increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Transdermal patch:

Opioid-naive patients: Initial: Transdermal: 5 mcg/hour applied once every 7 days.

Opioid-experienced patients (conversion from other opioids to buprenorphine): Discontinue all other around-the-clock opioid drugs when buprenorphine therapy is initiated. Short-acting analgesics as needed may be continued until analgesia with transdermal buprenorphine is attained. There is a potential for buprenorphine to precipitate withdrawal in patients already receiving opioids.

Patients who were receiving daily dose of <30 mg of oral morphine equivalents: Initial: Transdermal: Buprenorphine 5 mcg/hour patch applied once every 7 days.

Patients who were receiving daily dose of 30 to 80 mg of oral morphine equivalents: Taper the current around-the-clock opioid for up to 7 days to ≤30 mg/day of oral morphine or equivalent before initiating therapy. Initial: Transdermal: Buprenorphine 10 mcg/hour patch applied once every 7 days.

Patients who were receiving daily dose of >80 mg of oral morphine equivalents: Buprenorphine transdermal patch, even at the maximum dose of 20 mcg/hour applied once every 7 days, may not provide adequate analgesia; consider the use of an alternate analgesic.

Dose titration (opioid-naive or opioid-experienced patients): May increase dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments (using no more than two patches), based on patient's supplemental short-acting analgesic requirements, with a minimum titration interval of 72 hours (maximum dose: 20 mcg/hour applied once every 7 days; risk for QTc prolongation increases with doses >20 mcg/hour patch).

Discontinuation of therapy: When discontinuing transdermal patch, use a gradual downward titration, such as decreasing the dose by no more than 10% to 25% in a physically dependent patient and continue downward titration every 2 to 4 weeks. If patient displays withdrawal symptoms, temporarily interrupt the taper or increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Opioid use disorder

Opioid use disorder:

Note: Prior to induction, consider type of opioid use (ie, long- or short-acting opioid) and time since last use of opioid. Patients on heroin or short-acting opioids should initiate buprenorphine when signs of opioid withdrawal occur, but no sooner than 12 hours after the last opioid use (Ref). See dosing section below on “Switching therapies” for guidance on transitioning from methadone to buprenorphine.

ER injection: SUBQ: Initial: 300 mg monthly (eg, doses ≥26 days apart) for the first 2 months, after treatment has been inducted and adjusted with 8 to 24 mg of a transmucosal buprenorphine-containing product for a minimum of 7 days. Maintenance: 100 mg monthly (eg, doses ≥26 days apart), increasing to 300 mg monthly for patients who tolerate the 100 mg dose but do not demonstrate a satisfactory clinical response (as evidenced by self-reported illicit opioid use or urine drug screens positive for illicit opioid use).

Missed dose: Administer a missed dose as soon as possible, with the following dose given no less than 26 days later; dosing delays of up to 2 weeks are not expected to impact treatment.

Extended interval dosing (only for use in select instances such as extended travel): Patients established on a maintenance dose of 100 mg monthly may receive a single 300 mg dose to cover a 2-month period followed by resumption of the 100 mg monthly dose. Patients should be cautioned about sedation and other buprenorphine-related effects due to higher peak levels following the 300 mg dose.

Transition from long-term buprenorphine transmucosal treatment: Patients established on long-term transmucosal buprenorphine 8 to 24 mg treatment and whose disease symptoms are controlled may be directly transitioned to the ER injection:

Transmucosal buprenorphine 8 to 18 mg: Initial: ER injection: SUBQ: 300 mg, followed ≥26 days later by 100 mg for the second dose; may consider 300 mg for second injection in patients still experiencing craving or withdrawal symptoms after initial 300 mg dose. Maintenance: 100 mg monthly (eg, doses ≥26 days apart).

Transmucosal buprenorphine 20 to 24 mg: Initial: ER injection: SUBQ: 300 mg monthly (eg, doses ≥26 days apart) for first 2 months. Maintenance: 100 mg monthly (eg, doses ≥26 days apart).

Subdermal implant: Insert 4 implants subdermally in the inner side of the upper arm 12 to 24 hours after last dose of transmucosal buprenorphine-containing product (Ref). Some patients may require small doses of supplemental transmucosal buprenorphine (2 mg/day) for symptom control (Ref). Remove no later than 6 months after the date of insertion; if continued treatment is desired, insert 4 new implants subdermally in the inner side of the contralateral arm. After one insertion in each arm, discontinue treatment with subdermal implants.

Converting back to sublingual tablet: On day of implant removal, resume buprenorphine treatment at previous sublingual dose.

Sublingual tablet:

Initial: 2 to 4 mg; consider an initial dose of 1 mg (using the buprenorphine and naloxone formulation) in patients with a history of opioid use disorder with a high risk of relapse but not currently dependent on opioids; titration in these patients should occur much more slowly than tolerant patients to avoid oversedation/overdose. If no signs of precipitated withdrawal after 1 to 2 hours and dose is tolerated, may increase dose in increments of 2 to 4 mg to a dose that is clinically effective and provides 24 hours of stabilization (Ref). Initial doses up to 8 mg and total day 1 doses up to 32 mg have been safely used in emergency department settings (Ref).

Maintenance: After the first day of treatment, maintain total daily dose from day 1 and adjust dose in increments of 4 mg to a level that maintains treatment and suppresses opioid withdrawal symptoms. Doses ≥16 mg/day have been associated with greater efficacy; limited evidence exists for doses >24 mg/day. In patients with pain, temporarily increasing the dose by 20% to 25% or dosing frequency (eg, divide total daily dose over 3 to 4 times per day) may maximize the analgesic properties for pain management (Ref). Buprenorphine may be safely dosed 2 or 3 times a week instead of once daily when more convenient dosing schedules are needed; divide the total weekly dose over 2 or 3 days per week (Ref).

Discontinuation of therapy: When discontinuing sublingual buprenorphine for long-term treatment of opioid use disorder, use a gradual downward titration of the dose over several months to prevent withdrawal; do not abruptly discontinue (Ref).

Switching therapies:

Buprenorphine to methadone: No time delay is required (Ref).

Methadone to buprenorphine: Taper the methadone dose gradually to 30 to 40 mg per day and remain on that dose for ≥7 days. The patient should be in mild withdrawal before starting buprenorphine; this is typically 24 to 48 hours after the last dose of methadone. Initiating buprenorphine at lower doses (eg, 2 mg) decreases risk of precipitated methadone withdrawal (Ref).

Buprenorphine to naltrexone: Taper the buprenorphine dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone. A naloxone challenge may be used to demonstrate an absence of physical dependence (Ref).

Naltrexone to buprenorphine: Begin buprenorphine ~1 day following last dose of oral naltrexone and ~28 days following last dose of IM naltrexone (Ref).

Opioid withdrawal in heroin-dependent hospitalized patients

Opioid withdrawal in heroin-dependent hospitalized patients (off-label use): IR injection: IV infusion: 0.3 to 0.9 mg (diluted in 50 to 100 mL of NS) over 20 to 30 minutes every 6 to 12 hours (Ref).

Perineural anesthesia

Perineural anesthesia (off-label use): IR perineural injection: 200 to 300 mcg added to local anesthetic (eg, bupivacaine, mepivacaine, tetracaine) with or without epinephrine and administered as a single injection (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been adequately studied); use with caution. In pharmacokinetic studies, renal impairment (including administration pre- or post-hemodialysis) was not associated with increased buprenorphine plasma concentrations.

Dosing: Hepatic Impairment: Adult

Buccal film:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): No dosage adjustment necessary; use caution and monitor for signs and symptoms of toxicity or overdose.

