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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
FDA Requiring Updates to Opioid Prescribing Information April 2023

The FDA has issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use. The required safety labeling changes include stating:

  • the risk of overdose increases as the dosage increases for all opioid pain medicines;

  • IR opioids should not be used for an extended period of time unless a patient's pain remains severe enough to require them and alternative treatment options continue to be inadequate;

  • many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine;

  • it is recommended to reserve ER/LA opioid pain medicines for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate; and

  • a warning about opioid-induced hyperalgesia (OIH), including information on differentiating OIH symptoms from those of opioid tolerance and withdrawal.

Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use.

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 [Brixadi]):

Serious harm or death could result if administered intravenously. The buprenorphine extended-release injection forms a liquid crystalline gel 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 BRIXADI REMS. Health care settings and pharmacies that order and dispense buprenorphine extended-release injection must be certified in this program and comply with the REMS requirements.

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

Serious harm or death could result if extended-release injection is administered intravenously. The buprenorphine extended-release 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;
  • Brixadi;
  • Brixadi (Weekly);
  • Buprenex [DSC];
  • Butrans;
  • Probuphine Implant Kit [DSC];
  • Sublocade
Brand Names: Canada
  • BuTrans 10;
  • BuTrans 15;
  • BuTrans 20;
  • BuTrans 5;
  • Probuphine [DSC];
  • Sublocade;
  • Subutex
Pharmacologic Category
  • Analgesic, Opioid;
  • Analgesic, Opioid Partial Agonist
Dosing: Adult
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.

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).

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:

Brixadi:

Note: Only health care providers should prepare and administer. Available as a weekly or monthly injection (do not combine weekly product to yield a monthly dose); the monthly product is not intended for patients who are not currently receiving buprenorphine treatment.

Weekly dosing for patients not currently receiving buprenorphine treatment : Note: To avoid precipitating an opioid withdrawal syndrome, transmucosal buprenorphine test dose should be administered prior to administration of ER injection.

SUBQ: Initial dose: If the test dose is tolerated without precipitating withdrawal, administer 16 mg (weekly), followed by an additional 8 mg (weekly) within 3 days of the initial dose for a total recommended weekly dose of 24 mg. May administer an additional 8 mg (weekly) after at least 24 hours after the previous dose, for a total weekly dose of 32 mg.

Maintenance dose: SUBQ: 16 to 32 mg once weekly; titrate at weekly intervals as needed up to a maximum of 32 mg once weekly.

Weekly or monthly dosing for patients currently receiving buprenorphine treatment:

Transitioning from transmucosal buprenorphine containing products: May transition to weekly or monthly therapy.

Transitioning From Transmucosal Buprenorphine Containing Products to ER SUBQ Monthly or Weekly Dosing

Sublingual buprenorphinea (daily dose)

ER SUBQ injection (weekly dose)

ER SUBQ injection (monthly dose)

a One buprenorphine 8 mg and naloxone 2 mg sublingual tablet provides equivalent buprenorphine exposure to one buprenorphine 8 mg sublingual tablet or one buprenorphine 5.7 mg and naloxone 1.4 mg sublingual tablet.

≤6 mg

8 mg

NA

8 to 10 mg

16 mg

64 mg

12 to 16 mg

24 mg

96 mg

18 to 24 mg

32 mg

128 mg

Dosage adjustments: An additional 8 mg (weekly injection) may be administered during a dosing interval up to a maximum of 32 mg/week (weekly) or 128 mg/month (monthly).

Missed dose: Administer a missed dose as soon as possible, then resume every 7-day interval from the last administered dose (weekly) or every 28-day interval from last administered dose (monthly). To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point and the monthly dose may be administered up to 1 week before or after the monthly time point.

Transitioning from weekly and monthly dosing: Note: Patients may be transitioned from weekly to monthly or from monthly to weekly dosing.

Transitioning From Weekly and Monthly ER SUBQ Dosing

Weekly ER SUBQ injection dose

Monthly ER SUBQ injection dose

16 mg

64 mg

24 mg

96 mg

32 mg

128 mg

Sublocade:

Initial: SUBQ: 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: SUBQ: 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): SUBQ: 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): I R 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).