Severe impairment (Child-Pugh class C): Reduce starting dose and reduce titration dose by 50% (ie, from 150 mcg to 75 mcg).

ER injection (SUBQ):

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.

Moderate to severe impairment: Use is not recommended. If signs and symptoms of hepatic impairment occur within 2 weeks of injection, removal of depot may be required. In the event the depot from an ER injection must be removed, it can be surgically excised under local anesthesia within 14 days of injection. See prescribing information for details. Monitor for signs and symptoms of toxicity or overdose.

IR injection (IM, IV):

Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, need for dosage adjustment is unlikely as systemic exposure following IV buprenorphine in these patients was similar to healthy subjects.

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Subdermal implant:

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Moderate or severe impairment: Use is not recommended.

Sublingual tablet:

Mild impairment: No dosage adjustment necessary.

Moderate impairment: No dosage adjustment necessary; use caution and monitor for signs and symptoms of toxicity or overdose.

Severe impairment: Consider reducing initial and titration incremental dose by 50%; monitor for signs and symptoms of toxicity or overdose.

Transdermal patch:

Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, need for dosage adjustment is unlikely as systemic exposure following IV buprenorphine in these patients was similar to that observed in healthy subjects.

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); consider alternative therapy with more flexibility for dosing adjustments.

Dosing: Pediatric

(For additional information see "Buprenorphine: Pediatric drug information")

Acute pain

Acute pain (moderate to severe): Dose should be titrated to appropriate effect. The following recommendations are guidelines and do not represent the maximum doses that may be required in all patients.

Children 2 to 12 years: IM, slow IV injection: Initial: Opioid-naive: 2 to 6 mcg/kg/dose every 4 to 6 hours (Ref); Note: Not all children have faster clearance rates than adults; some children may require dosing intervals of every 6 to 8 hours; observe clinical effects to establish the proper dosing interval.

Adolescents: IM, slow IV injection: Initial: Opioid-naive: 0.3 mg every 6 to 8 hours as needed; initial dose may be repeated once in 30 to 60 minutes if clinically needed

Chronic pain

Chronic pain (moderate to severe): Adolescents ≥18 years: Transdermal patch:

Opioid-naive patients: Initial: 5 mcg/hour applied once every 7 days

Opioid-experienced patients (conversion from other opioids to buprenorphine patch): Discontinue all other around-the-clock opioid drugs when buprenorphine therapy is initiated. Short-acting analgesics as needed may be continued until analgesia with transdermal buprenorphine is attained. There is a potential for buprenorphine to precipitate withdrawal in patients already receiving opioids.

Patients who were receiving daily dose of <30 mg of oral morphine equivalents: Initial: 5 mcg/hour applied once every 7 days

Patients who were receiving daily dose of 30 to 80 mg of oral morphine equivalents: Taper the current around-the-clock opioid for up to 7 days to ≤30 mg/day of oral morphine or equivalent before initiating therapy. Initial: 10 mcg/hour applied once every 7 days.

Patients who were receiving daily dose of >80 mg of oral morphine equivalents: Buprenorphine transdermal patch, even at the maximum dose of 20 mcg/hour applied once every 7 days, may not provide adequate analgesia; consider the use of an alternate analgesic.

Dose titration (opioid-naive or opioid-experienced patients): May increase dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments (using no more than two 5 mcg/hour patches); titrate no more frequently than every 72 hours; maximum dose: 20 mcg/hour applied once every 7 days due to risk of QTc prolongation associated with higher doses.

Discontinuation of therapy: Taper dose gradually every 7 days to prevent withdrawal in the physically dependent patient; consider initiating immediate-release opioids, if needed for signs and symptoms of withdrawal.

Opioid dependence

Opioid dependence: Note: Do not start induction with buprenorphine until objective and clear signs of withdrawal are apparent (otherwise withdrawal may be precipitated).

Sublingual tablet: Note: The combination product, buprenorphine and naloxone, is preferred therapy over buprenorphine monotherapy for induction treatment (and stabilization/maintenance treatment) for short-acting opioid dependence (Ref).

American Society of Addiction Medicine Guidelines (Ref): Limited data available: Adolescents: Sublingual tablet:

Note: Buprenorphine treatment initiation should begin after mild to moderate opioid withdrawal signs appear (to avoid precipitated withdrawal), which is generally at least 6 to 12 hours after last use of short-acting opioids (eg, heroin, oxycodone) and 24 to 72 hours after last use of long-acting opioids (methadone).

Induction: Initial: 2 to 4 mg; if no signs of precipitated withdrawal after 60 to 90 minutes, may increase in increments of 2 to 4 mg. Once initial dose is tolerated, may increase to a dose that is clinically effective and provides 24 hours of stabilization.

After induction and titration, daily dose usually ≥8 mg/day are necessary. In patients continuing to use opioids, consider increasing the dose by 4 to 8 mg to a daily dose of ≥12 to 16 mg/day. Maximum daily dose 24 mg/day.

Manufacturer's labeling: Adolescents ≥16 years:

Induction: Day 1: 8 mg/day divided in 2 to 4 mg increments; day 2 and subsequent induction days dose dependent upon patient response. In 1 study, patients received 8 mg on day 1, followed by 16 mg on day 2; induction usually accomplished over 3 to 4 days. Treatment should begin only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after last use of heroin or other short-acting opioids or not less than 24 hours after last use of methadone or other long-acting opioids. Titrating dose to clinical effectiveness should be done as rapidly as possible to prevent undue withdrawal symptoms and patient drop-out during the induction period.

Maintenance: Target dose: 16 mg/day; reported range: 4 to 24 mg/day; doses higher than 24 mg/day have not been demonstrated to provide any clinical advantage; patients should be switched to the buprenorphine/naloxone combination product for maintenance and unsupervised therapy

Subdermal implant: Adolescents ≥16 years: Insert 4 implants subdermally in the inner side of the upper arm. Remove no later than 6 months after the date of insertion; if continued treatment is desired, insert 4 new implants subdermally in the inner side of the contralateral arm. After 1 insertion in each arm, discontinue treatment with subdermal implants.

To convert back to sublingual tablet: On day of implant removal, resume buprenorphine treatment at previous sublingual dose

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling (has not been studied); use with caution. In pharmacokinetic studies, renal impairment (including administration pre- or posthemodialysis) was not associated with increased buprenorphine plasma concentrations.

Dosing: Hepatic Impairment: Pediatric

Injection (immediate release): Children ≥2 years and Adolescents: Use caution due to extensive hepatic metabolism; dosage adjustments may be necessary.

Subdermal implant: Adolescents ≥16 years:

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Moderate or severe impairment: Use is not recommended.