Discontinuation or tapering of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. If ER injection is discontinued, monitor the patient for several months for signs and symptoms of withdrawal and treat appropriately; after steady state has been achieved, patients discontinuing ER injections may have detectable plasma levels of buprenorphine for ~1 month (Brixadi weekly) and for ~4 months (Brixadi monthly) and for ~12 months (Sublocade). Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (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

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction. Norbuprenorphine metabolite does have the potential to accumulate with long-term use; however, the clinical relevance remains unclear as it is weakly active and does not cross the blood brain barrier (Ref).

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed: No supplemental dose or dosage adjustment necessary (Ref).

Peritoneal dialysis: Not significantly dialyzed (large Vd, highly protein bound): No dosage adjustment necessary (Ref).

CRRT: No dosage adjustment necessary (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).

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:

Brixadi: Use is not recommended. Patients who develop moderate to severe impairment during treatment should be monitored for signs and symptoms of toxicity or overdose; may require dosage adjustment.

Sublocade: 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: Older Adult

Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).

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

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 general guidance and do not represent the maximum doses that may be required in all patients.

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

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.

Opioid use disorder

Opioid use disorder: Note: Do not start induction with buprenorphine until objective and clear signs of withdrawal are apparent (otherwise withdrawal may be precipitated). Withdrawal usually occurs 8 to 12 hours after last short-acting agonist (eg, heroin, oxycodone) and 24 to 72 hours after last long-acting agonist (eg, methadone). Psychosocial treatment is recommended in combination with pharmacotherapy in adolescent patients (Ref).

Sublingual tablet: Limited data available:

Adolescents: Sublingual: Initial: 2 to 4 mg; if no signs of precipitated withdrawal after 60 to 90 minutes, may increase in increments of 2 to 8 mg. Once initial dose is tolerated, may increase to a dose that is clinically effective and provides 24 hours of stabilization. Usual maintenance dose range: 4 to 24 mg/day. Doses ≥16 mg/day have been associated with greater efficacy; however, doses >24 mg/day have not been shown to be more effective and may increase risk of diversion. Continue effective maintenance dose for as long as necessary for opioid use disorder; there are no recommended limits on duration of therapy (Ref).

Subdermal implant (eg, Probuphine): 80 mg/implant:

Note: Should only be used in patients who have been clinically stable while receiving ≤8 mg/day maintenance transmucosal therapy (eg, for ≥3 months).

Adolescents ≥16 years: 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. 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 (Ref).

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

Discontinuation of therapy: When discontinuing buprenorphine for long-term treatment of opioid use disorder, gradually decrease the dose over several months to prevent withdrawal; do not abruptly discontinue (Ref). A standard tapering approach does not exist; taper should be individualized based on patient response.

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, kidney 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.

Adverse Reactions (Significant): Considerations
Dental effects

Cases of tooth decay, dental caries (cavities), oral infections, and tooth loss have been reported with the use of transmucosal (eg, buccal, sublingual) buprenorphine-containing products in patients with and without a history of dental disease (Ref).

Mechanism: Non–dose-related; idiosyncratic; mechanism not clearly established. May be related to prolonged tooth exposure to the acidic medication formulation (Ref).

Onset: Delayed; identification of dental problems occurred a mean of 45.7 months (range: 5 to 77 months) after initiation of buprenorphine-containing transmucosal therapy in one case series (Ref).

Opioid-induced constipation

Opioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction, which is a broader term that encompasses additional GI opioid-induced adverse reactions including nausea, vomiting, and gastroesophageal reflux. Symptoms of OIC may include decreased frequency of bowel movements, straining to pass bowel movements, a sense of incomplete evacuation, and/or hard stools (Ref). Tolerance does not develop to OIC, and symptoms are reversible after discontinuation of the opioid (Ref). Buprenorphine, as a partial mu agonist, is associated with a lower incidence of OIC than morphine (Ref).

Mechanism: Time-related; mu-opioid receptor stimulation in the GI tract results in delayed gastric emptying, decreased peristalsis, decreased water and chloride secretion into the intestinal lumen, and slowed bowel motility (Ref).

Onset: Varied; changes in peristalsis may occur 5 to 25 minutes after administration of opioids (Ref). However, OIC is defined based on a 7-day period of change (Ref).