Dosing: Older Adult

Refer to adult dosing; use caution and titrate slowly due to potential for increased risk of adverse effects.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Film, Buccal:

Belbuca: 75 mcg (1 ea, 60 ea); 150 mcg (1 ea, 60 ea); 300 mcg (1 ea, 60 ea); 450 mcg (1 ea, 60 ea); 600 mcg (1 ea, 60 ea); 750 mcg (1 ea, 60 ea); 900 mcg (1 ea, 60 ea) [contains methylparaben, propylparaben, saccharin sodium, sodium benzoate; peppermint flavor]

Implant, Subcutaneous, as hydrochloride:

Probuphine Implant Kit: 74.2 mg (4 ea [DSC])

Patch Weekly, Transdermal:

Butrans: 5 mcg/hr (4 ea); 7.5 mcg/hr (4 ea); 10 mcg/hr (4 ea); 15 mcg/hr (4 ea); 20 mcg/hr (4 ea)

Generic: 5 mcg/hr (1 ea, 4 ea); 7.5 mcg/hr (1 ea, 4 ea); 10 mcg/hr (1 ea, 4 ea); 15 mcg/hr (1 ea, 4 ea); 20 mcg/hr (1 ea, 4 ea)

Solution, Injection, as hydrochloride:

Buprenex: 0.3 mg/mL (1 mL)

Generic: 0.3 mg/mL (1 mL)

Solution, Injection, as hydrochloride [preservative free]:

Generic: 0.3 mg/mL (1 mL)

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Sublocade: 100 mg/0.5 mL [extended-release] (0.5 mL); 300 mg/1.5 mL [extended-release] (1.5 mL) [contains methylpyrrolidone, polylactide-coglycolide]

Tablet Sublingual, Sublingual, as hydrochloride:

Generic: 2 mg, 8 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms Considerations

Note: Subdermal implant and subcutaneous implant both refer to Probuphine.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Film, Buccal:

Belbuca: 75 mcg ([DSC]); 150 mcg ([DSC]); 300 mcg ([DSC]); 450 mcg ([DSC]) [contains methylparaben, propylparaben, saccharin sodium, sodium benzoate]

Implant, Subcutaneous, as hydrochloride:

Probuphine: 74.2 mg (4 ea)

Patch Weekly, Transdermal:

BuTrans 5: 5 mcg/hr (4 ea)

BuTrans 10: 10 mcg/hr (4 ea)

BuTrans 15: 15 mcg/hr (4 ea)

BuTrans 20: 20 mcg/hr (4 ea)

Solution Prefilled Syringe, Subcutaneous:

Sublocade: 100 mg/0.5 mL [extended-release] (0.5 mL); 300 mg/1.5 mL [extended-release] (1.5 mL)

Tablet Sublingual, Sublingual, as hydrochloride:

Subutex: 2 mg, 8 mg

Controlled Substance

C-III

Prescribing and Access Restrictions

Extended-release injection: Prescribing of the extended release injection is limited to healthcare providers who meet qualifying requirements, have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number to include on every prescription.

Subdermal implant: Prescribing of implants and inserting or removing implants are limited to healthcare providers who have completed a live training program. Additionally, inserting or removing implants is limited to healthcare providers who have demonstrated procedural competency. As a prerequisite for participating in the live training program, the healthcare provider must have performed at least one qualifying surgical procedure in the last 3 months. Qualifying procedures are those performed under local anesthesia using aseptic technique and include, at a minimum, making skin incisions or placing sutures. Buprenorphine subdermal implant will only be distributed to certified prescribers through a restricted distribution program. Information concerning the insertion and removal procedures can be obtained by calling 1-844-859-6341.

Sublingual tablet: Prescribing of tablets for opioid dependence is limited to physicians who have met the qualification criteria and have received a DEA number specific to prescribing this product. Tablets will be available through pharmacies and wholesalers which normally provide controlled substances.

Administration: Adult

Buccal: Prior to placing the film, moisten inside of cheek with tongue or water. Apply film with a dry finger immediately after removing it from packaging. Place yellow side of film against the inside of the moistened cheek; press and hold the film in place for 5 seconds with finger (film should stay in place after this period). Keep film in place until it dissolves completely (usually within 30 minutes of application). Do not chew, swallow, touch, or move film after placement. Once film is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth. Avoid eating or drinking until film dissolves. Do not cut or tear the film. Avoid application to areas of the mouth with any open sores or lesions. To dispose of film; remove foil overwrap from any unused, unneeded films and dispose by flushing down the toilet (if a drug take-back option is not readily available).

IM: Administer IR injection via deep IM injection.

IV: Administer IR injection slowly, over at least 2 minutes. Administration over 20 to 30 minutes preferred when managing opioid withdrawal in heroin-dependent hospitalized patients (Ref).

Sublingual tablet: Tablet should be placed under the tongue until dissolved (can take up to 10 minutes to fully dissolve (Ref)); should not be cut, chewed, or swallowed (swallowing tablets before dissolved reduces bioavailability). If 2 or more tablets are needed per dose, all may be placed under the tongue at once, or 2 at a time. To ensure consistent bioavailability, subsequent doses should always be taken the same way. Once tablet is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth.

SUBQ: Administer ER injection as an abdominal SUBQ injection only, using only the syringe and safety needle included with product. Do not administer IV, IM, or intradermally. Inject between the transpyloric and transtubercular planes in an area with adequate SUBQ tissue that is free of skin conditions (eg, nodules, lesions, excessive pigment). Rotate the injection site between injections. Subsequent precipitation following injection results in a solid depot which will gradually release buprenorphine. The patient may have a lump for several weeks that will decrease over time; advise not to rub or massage the injection site. Wipe any blood or fluid at injection site with a cotton ball or gauze prior to applying a gauze pad or bandage (use minimal pressure when applying). In the event the depot from an ER injection must be removed, it can be surgically excised under local anesthesia within 14 days of injection. See prescribing information for details.

Subdermal implant: For insertion under local anesthesia by health care providers trained in the insertion and removal procedure through the REMS program. See prescribing information for details.

Transdermal patch: Remove patch from protective pouch immediately before application. Apply patch to intact, nonirritated skin only. Apply to a hairless or nearly hairless skin site. If hairless site is not available, do not shave skin; hair at application site should be clipped. Prior to application, if the site must be cleaned, clean with clear water and allow to dry completely; do not use soaps, alcohol, oils, lotions, or abrasives due to potential for increased skin absorption. Do not use any patch that has been damaged, cut or manipulated in any way. Remove the protective backing and apply the sticky side of the patch to one of eight possible application sites (upper outer arm, upper chest, upper back or the side of the chest [each site on either side of the body]). Up to 2 patches may be applied at the same time adjacent to one another at the same application site. Firmly press patch in place and hold for ~15 seconds. Change patch every 7 days. Rotate patch application sites whenever a patch is replaced or added; wait ≥21 days before reapplying another patch to the same skin site. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub). Incidental exposure to water while bathing or showering is acceptable based on experience during clinical studies. If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape. If ineffective, the system may be covered with waterproof or semipermeable adhesive dressings suitable for 7 days of wear. If the patch falls off during the 7-day dosing interval, dispose of the patch and apply a new patch to a different skin site. Dispose of patches using the Patch-Disposal Unit or by folding the adhesive sides of the patch together and then flushing down the toilet. In Canada, disposal via a pharmacy take back program is recommended; trash disposal is not advised.

Administration: Pediatric

Oral:

Sublingual solution: Neonates: Place dose under tongue; insert pacifier to help reduce swallowing of dose (Ref)

Sublingual tablet: Adolescents ≥16 years: Place tablet under the tongue until dissolved; do not chew or swallow (swallowing tablets before dissolved reduces bioavailability). If 2 or more tablets are needed per dose, all tablets may be placed under the tongue at once, or 2 tablets may be placed under the tongue at a time; to ensure consistent bioavailability, subsequent doses should always be taken the same way. Once tablet is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth.

Parenteral:

Immediate-release injection: Children ≥2 years and Adolescents:

IM: Administer via deep IM injection

IV: Administer slowly, over at least 2 minutes

Subdermal/Topical:

Subdermal implant: Adolescents ≥16 years: For insertion under local anesthesia by health care providers trained in the insertion and removal procedure through the REMS program. See prescribing information for details.

Transdermal patch: Adolescents ≥18 years: Apply patch to intact, nonirritated skin only. Apply to a hairless or nearly hairless skin site. If hairless site is not available, do not shave skin (as absorption from patch can be increased); hair at application site should be clipped. Prior to application, if the site must be cleaned, clean with clear water and allow to dry completely; do not use soaps, alcohol, lotions, or abrasives due to potential for increased skin absorption. Do not use any patch that has been damaged, cut, or manipulated in any way. Remove patch from protective pouch immediately before application. Remove the protective backing and apply the sticky side of the patch to 1 of 8 possible application sites (upper outer arm, upper chest, upper back, or the side of the chest [each site on either side of the body]). Up to 2 patches may be applied at the same time adjacent to one another at the same application site. Firmly press patch in place and hold for ~15 seconds. Change patch every 7 days. Rotate patch application sites whenever a patch is replaced or added; wait ≥21 days before reapplying another patch to the same skin site. Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub). Incidental exposure to water while bathing or showering is acceptable based on experience during clinical studies. If there is difficulty with patch adhesion, the edges of the system may be taped in place with first-aid tape. If the patch falls off during the 7-day dosing interval, dispose of the patch and apply a new patch to a different skin site. Dispose of patches using the Patch-Disposal Unit or by folding the adhesive sides of the patch together and then flushing down the toilet.

Use: Labeled Indications

Opioid use disorder:

Extended-release injection: Maintenance treatment of moderate to severe opioid use disorder in patients who have initiated treatment with 8 to 24 mg of a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

Subdermal implant: Maintenance treatment of opioid use disorder in patients who have achieved and sustained prolonged clinical stability on low to moderate doses (≤8 mg/day) of a transmucosal buprenorphine-containing product for 3 months or longer with no need for supplemental dosing or adjustments

Sublingual tablet: Medically supervised withdrawal and maintenance treatment of opioid use disorder.

Limitations of use: Buprenorphine should be used as part of a complete treatment program to include counseling and psychosocial support.

Pain management:

Buccal film, transdermal patch: Management of pain severe enough to require around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Immediate-release injection: Management of pain severe enough to require an opioid analgesic and for which treatments are inadequate

Limitations of use: Reserve buprenorphine for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Buprenorphine buccal film and transdermal patch are not indicated as an as needed analgesic.

Use: Off-Label: Adult

Opioid withdrawal in heroin-dependent hospitalized patients (IR injection); Perineural anesthesia

Medication Safety Issues
Sound-alike/look-alike issues:

Buprenex may be confused with Brevibloc, Bumex

Buprenorphine may be confused with HYDROmorphone

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Buccal film:

1% to 10%:

Cardiovascular: Hypertension (1% to <5%), peripheral edema (1% to <5%)

Dermatologic: Hyperhidrosis (1% to <5%), pruritus (1% to <5%), skin rash (1% to <5%)

Endocrine & metabolic: Hot flash (1% to <5%)

Gastrointestinal: Abdominal pain (1% to <5%), constipation (3% to ≥5%), decreased appetite (1% to <5%), diarrhea (≥5%), gastroenteritis (1% to <5%), nausea (9% to 10%), vomiting (4% to ≥5%), xerostomia (≥5%)

Genitourinary: Urinary tract infection (1% to <5%)

Hematologic & oncologic: Anemia (1% to <5%), bruise (1% to <5%)

Nervous system: Anxiety (1% to <5%), depression (1% to <5%), dizziness (2% to ≥5%), drowsiness (1% to ≥5%), falling (1% to <5%), fatigue (≥5%), headache (4% to ≥5%), insomnia (1% to <5%), opioid withdrawal syndrome (1% to <5%)

Neuromuscular & skeletal: Back pain (1% to <5%), muscle spasm (1% to <5%)

Respiratory: Bronchitis (1% to <5%), nasopharyngitis (1% to <5%), oropharyngeal pain (1% to <5%), paranasal sinus congestion (1% to <5%), sinusitis (1% to <5%), upper respiratory tract infection (≥5%)

Miscellaneous: Fever (1% to <5%)

<1%:

Cardiovascular: Atrial fibrillation, cerebrovascular accident, chest pain, coronary artery disease, prolonged QT interval on ECG, transient ischemic attacks, syncope

Dermatologic: Cellulitis, excoriation of skin

Endocrine & metabolic: Decreased plasma testosterone, dehydration

Gastrointestinal: Abdominal distress, cholecystitis, dyspepsia, intestinal obstruction, toothache

Hepatic: Abnormal hepatic function tests, increased serum aspartate aminotransferase

Infection: Tooth abscess

Nervous system: Chills, hypoesthesia, lethargy, migraine, noncardiac chest pain

Neuromuscular & skeletal: Asthenia, bone fracture, musculoskeletal pain, neck pain, osteoarthritis, tremor

Respiratory: Acute sinusitis, cough, dyspnea, nasal congestion, pneumonia, rhinorrhea

Miscellaneous: Laceration

Implant:

>10%:

Local: Local pain (13%; at implant site), local pruritus (12%; at implant site)

Nervous system: Headache (13%)

1% to 10%:

Cardiovascular: Chest pain (1%)

Dermatologic: Excoriation (1% to 2%; including scratch), localized erythema (10%; at implant site), skin lesion (1%), skin rash (2%)

Gastrointestinal: Constipation (6%), flatulence (1%), nausea (6%), toothache (5%), upper abdominal pain (3%), vomiting (6%)

Hematologic & oncologic: Local hemorrhage (7%; at implant site)

Local: Localized edema (5%; at implant site), local swelling (1%)

Nervous system: Chills (2%), depression (6%), dizziness (4%), drowsiness (3%), fatigue (3%), migraine (2%), pain (4%), paresthesia (1%), sedated state (1%), sensation of cold (1%)

Neuromuscular & skeletal: Asthenia (2%), back pain (6%), limb pain (3%)

Respiratory: Cough (3%), dyspnea (1%), oropharyngeal pain (5%)

Miscellaneous: Fever (3%), laceration (3%)

<1%:

Nervous system: Opioid withdrawal syndrome

Respiratory: Respiratory depression

Injection:

>10%: Nervous system: Sedated state (≤66%)

1% to 10%:

Cardiovascular: Hypotension (1% to 5%)

Dermatologic: Diaphoresis (1% to 5%), injection site pruritus (6% to 10%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (3% to 4%)

Gastrointestinal: Constipation (8% to 9%), nausea (5% to 10%), vomiting (1% to 9%)

Hepatic: Increased serum alanine aminotransferase (1% to 5%), increased serum aspartate aminotransferase (3% to 5%)

Local: Bruising at injection site (1%), erythema at injection site (3% to 4%), induration at injection site (1%), pain at injection site (5% to 6%), swelling at injection site (≤1%)

Nervous system: Dizziness (2% to 10%), drowsiness (2% to 5%), fatigue (4% to 6%), headache (1% to 9%), vertigo (5% to 10%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (3% to 5%)

Ophthalmic: Miosis (1% to 5%)

Respiratory: Hypoventilation (1% to 5%)

<1%:

Cardiovascular: Bradycardia, flushing, Mobitz type I second degree atrioventricular block, tachycardia

Dermatologic: Pallor

Gastrointestinal: Diarrhea, xerostomia

Genitourinary: Urinary retention

Local: Cellulitis at injection site, injection site reaction

Nervous system: Abnormal dreams, agitation, confusion, depersonalization, depression, dysphoria, euphoria, local discomfort, localized warm feeling, nervousness, opioid withdrawal syndrome, sensation of cold, slurred speech

Ophthalmic: Amblyopia, blurred vision, conjunctivitis, diplopia, visual disturbance

Otic: Tinnitus

Respiratory: Apnea, cyanosis, dyspnea, respiratory depression

Sublingual tablet:

>10%:

Dermatologic: Diaphoresis (13%)

Gastrointestinal: Abdominal pain (12%), nausea (14%)

Infection: Infection (12%)

Nervous system: Headache (29%), insomnia (21%)

1% to 10%: Gastrointestinal: Constipation (8%), vomiting (8%)