Risk factors:

• Concurrent use of other medications that cause constipation (eg, anticholinergic medications) (Ref)

Opioid-induced respiratory depression

Serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of buprenorphine, especially during dose escalation or with misuse (Ref). Effects may include hypoventilation, hypoxia, hypercapnia, respiratory acidosis, and reduced ventilatory responses to hypoxia and hypercapnia (Ref). Buprenorphine is a partial mu agonist, resulting in a dose-response ceiling regarding respiratory depression; however, clinically significant respiratory depression may occur (Ref). Reversal of buprenorphine-induced respiratory depression may be relatively resistant to naloxone due to its high mu-opioid receptor affinity and slow receptor dissociation kinetics. A higher naloxone bolus dose (ie, 2 to 3 mg IV), followed by a continuous infusion (ie, 4 mg/hour) and/or mechanical ventilation may be required for long-term management and stabilization (Ref).

Mechanism: Dose-related at lower doses with a ceiling effect (plateau) at higher doses; stimulation of mu-opioid receptors in the brainstem leads to suppression of the respiratory control network and depression of normal hypoxic and hypercapnic ventilatory responses (Ref).

Onset: Rapid; OIRD has been reported within 1 to 2 hours of IV and 2 to 6 hours of sublingual buprenorphine administration (Ref).

Risk factors:

• Initiation of therapy or dose increase

• Concurrent use of benzodiazepines or other CNS depressants, including alcohol

• Preexisting respiratory disease (eg, chronic obstructive pulmonary disease) (Ref)

• Acute overdose

Withdrawal, opioid-induced or precipitated

Abruptly stopping or reducing opioid use in patients with physical opioid dependence can result in opioid-induced withdrawal (OIW) (Ref). Physical symptoms may include nausea, vomiting, diarrhea, abdominal cramps, tachycardia, chills, muscle aches, bone pain, agitation, anxiety, and insomnia. Psychosis has also been described in case reports (Ref). Spontaneous withdrawal symptoms due to buprenorphine abstinence are generally milder than those experienced with full opioid agonists (Ref). Initiation of buprenorphine may cause precipitated opioid withdrawal symptoms (similar to OIW but faster onset) (Ref) in patients currently or recently taking full mu-opioid agonists (prescribed and/or non-prescribed) for a prolonged period (Ref). Precipitated opioid withdrawal is associated with a decrease in opioid use disorder treatment retention (Ref).

Mechanism:

• OIW: Withdrawal; opioids bind to mu-opioid receptors on neurons in the locus coeruleus (LC) of the brainstem, causing decreased norepinephrine (NE) release. Upon abrupt discontinuation, the absence of opioid stimulation causes LC hyperactivity, excessive NE release, and subsequent autonomic hyperactivity (Ref).

• Precipitated opioid withdrawal: Withdrawal; buprenorphine displaces full agonists at the mu-opioid receptor (Ref). The sudden shift from full to partial opioid agonism leads to withdrawal symptoms and/or uncontrolled pain.

Onset:

• OIW: Varied; symptoms typically occur within 2 to 15 days of buprenorphine discontinuation and gradually decrease over the following 4 to 7 days (Ref).

• Precipitated opioid withdrawal: Rapid; symptoms typically occur within 30 minutes to 2 hours after buprenorphine administration and gradually decrease over the following 6 to 24 hours (Ref).

Risk factors, OIW:

• Abrupt discontinuation, rapid taper (Ref)

• Opioid use disorder (Ref)

Risk factors, precipitated opioid withdrawal:

• High level of physical opioid dependence (Ref)

• Recent fentanyl or methadone use (Ref)

• Recent benzodiazepine use (Ref)

• No prior buprenorphine use (Ref)

• Low initial dose of buprenorphine/naloxone (Ref)

• Initiation (induction phase) of buprenorphine therapy for opioid use disorder (Ref)

• Chronic kidney disease (Ref)

• Cirrhosis (Ref)

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 4%) (table 1), decreased appetite (1% to 5%), diarrhea (1% to 5%), gastroenteritis (1% to 5%), nausea (9% to 10%), vomiting (4% to 5%), xerostomia (1% to 5%)

Buprenorphine: Adverse Reaction: Constipation (Buccal Film)

Drug (Buprenorphine)

Placebo

Population

Dosage Form

Indication

Number of Patients (Buprenorphine)

Number of Patients (Placebo)

Comments

4%

2%

Adults

Buccal film

Chronic pain

600

606

N/A

4%

3%

Adults

Buccal film

Chronic pain

229

232

Opioid-naive patients

3%

1%

Adults

Buccal film

Chronic pain

254

256

Opioid-experienced patients

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%), drowsiness (1%), falling (1% to 5%), fatigue (≥5%), headache (4%), insomnia (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 (1% to 5%)

Miscellaneous: Fever (1% to 5%)

<1%:

Cardiovascular: Atrial fibrillation, chest pain, coronary artery disease, prolonged QT interval on ECG, syncope

Dermatologic: Cellulitis, excoriation of skin

Endocrine & metabolic: Decreased plasma testosterone, dehydration

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

Hepatic: Abnormal hepatic function tests, increased serum aspartate aminotransferase

Nervous system: Asthenia, cerebrovascular accident, chills, hypoesthesia, lethargy, migraine, noncardiac chest pain, transient ischemic attacks, tremor

Neuromuscular & skeletal: Bone fracture, musculoskeletal pain, neck pain, osteoarthritis

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 of skin (1% to 2%; including scratch), skin lesion (1%), skin rash (2%)

Gastrointestinal: Constipation (6%) (table 2), flatulence (1%), nausea (6%), toothache (5%), upper abdominal pain (3%), vomiting (6%)

Buprenorphine: Adverse Reaction: Constipation (Implant)

Drug (Buprenorphine)

Comparator (Sublingual Buprenorphine)

Population

Dosage Form

Indication

Number of Patients (Buprenorphine)

Number of Patients (Sublingual Buprenorphine)

6%

3%

Adults

Implant

Opioid dependence

309

317

Local: Local hemorrhage (7%; at implant site), local swelling (1%), localized edema (5%; at implant site), localized erythema (10%; at implant site)

Nervous system: Asthenia (2%), 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: Back pain (6%), limb pain (3%)

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

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

Injection: Note: Reported incidences are for immediate release (IR) and extended release (ER) formulations unless otherwise indicated.

>10%:

Local: Injection-site reaction (ER: ≤19%; including bruising at injection site [1%], cellulitis at injection site [<1%], discomfort at injection site [<1%], erythema at injection site [3% to 4%], induration at injection site [1%], injection-site pruritus [6% to 10%], pain at injection site [5% to 6%], skin ulceration at injection site [<1%], swelling at injection site [≤1%])

Nervous system: Sedated state (ER: 2% to 3%; IR: ~66%)

1% to 10%:

Cardiovascular: Hypotension (IR: 1% to 5%)

Dermatologic: Diaphoresis (IR: 1% to 5%)

Gastrointestinal: Constipation (≤9%) (table 3), nausea (1% to 9%), vomiting (1% to 9%)

Buprenorphine: Adverse Reaction: Constipation (Injection)

Drug (Buprenorphine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Buprenorphine)

Number of Patients (Placebo)

9%

0%

Adults

300 mg for the first two doses followed by 4 doses of 100 mg

Extended-release SUBQ injection

Moderate to severe opioid use disorder

203

100

8%

0%

Adults

6 doses of 300 mg

Extended-release SUBQ injection

Moderate to severe opioid use disorder

201

100

<1%

N/A

N/A

N/A

Immediate-release IV or IM injection

Pain

N/A

N/A

Hepatic: Increased gamma-glutamyl transferase (ER: 3% to 4%), increased serum alanine aminotransferase (ER: 1% to 5%), increased serum aspartate aminotransferase (ER: 3% to 5%)

Nervous system: Dizziness (3% to 10%; including vertigo), drowsiness (ER: 2% to 5%), fatigue (≤6%), headache (1% to 9%)

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

Ophthalmic: Miosis (IR: 1% to 5%)

Respiratory: Hypoventilation (IR: 1% to 5%)

<1% (IR):

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

Dermatologic: Pallor, pruritus, skin rash, urticaria

Gastrointestinal: Anorexia, diarrhea, dyspepsia, flatulence, xerostomia

Genitourinary: Urinary retention

Local: Localized warm feeling

Nervous system: Abnormal dreams, agitation, asthenia, ataxia, chills, coma, confusion, depersonalization, depression, dysphoria, euphoria, hallucination, malaise, nervousness, paresthesia, psychosis, seizure, sensation of cold, slurred speech, tremor

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

Otic: Tinnitus

Respiratory: Apnea, cyanosis, dyspnea

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%) (table 4), vomiting (8%)

Buprenorphine: Adverse Reaction: Constipation (Sublingual Tablets)