<1%:

Nervous system: Opioid withdrawal syndrome

Respiratory: Respiratory depression

Transdermal patch:

>10%:

Gastrointestinal: Constipation (3% to 13%), nausea (6% to 21%)

Local: Application-site pruritus (5% to 15%)

Nervous system: Dizziness (2% to 15%), drowsiness (2% to 13%), headache (3% to 14%)

1% to 10%:

Cardiovascular: Chest pain (<5%), hypertension (<5%), peripheral edema (1% to <5%)

Dermatologic: Hyperhidrosis (1% to <5%), pruritus (1% to 5%), skin rash (1% to <5%)

Gastrointestinal: Anorexia (1% to <5%), diarrhea (1% to <5%), dyspepsia (1% to <5%), upper abdominal pain (1% to <5%), stomach discomfort (2%), vomiting (≤9%), xerostomia (≥5% to 6%)

Genitourinary: Urinary tract infection (1% to <5%)

Infection: Influenza (1% to <5%)

Local: Application site erythema (5% to 10%), application site irritation (1% to 6%), application site rash (5% to 8%)

Nervous system: Anxiety (1% to <5%), depression (1% to <5%), falling (1% to <5%), fatigue (≤5%), hypoesthesia (1% to <5%), insomnia (<5%), migraine (1% to <5%), pain (1% to <5%), paresthesia (1% to <5%)

Neuromuscular & skeletal: Arthralgia (1% to <5%), asthenia (1% to <5%), back pain (1% to <5%), joint swelling (1% to <5%), limb pain (1% to <5%), muscle spasm (1% to <5%), musculoskeletal pain (1% to <5%), myalgia (1% to <5%), neck pain (1% to <5%), tremor (1% to <5%)

Respiratory: Bronchitis (1% to <5%), cough (1% to <5%), dyspnea (1% to <5%), nasopharyngitis (1% to <5%), pharyngolaryngeal pain (1% to <5%), sinusitis (1% to <5%), upper respiratory tract infection (1% to <5%)

Miscellaneous: Fever (1% to <5%)

<1%:

Cardiovascular: Angina pectoris, facial edema, flushing, hypotension, increased blood pressure, orthostatic hypotension, palpitations, syncope, tachycardia, vasodilation

Dermatologic: Contact dermatitis, xeroderma

Endocrine & metabolic: Decreased libido, dehydration, hot flash, weight loss

Gastrointestinal: Abdominal distention, abdominal pain diverticulitis of the gastrointestinal tract, dysgeusia, dysphagia, flatulence, hiccups, intestinal obstruction

Genitourinary: Sexual disorder, urinary hesitancy, urinary incontinence, urinary retention

Hepatic: Increased serum alanine aminotransferase

Local: Application-site dermatitis

Nervous system: Abnormal gait, agitation, apathy, ataxia, chills, confusion, decreased mental acuity, depressed mood, disorientation, disturbance in attention, dysarthria, emotional lability, euphoria, hallucination, loss of consciousness, malaise, memory impairment, mental status changes, myasthenia, nightmares, opioid withdrawal syndrome, psychosis, restlessness, sedated state, vertigo

Ophthalmic: Miosis, visual disturbance, xerophthalmia

Otic: Tinnitus

Respiratory: Changes in respiration, exacerbation of asthma, hyperventilation, hypoventilation, respiratory depression, respiratory distress, respiratory failure, rhinitis, wheezing

Miscellaneous: Accidental injury

Postmarketing (any route):

Dermatologic: Pruritus, skin necrosis (following inadvertent dermal injection of extended release SUBQ injection) (Crouse 2021), skin rash, urticaria

Gastrointestinal: Dental caries (including tooth fracture, tooth loss; buccal, sublingual) (FDA 2022), gallbladder disease (intracholedochal pressure), glossalgia, glossitis, infection of mouth (including tooth infection; buccal, sublingual) (FDA 2022), oral hypoesthesia, oral mucosal erythema, stomatitis

Genitourinary: Hypogonadism

Hepatic: Hepatic encephalopathy, hepatic failure, hepatic necrosis, hepatitis (including cytolytic), hepatorenal syndrome, increased serum transaminases, jaundice

Hypersensitivity: Anaphylactic shock, angioedema, hypersensitivity reaction

Local: Application site burning, application site discharge, application site reaction, application site vesicles

Nervous system: Coma, drug dependence (physical dependence), seizure

Respiratory: Bronchospasm

Contraindications

Hypersensitivity (eg, anaphylaxis) to buprenorphine or any component of the formulation.

Buccal film, IR injection, transdermal patch: Additional contraindications: Significant respiratory depression; acute or severe asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected).

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Acute respiratory depression; hypercapnia; cor pulmonale; acute alcoholism or current physiological alcohol dependence; delirium tremens; convulsive disorders; severe CNS depression; increased cerebrospinal or intracranial pressure; head injury; severe hepatic insufficiency.

Buccal film, transdermal patch: Additional contraindications: Hypersensitivity to other opioids; suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild, intermittent or short duration pain that can otherwise be managed; management of acute pain, including use in outpatient or day surgeries; management of perioperative pain relief, or in other situations characterized by rapidly varying analgesic requirements; obstructive airway (other than asthma); status asthmaticus; concurrent use or use within 14 days of monoamine oxidase inhibitors (MAOIs); myasthenia gravis; patients with opioid use disorder and for opioid withdrawal treatment; pregnancy or during labor and delivery; breastfeeding; known or suspected oral mucositis (buccal film only).

ER injection: Additional contraindications: Suspected surgical abdomen (eg, acute appendicitis or pancreatitis); obstructive airway (other than asthma); status asthmaticus; concurrent use with or within 14 days of MAOIs; known or suspected GI obstruction (bowel obstruction or stricture) or any condition affecting bowel transit (ileus of any type); congenital long QT syndrome or QTc prolongation at baseline; uncorrected hypokalemia, hypomagnesemia, hypocalcemia.

Subdermal implant: Additional contraindications: Severe respiratory insufficiency, opioid-naive patients, known or suspected GI obstruction or any condition affecting bowel transit, congenital long QT prolongation or QTc prolongation at baseline, uncorrected hypokalemia, hypomagnesemia, hypocalcemia.

Warnings/Precautions

Concerns related to adverse effects:

• Accidental opioid overdose: Patients who had been treated with buprenorphine may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Patients should be aware that they may be more sensitive to lower doses of opioids after treatment with buprenorphine, after a missed dose, or near the end of the dosing interval.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Hepatic events: Hepatitis has been reported; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic impairment. Remove buprenorphine subdermal implant if signs and symptoms of buprenorphine toxicity develop concurrent with hepatic impairment. If signs and symptoms of toxicity or overdose occur within 2 weeks of extended-release injection, removal of the depot may be required.

• Hypersensitivity reactions: Hypersensitivity, including bronchospasm, angioneurotic edema, and anaphylactic shock, have been reported. The most common symptoms include rash, hives, and pruritus.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• Infection: Subdermal implant: Infection may occur at site of insertion or removal, with excessive palpation shortly after insertion and improper removal increasing the risk.

• QT prolongation: Buprenorphine has been observed to cause QTc prolongation. Do not exceed a dose of 900 mcg every 12 hours buccal film or one 20 mcg/hour transdermal patch. Avoid using in patients with a personal or family history of long QT syndrome or in patients taking concurrent class IA or III antiarrhythmics or other medications that prolong the QT interval. Use with caution in patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable heart failure, unstable atrial fibrillation, symptomatic bradycardia, or active MI.

• Respiratory depression: Buccal film, ER and IR injection, transdermal patch: Serious, life-threatening, or fatal respiratory depression may occur. Misuse by self-injection of buprenorphine or the concomitant use of buprenorphine and benzodiazepines (or other CNS depressants, including alcohol) may result in coma or death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. If the ER injection is discontinued due to respiratory depression, monitor the patient for ongoing respiratory depression for several months due to its ER characteristics. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause adrenal insufficiency (nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low BP) or secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.

• Bowel obstruction: Use with caution in patients with a history of ileus or bowel obstruction; buccal film, IR injection, and transdermal patch are contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma because these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Dermatological conditions: Subdermal implant: Use subdermal implants with caution in patients with a history of keloid formation, connective tissue disease (ie, scleroderma), or history of recurrent MRSA infections.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

• Hepatic impairment: Use buccal film and sublingual tablet with caution in patients with moderate hepatic impairment; dosage adjustment recommended in severe hepatic impairment. Use IR injection with caution in patients with severe impairment. Subdermal implants should not be used in patients with preexisting moderate to severe hepatic impairment. Transdermal patch should not be used in patients with severe hepatic impairment; consider alternative therapy with more flexibility for dosing adjustments. Patients with preexisting moderate or severe hepatic impairment are not candidates for the ER injection. If moderate or severe impairment develops during treatment with the ER injection, continue with caution and monitor for toxicity for several months.

• Obesity: Use with caution in patients who are morbidly obese.

• Oral mucositis: Buccal film: Oral mucositis may lead to more rapid absorption and higher buprenorphine plasma levels; reduce dose in patients with oral mucositis and monitor closely for signs and symptoms of toxicity or overdose.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizure: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines and other CNS depressants: Concomitant use of benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death. Prohibiting medication-based opioid use disorder treatment may increase the risk of morbidity and mortality, therefore, patients should be educated on the risks of concomitant use with benzodiazepines, sedatives, opioid analgesics, and alcohol. Strategies should be developed to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of or during treatment with buprenorphine; adjustments to induction procedures and additional monitoring may be required. If appropriate, delay or omit buprenorphine dose if a patient is sedated at time of buprenorphine dosing. Discontinuation of benzodiazepines or other CNS depressants is preferred; gradual tapering of benzodiazepine or other CNS depressant, decreasing to lowest effective dose, or monitoring in a higher level of care for taper may be appropriate. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids. Benzodiazepines are not the treatment of choice for anxiety or insomnia for patients in buprenorphine treatment; make sure patients are appropriately diagnosed and consider alternative medications for anxiety and insomnia prior to coadministration of benzodiazepines and buprenorphine.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for life-threatening respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Older adult: Use with caution in elderly patients; may be more sensitive to adverse effects (eg, life-threatening respiratory depression). In chronic pain, monitor opioid use closely in this age group due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: Buccal film, ER and IR injection, transdermal patch: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome; signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Buccal film/sublingual tablet: Dental adverse events, including cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and sometimes total tooth loss, have been reported with the buccal film and sublingual tablets. Cases may be severe and have occurred in patient without prior dental problems. Tooth extraction, root canal, dental surgery, and other restorative procedures (eg, fillings, crowns, implants, dentures) may be required for treatment. Educate patients on the importance of regular dental appointments and dental hygiene.

• ER injection: Injection-site reactions (eg, pain, erythema, pruritus), some resulting in abscess, ulceration, or necrosis, have been reported; may require surgical intervention and/or discontinuation of the ER injection. Risk may be increased with inadvertent IM or intradermal administration. Administer via SUBQ route only; do not administer IM, IV, or intradermally.

• Transdermal patch: Avoid exposure of application site and surrounding area to direct external heat sources (eg, heating pads, electric blankets, heat or tanning lamps, hot baths/saunas, hot water bottles, direct sunlight). Buprenorphine release from the patch is temperature-dependent and may result in overdose. Patients who experience fever or increase in core temperature should be monitored closely and adjust dose if signs of respiratory depression or CNS depression occur. Application-site reactions, including rare cases of severe reactions (eg, vesicles, discharge, "burns"), have been observed with use; onset varies from days to months after initiation; patients should be instructed to report severe reactions promptly and discontinue therapy.

Special handling:

• Disposal:

- ER injection and subdermal implant: Handle the removed depots or implants with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

- Transdermal patch: To properly dispose of transdermal patch, fold it over on itself and flush down the toilet immediately (if a drug take-back option is not readily available); alternatively, seal the used patch in the provided Patch-Disposal Unit and dispose of in the trash.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent to opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of opioid agonist/antagonist analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Withdrawal signs and symptoms will be delayed in patients who discontinue the ER injection or have it removed; transmucosal buprenorphine may be needed to treat withdrawal in these patients. Tablets, which are used for induction treatment of opioid use disorder, should not be started until objective and clear signs of moderate withdrawal are evident. If subdermal implants are not immediately replaced in contralateral arm after removal, maintain patients on their previous dosage of sublingual buprenorphine.

• Abuse/misuse/diversion: Buccal film, ER and IR injection, transdermal patch: Use with caution in patients with a history of substance use disorder; potential for opioid use disorder exists. Other factors associated with an increased risk for misuse include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]). The misuse of buccal film by swallowing or of transdermal patch by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death.

• Acute pain: When using buprenorphine for treatment of opioid use disorder, treat acute pain with nonopioid analgesics whenever possible. If treatment with a high-affinity full opioid analgesic is required, monitor closely for respiratory depression because high doses may be necessary to achieve pain relief.

• Appropriate use: Buccal film and transdermal patch are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment; should not be used for as-needed pain relief. Therapy with the buccal film, IR injection, or transdermal patch is not appropriate for use in the management of opioid use disorder. When used for chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment) in outpatient setting in adults, opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 MME/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).

• Appropriate use: Subdermal implant: Not appropriate for patients who are new to treatment or have not sustained prolonged clinical stability on buprenorphine ≤8 mg/day.

• Discontinuation of therapy: ER injection and sublingual tablet: There is no maximum recommended duration for maintenance treatment of opioid use disorder; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-based opioid use disorder treatment. If the ER injection is discontinued or the depot is removed, monitor the patient for several months for signs and symptoms of withdrawal. After steady-state has been achieved (4 to 6 months), patients discontinuing ER injections may have detectable plasma and urine levels of buprenorphine for 12 months or longer.

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

• Optimal pain regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Partial opioid agonist and mixed opioid agonist/antagonist overdose: Reversal of partial opioid agonists or mixed opioid agonist/antagonists (eg, buprenorphine, pentazocine) may be incomplete and higher than normal doses and repeated administration of naloxone may be required.

• Surgery: In patients undergoing elective surgery (excluding caesarean section), consider discontinuation of buprenorphine the day before or day of surgery. In patients unable to abruptly discontinue buprenorphine prior to surgery, full opioid agonists may be added to the buprenorphine to maintain proper analgesia. If opioid therapy is required as part of analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in in the conduct of the surgical or diagnostic procedure. The decision whether to discontinue buprenorphine prior to elective surgery should be made in consultation with the surgeon and anesthesiologist. If discontinued, buprenorphine can be resumed postoperatively when there is no longer a need for full opioid agonist therapy; in general, presurgery daily doses may be resumed if held for <2 to 3 days (ASAM 2020).