Drug (Buprenorphine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Buprenorphine)

Number of Patients (Placebo)

8%

3%

Adults

16 mg/day

Sublingual tablets

Opioid dependence

103

107

Transdermal patch:

>10%:

Gastrointestinal: Constipation (3% to 13%) (table 5), nausea (6% to 21%)

Buprenorphine: Adverse Reaction: Constipation (Transdermal Patch)

Drug (Buprenorphine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Buprenorphine)

Number of Patients (Placebo)

Comments

13%

5%

Adults

N/A

Transdermal patch

Chronic pain

392

261

Titration-to-effect trials

6%

N/A

Adults

20 mcg/hour

Transdermal patch

Chronic pain

219

N/A

Opioid-experienced patients

4%

1%

Adults

10 or 20 mcg/hour

Transdermal patch

Chronic pain

256

283

Opioid-naive patients

3%

N/A

Adults

5 mcg/hour

Transdermal patch

Chronic pain

221

N/A

Opioid-experienced patients

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 (1% to 5%), hypertension (1% to 5%), peripheral edema (3%)

Dermatologic: Hyperhidrosis (4%), pruritus (3%), skin rash (1% to 5%)

Gastrointestinal: Anorexia (1% to 5%), diarrhea (1% to 5%), dyspepsia (1% to 5%), stomach discomfort (2%), upper abdominal pain (1% to 5%), vomiting (4% to 9%), xerostomia (6%)

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

Infection: Influenza (1% to 5%)

Local: Application-site erythema (5% to 10%), application-site irritation (2% to 6%), application-site rash (6% to 8%)

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

Neuromuscular & skeletal: Arthralgia (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%)

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, bradycardia, flushing, hypotension, orthostatic hypotension, palpitations, syncope, tachycardia, vasodilation

Dermatologic: Contact dermatitis, urticaria, 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

Hypersensitivity: Angioedema, facial edema

Local: Application-site dermatitis

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

Ophthalmic: Blurred vision, dry eye syndrome, miosis, visual disturbance

Otic: Tinnitus

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

Frequency not defined: Local: Application-site burning, application-site discharge, application-site vesicles

Postmarketing (any route):

Dermatologic: Skin necrosis (following inadvertent dermal injection of ER SUBQ injection) (Crouse 2021)

Gastrointestinal: Dental caries (including tooth enamel erosion, 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 (Brennan 2013, Debono 2011)

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

Hypersensitivity: Anaphylactic shock, hypersensitivity reaction

Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), drug abuse, opioid withdrawal syndrome (precipitated) (Quattlebaum 2022)

Respiratory: Bronchospasm, respiratory depression (Richards 2017)

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).

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 (buccal film only); history of application-site reactions (eg, allergic contact dermatitis) to transdermal patches; 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; ileus of any type (transdermal patch only); 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.

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

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.

• 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: 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 (Sublocade) or for ~1 month for weekly Brixadi and ~4 months for monthly Brixadi. 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 hepatic impairment develops during treatment with the ER injection, continue with caution and monitor for toxicity for several months.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, posttraumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).

• 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: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).

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

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 opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.

Dosage form specific issues:

• 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. Brixadi is available as a weekly or monthly injection (do not combine weekly product to yield a monthly dose); the monthly product is not intended for patients who are not currently receiving buprenorphine treatment.

• Latex: Some products may contain latex.

• 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 syringes and 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:

• 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 increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone in patients 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), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]). 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. Opioids should not be used as first-line therapy for acute (<1 month duration), subacute (1 to 3 month duration), or chronic pain (>3 month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, 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. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]).

• 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 (Sublocade) or detectable plasma levels 1 month (weekly Brixadi) or 4 months (monthly Brixadi); the correlation between plasma concentrations of buprenorphine and those detectable in urine for Brixadi is unknown.

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider offering 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 opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider offering 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).