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): May enhance the CNS depressant effect of Buprenorphine. Management: Advise patients receiving buprenorphine about the increased risk of CNS depression if they consume alcohol. Consider alternatives to buprenorphine for opioid addiction treatment in patients who are dependent on alcohol. Risk D: Consider therapy modification

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Atazanavir: Buprenorphine may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Buprenorphine. Management: Buprenorphine is not recommended in patients taking atazanavir without ritonavir. In patients taking atazanavir with ritonavir or cobicistat, monitor for opioid excess if coadministered with buprenorphine and consider buprenorphine dose reductions. Risk X: Avoid combination

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Buprenorphine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Buprenorphine. Risk C: Monitor therapy

Daclatasvir: May increase the serum concentration of Buprenorphine. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: Buprenorphine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Nefazodone: Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4). Management: If concomitant use of opioid agonists that are metabolized by CYP3A4 and nefazodone is necessary, consider dose reduction of the opioid until stable drug effects are achieved. Monitor for increased opioid effects and serotonin syndrome/serotonin toxicity. Risk D: Consider therapy modification

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: Opioids (Mixed Agonist / Antagonist) may diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination

Opioids (Mixed Agonist / Antagonist): May diminish the therapeutic effect of Buprenorphine. This combination may also induce opioid withdrawal. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

PHENobarbital: May enhance the CNS depressant effect of Buprenorphine. PHENobarbital may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May enhance the CNS depressant effect of Buprenorphine. Primidone may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider therapy modification

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Reproductive Considerations

Pregnancy testing is recommended prior to initiating therapy for opioid use disorders. Long-term opioid use and misuse may cause infertility, including erectile dysfunction, decreased sperm motility, menstrual disorders, and amenorrhea in patients of reproductive potential (SAMHSA 2021). Initiation of buprenorphine maintenance treatment may improve fertility resulting in unplanned pregnancy (Dow 2012). Contraception counseling is recommended (Dow 2012; SAMHSA 2021).

Pregnancy Considerations

Buprenorphine crosses the placenta; buprenorphine and norbuprenorphine can be detected in newborn serum, urine, hair, and meconium following in utero exposure (Di Trana 2019).

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 209 2019).

[US Boxed Warning]: Prolonged use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure appropriate treatment will be available. Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). The risk of neonatal opioid withdrawal is greater following illicit opioid use than when buprenorphine is used as part of a treatment program (ASAM 2020). The onset and duration of neonatal withdrawal symptoms are dependent upon the specific opioid used, maternal dosing, and rate of elimination by the newborn. NAS associated with buprenorphine may correlate to concentrations of norbuprenorphine in the cord blood (Shah 2016). Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during pregnancy and/or labor should be monitored.

Opioid agonist pharmacotherapy is recommended for pregnant patients with an opioid use disorder (ACOG 2017; ASAM 2020; SAMHSA 2021). Treatment should begin as early in pregnancy as possible (ASAM 2020). Transmucosal buprenorphine is a recommended treatment option; information related to the use of other dosage forms in pregnancy is limited (ACOG 2017; SAMHSA 2021). Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of sublingual buprenorphine may be altered (Bastian 2017; Caritis 2017; Zhang 2018). Dose adjustments or splitting of a once daily dose may be required in some patients (ASAM 2020). Maintenance doses of buprenorphine will not provide adequate pain relief during labor. Patients receiving buprenorphine for the treatment of opioid use disorder should be maintained on their daily dose of buprenorphine in addition to receiving the same pain management options during labor and delivery as opioid-naive patients; Opioid agonist-antagonists should be avoided for the treatment of labor pain in patients maintained on buprenorphine due to the risk of precipitating acute withdrawal. Use of a multimodal approach to pain relief which can maximize non-opioid interventions is recommended. Monitor for maternal over sedation and somnolence (ACOG 2017; Krans 2019; SAMHSA 2021).

Breastfeeding Considerations

Buprenorphine is present in breast milk.

Product labeling notes the relative infant dose (RID) of buprenorphine to be <1% when calculated using median breast milk concentrations and compared to weight-adjusted maternal doses following sublingual dosing. In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

The RID of buprenorphine is available from two published studies. One is based on data from six women taking a median sublingual dose of buprenorphine 0.29 mg/kg/day (range: 0.06 to 0.41 mg/kg/day), 5 to 8 days' postpartum. The RID of buprenorphine and the norbuprenorphine metabolite were 0.2% (range: 0.03% to 0.31%) and 0.12% (range: 0.04% to 0.18%) of the weight-adjusted maternal dose, respectively. Breast milk concentrations varied in parallel to the maternal plasma concentrations (Lindemalm 2009). A second study used data from seven women taking an average sublingual dose of buprenorphine 7 mg/day (range: 2.4 to 24 mg/day), ~1 month postpartum. The mean RID of buprenorphine was calculated to be 0.38% (range: 0.04% to 0.63%) of the weight-adjusted maternal dose, using a mean milk concentration of 3.65 mcg/L (range: 0.83 to 8.27 mcg/L), providing an estimated daily infant dose via breast milk of 0.55 mcg/kg/day (range: 0.12 to 1.24 mcg/kg/day). The mean RID of norbuprenorphine was calculated to be 0.18% (range: 0.03% to 0.31%) of the weight-adjusted maternal dose, using a mean milk concentration of 1.94 mcg/L (range: 0.45 to 4.96 mcg/L), providing an estimated daily infant dose via breast milk of 0.29 mcg/kg/day (range: 0.07 to 0.74 mcg/kg/day) (Ilett 2012). Higher breast milk concentrations of buprenorphine have also been reported following chronic maternal use (Jansson 2016). Buprenorphine and norbuprenorphine were detected in the urine and serum of breasted infants (Jansson 2016; Lindemalm 2009); adverse events were not observed (Ilett 2012; Lindemalm 2009).

Nonopioid analgesics are preferred for breastfeeding patients who require pain control peripartum or for surgery outside of the postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]). However, when a narcotic is needed to treat maternal pain following surgery in a breastfeeding patient, use of buprenorphine can be considered. The lowest effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant (ABM [Reece-Stremtan 2017]).

When buprenorphine is used to treat opioid use disorder in breastfeeding patients, most guidelines allow breastfeeding as long as the infant is tolerant to the dose and other contraindications, such as HIV infection or other illicit drug use do not exist (AAP 2012; ABM [Reece-Stremtan 2015]; ACOG 2017; SAMHSA 2021). Breastfeeding can be encouraged for patients on stable maintenance doses, regardless of maternal buprenorphine dose (ABM [Reece-Stremtan 2015]). If additional illicit substances are being abused, patients treated with buprenorphine should express and discard breast milk until sobriety is established (Dow 2012).

The decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Breastfeeding patients using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness, sedation, feeding difficulties, or limpness (ACOG 209 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.

Monitoring Parameters

BP (monitor for hypotension during initiation and titration); LFTs (prior to initiation and during therapy; monthly for 300 mg maintenance treatment with extended-release injection); pregnancy test (prior to initiation); hepatitis and HIV tests (prior to initiation), particularly for patients with opioid use disorder (SAMHSA 2021); pain relief, respiratory and mental status, CNS depression (especially in elderly, debilitated or cachectic patients particularly during treatment initiation or titration, or when using concomitant CNS depressants); signs of dependence, abuse, or misuse; symptoms of withdrawal; patients with biliary tract disease for worsening symptoms; application site reactions (transdermal patch); signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs and symptoms of toxicity or overdose (especially in patients with hepatic impairment); signs of infection or problems with wound healing one week after insertion of subdermal implant; dental changes (cavities, tooth erosion/decay, loss of fillings, tooth loss) (sublingual tablet).

Additional monitoring parameters with use for chronic pain (eg, long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Note: Patients undergoing planned surgical procedures, in advance of a procedure, should consult with their buprenorphine prescriber in collaboration with the surgeon, to consider buprenorphine taper and alternative opioid management. Patients undergoing urgent or emergent procedures may require higher than expected opioid doses to achieve adequate analgesia and should be monitored carefully for decreasing opioid requirements as buprenorphine is eliminated. Some patients may achieve adequate analgesia with continued or increased buprenorphine (Alford 2006; Chern 2013; Huang 2014).