Dosage Forms Considerations

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

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 [DSC])

Generic: 0.3 mg/mL (1 mL)

Solution, Injection, as hydrochloride [preservative free]:

Generic: 0.3 mg/mL (1 mL)

Solution Prefilled Syringe, Subcutaneous:

Brixadi: 64 mg/0.18 mL [extended-release] (0.18 mL); 96 mg/0.27 mL [extended-release] (0.27 mL); 128 mg/0.36 mL [extended-release] (0.36 mL)

Brixadi (Weekly): 8 mg/0.16 mL [extended-release] (0.16 mL); 16 mg/0.32 mL [extended-release] (0.32 mL); 24 mg/0.48 mL [extended-release] (0.48 mL); 32 mg/0.64 mL [extended-release] (0.64 mL) [contains alcohol, usp]

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

Pricing: US

Film (Belbuca Buccal)

75 mcg (per each): $8.56

150 mcg (per each): $8.56

300 mcg (per each): $13.44

450 mcg (per each): $18.27

600 mcg (per each): $19.49

750 mcg (per each): $20.50

900 mcg (per each): $21.10

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): $61.37

7.5 mcg/hr (per each): $86.29

10 mcg/hr (per each): $92.46

15 mcg/hr (per each): $156.55

20 mcg/hr (per each): $164.67

Solution (Buprenorphine HCl Injection)

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

Solution Prefilled Syringe (Brixadi (Weekly) Subcutaneous)

8MG/0.16ML (per 0.16 mL): $512.40

16MG/0.32ML (per 0.32 mL): $512.40

24MG/0.48ML (per 0.48 mL): $512.40

32MG/0.64ML (per 0.64 mL): $512.40

Solution Prefilled Syringe (Brixadi Subcutaneous)

64MG/0.18ML (per 0.18 mL): $2,049.60

96MG/0.27ML (per 0.27 mL): $2,049.60

128MG/0.36ML (per 0.36 mL): $2,049.60

Solution Prefilled Syringe (Sublocade Subcutaneous)

100 mg/0.5 mL (per 0.5 mL): $2,419.82

300 mg/1.5 mL (per mL): $1,613.21

Sublingual (Buprenorphine HCl Sublingual)

2 mg (per each): $0.37 - $4.50

8 mg (per each): $0.72 - $8.46

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.

Dosage Forms: Canada

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

Implant, Subcutaneous, as hydrochloride:

Probuphine: 74.2 mg ([DSC])

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

Previously, in order to prescribe buprenorphine for opioid use disorder (OUD) in the United States, clinicians had to apply for a federally required DATA Waiver (X-Waiver). In January 2023, the Consolidated Appropriations Act of 2023 removed this requirement and allowed clinicians with schedule III authority on their Drug Enforcement Administration (DEA) registration to prescribe buprenorphine for OUD treatment if permitted by applicable state law (https://www.samhsa.gov/medications-substance-use-disorders/removal-data-waiver-requirement; https://www.deadiversion.usdoj.gov/pubs/docs/index.html).

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.

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: Extended release:

Brixadi: Only health care providers should prepare and administer. Do not administer IV, IM, or intradermally. Weekly and monthly formulations are available; weekly formulation cannot be combined to yield a monthly dose. Do not divide doses; administer as a single SUBQ injection using only the syringe and safety needle included (needle cap is synthetically derived from natural rubber latex). Administer by slow SUBQ injection into the abdomen, buttocks, thigh, or upper arm; for weekly product, do not administer at the same site for at least 8 weeks; no rotation is required for monthly product. In patients who are not currently receiving buprenorphine treatment, administration of the weekly formulation into the upper arm should only be used after 4 consecutive weekly doses (once steady state achieved). Administer weekly product in 7-day intervals (may be administered up to 2 days before or after weekly time point) and monthly product in 28-day intervals (may be administered up to 1 week before and after the monthly time point). For weekly product in patients who are not currently receiving buprenorphine, administer a test dose of 4 mg of transmucosal buprenorphine to ensure buprenorphine is tolerated without precipitated withdrawal. After SUBQ injection, the solution transforms into a biodegradable gel depot that slowly biodegrades to release buprenorphine; the depot may not be palpable or conducive to surgical removal; removal of depot is not recommended. See manufacturer's labeling for further administration instructions.

Sublocade: 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 manufacturer's labeling for further administration instructions.

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. If dose volume >0.5 mL, administer in two aliquots separated by at least 2 minutes (Ref).

Sublingual tablet: Adolescents: 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:

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.

Use: Labeled Indications

Opioid use disorder:

Extended-release injection:

Brixadi: Maintenance treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single 4 mg dose of a transmucosal buprenorphine product or who are already being treated with a transmucosal buprenorphine product.

Sublocade: 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.

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.