Mechanism of Action

Buprenorphine exerts its analgesic effect via high-affinity binding to mu opiate receptors in the CNS; displays partial mu agonist and weak kappa antagonist activity. Due to it being a partial mu agonist, its analgesic effects plateau at higher doses and it then behaves like an antagonist. The extended-release formulation is injected subcutaneously as a liquid; subsequent precipitation following injection results in a solid depot which will gradually release buprenorphine via diffusion and biodegradation of the depot.

Pharmacokinetics

Onset of action: Analgesic: Immediate-release IM: ≥15 minutes.

Peak effect: Immediate-release IM: ~1 hour.

Duration: Immediate-release IM: ≥6 hours; Extended-release SubQ: 28 days.

Absorption: Immediate-release IM and SubQ: 30% to 40%. Application of a heating pad onto the transdermal system may increase blood concentrations of buprenorphine 26% to 55%. Ingestion of liquids decreases systemic exposure to buprenorphine from buccal film by 23% to 37%.

Distribution: CSF concentrations are ~15% to 25% of plasma concentrations.

Vd:

Premature neonates (GA: 27 to 32 weeks): 6.2 ± 2.1 L/kg (Barrett 1993).

Children 4 to 7 years: 3.2 ± 2 L/kg (Olkkola 1989).

Adults: 97 to 187 L/kg.

Protein binding: High (~96%, primarily to alpha- and beta globulin).

Metabolism: Primarily hepatic via N-dealkylation by CYP3A4 to norbuprenorphine (active metabolite), and to a lesser extent via glucuronidation by UGT1A1 and 2B7 to buprenorphine 3-O-glucuronide; the major metabolite, norbuprenorphine, also undergoes glucuronidation via UGT1A3; extensive first-pass effect.

Bioavailability (relative to IV administration): Buccal film: 46% to 65%; IR IM: 70% (McNicholas 2004); Sublingual tablet: 29% (McNicholas 2004); Transdermal patch: ~15%.

Half-life elimination:

Premature neonates (GA: 27 to 32 weeks): Immediate-release IV: 20 ± 8 hours (Barrett 1993).

Children 4 to 7 years: Immediate-release IV: ~1 hour (Olkkola 1989).

Adults: IV: 2.2 to 3 hours; Buccal film: 27.6 ± 11.2 hours; Apparent terminal half-life: ER injection: 43 to 60 days; Sublingual tablet: ~37 hours; Transdermal patch: ~26 hours. Note: Extended elimination half-life for sublingual administration may be due to depot effect (Kuhlman 1996).

Time to peak, plasma: Buccal film: 2.5 to 3 hours; Extended-release SubQ: 24 hours, with steady state achieved after 4 to 6 months; Subdermal implant: 12 hours after insertion, with steady state achieved by week 4; Sublingual: 30 minutes to 1 hour (Kuhlman 1996); Transdermal patch: Steady state achieved by day 3.

Excretion: Feces (~70%; 33% as unchanged drug; 5% as conjugated drug; 21% as norbuprenorphine; and 2% as conjugated norbuprenorphine); urine (27% to 30%; 1% as unchanged drug; 9.4% as conjugated drug; 2.7% as norbuprenorphine; and 11% as conjugated norbuprenorphine).

Clearance: Related to hepatic blood flow.

Premature neonates (GA: 27 to 32 weeks): 0.23 ± 0.07 L/hour/kg (Barrett 1993).

Children 4 to 7 years: 3.6 ± 1.1 L/hour/kg (Olkkola 1989).

Adults: 0.78 to 1.32 L/hour/kg.

Pharmacokinetics: Additional Considerations

Hepatic function impairment: Because buprenorphine is extensively metabolized, plasma levels and half-life were increased in patients with moderate and severe hepatic impairment.

Older adult: The pharmacokinetics are similar between younger adults and elderly, although elderly patients showed a trend toward higher plasma concentrations immediately after transdermal system removal.

Pricing: US

Film (Belbuca Buccal)

75 mcg (per each): $7.69

150 mcg (per each): $7.69

300 mcg (per each): $12.08

450 mcg (per each): $16.42

600 mcg (per each): $17.52

750 mcg (per each): $18.42

900 mcg (per each): $18.96

Patch weekly (Buprenorphine Transdermal)

5 mcg/hr (per each): $64.43 - $83.24

7.5 mcg/hr (per each): $90.20 - $129.31

10 mcg/hr (per each): $96.64 - $124.87

15 mcg/hr (per each): $139.41 - $180.12

20 mcg/hr (per each): $171.09 - $221.06

Patch weekly (Butrans Transdermal)

5 mcg/hr (per each): $102.09

7.5 mcg/hr (per each): $142.92

10 mcg/hr (per each): $153.13

15 mcg/hr (per each): $220.89

20 mcg/hr (per each): $271.09

Solution (Buprenex Injection)

0.3 mg/mL (per mL): $18.20

Solution (Buprenorphine HCl Injection)

0.3 mg/mL (per mL): $14.77 - $18.20

Solution Prefilled Syringe (Sublocade Subcutaneous)

100 mg/0.5 mL (per 0.5 mL): $2,194.86

300 mg/1.5 mL (per mL): $1,463.24

Sublingual (Buprenorphine HCl Sublingual)

2 mg (per each): $0.37 - $4.53

8 mg (per each): $0.72 - $8.48

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Acron (BD);
  • Addictex (TR);
  • Addnok (CZ, IN);
  • Astec (AT);
  • Bignanto (NO);
  • Brospina (CR, DO, GT, HN, MX, NI, PA, SV);
  • Brospina SL (CR, DO, GT, HN, NI, PA, SV);
  • Bugesic (BD);
  • Bupacal (AT);
  • Bupainx (CZ);
  • Bupannus (NZ);
  • Bupensan (EE, LT);
  • Bupine (IN);
  • Bupredermal (NZ);
  • Buprefarm (NO);
  • Bupren (AR, UA);
  • Bupretec (NZ);
  • Buprex (ES);
  • Buprotec (CZ);
  • Butrans (BH, GB, IE, IL, LB);
  • Dorfene (PK);
  • Feliben (ES);
  • Gabup (GB);
  • Hapoctasin (GB);
  • Nalgesic (BD);
  • Nopan (RU);
  • Norphin (IN);
  • Norspan (CN, ES, SK);
  • Norspan Patch (AU, DE, DK, EE, FI, HK, KR, NO, NZ, PH);
  • Norspan Tape (JP);
  • Pentorel (IN);
  • Restiva (AR);
  • Shumeifen (CN);
  • Sovenor (MY, SG);
  • Suboxone (AU, NZ);
  • Subutex (AE, AT, AU, BE, BG, CH, CZ, DE, DK, FR, GR, HR, ID, IE, IL, IS, LU, LV, MT, NO, PT, SE);
  • Temgesic (AE, AT, AU, BE, BF, BJ, BR, CH, CI, CY, DE, DK, EE, EG, ET, FI, FR, GB, GH, GM, GN, GR, HK, IQ, IR, IT, JO, KE, KW, LR, LU, LY, MA, ML, MR, MU, MW, MX, NE, NG, NL, NO, NZ, OM, PK, RU, SA, SC, SD, SE, SG, SK, SL, SN, SY, TN, TR, TW, TZ, UG, YE, ZA, ZM, ZW);
  • Tidigesic (IN);
  • Transtec (BE, CH, CL, CO, DE, DK, EC, ES, GB, HN, HR, HU, IE, IT, MX, NL, NO, PE, PH, PL, PT, SK)


For country code abbreviations (show table)
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