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

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

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. 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

Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification

Reproductive Considerations

Pregnancy testing is recommended prior to initiating therapy for opioid use disorders (ASAM 2020; SAMHSA 2021).

Chronic opioid use may cause hypogonadism and hyperprolactinemia which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).

Consider family planning, contraception, and the effects on fertility prior to prescribing opioids for chronic pain to patients who could become pregnant (ACOG 2017; CDC [Dowell 2022]). Contraception should also be discussed with patients undergoing treatment for opioid use disorders (ASAM 2020).

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).

Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]).

Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]). The risk of NAS/NOWS is not greater when buprenorphine is used as part of a treatment program compared to the risk following illicit opioid use (ASAM 2020). NAS/NOWS associated with buprenorphine may correlate to concentrations of norbuprenorphine in the cord blood (Shah 2016).

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; CDC [Dowell 2022]) and may continue when pregnancy occurs during treatment (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).

When opioids are needed to treat acute pain in pregnant patients, the lowest effective dose for only the expected duration of pain should be prescribed (CDC [Dowell 2022]). Monitor infants of mothers on long-term/chronic opioid therapy for symptoms of withdrawal. Symptom onset reflects the half-life of the opioid used. Monitor infants for at least 4 to 7 days following exposure to buprenorphine (AAP [Patrick 2020]; CDC [Dowell 2022]).

Breastfeeding Considerations

Buprenorphine is present in breast milk.

Multiple reports summarize data related to the presence of buprenorphine in breast milk following treatment for opioid use disorder:

• A study presents data from 6 lactating women taking a median sublingual dose of buprenorphine 0.29 mg/kg/day (range: 0.06 to 0.41 mg/kg/day). Breast milk was sampled over 12 hours prior to and after a dose 5 to 8 days' postpartum. The median relative infant dose (RID) of buprenorphine and the norbuprenorphine metabolite were calculated by authors of the study to be 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. Additional data are available from a seventh mother in this study after 9 months of breastfeeding. Buprenorphine 20 mg/day was initiated during the first week of pregnancy and continued after delivery. At 9 months postpartum, a single breast milk sample was obtained ~135 minutes following the maternal dose; maternal and infant serum and urine were also sampled. Buprenorphine and norbuprenorphine concentrations in the child were 4.5% and 11.7% of those in the maternal plasma, respectively. Maternal urine contained buprenorphine 74.8 nmol/L and norbuprenorphine 2,529 nmol/L, compared to concentrations of buprenorphine <0.5 nmol/L and norbuprenorphine 1.1 nmol/L in the child's urine. All infants in this study had appropriate weight gain at 1 month of age (Lindemalm 2009).

• A second study used data from 7 lactating women taking an average sublingual dose of buprenorphine 7 mg/day (range: 2.4 to 24 mg/day). All patients in the study were taking buprenorphine during pregnancy; breast milk was sampled over 24 hours at ~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). All infants (4 exclusively breastfed) had expected weight gain and appropriate sleeping patterns (Ilett 2012).

• Data are available from 10 lactating women taking sublingual buprenorphine 2 to 22 mg/day. Breast milk samples were obtained 2 to 2.5 hours after the maternal dose. Buprenorphine breast milk concentrations ranged from 0.2 to 20.8 mcg/L between 2 and 30 days postpartum. At 14 days of age, buprenorphine was detectable in the plasma of only 4 infants; buprenorphine metabolites were not detectable in any infant plasma samples (Jansson 2016).

• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

According to the manufacturer, 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.

When buprenorphine is used to treat opioid use disorder in lactating patients, breastfeeding may help mitigate potential newborn withdrawal. 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 [Patrick 2020]; 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]). Breastfeeding is not recommended if relapse with illicit drug use or legal substance misuse has occurred within 30 days prior to delivery, and breastfeeding should be suspended if a relapse occurs (ABM [Reece-Stremtan 2015]; ACOG 2017). Both mother and infant should be monitored (AAP [Patrick 2020]).

When chronic opioids are prescribed prenatally and continued postpartum, breastfeeding may be initiated to help mitigate potential newborn withdrawal; monitor both the mother and the infant (AAP [Meek 2022]; AAP [Patrick 2020]).

Nonopioid analgesics are preferred for lactating patients who require pain control peripartum or for surgery outside of the postpartum period. When opioids are needed for lactating patients, use the lowest effective dose for the shortest duration of time to limit adverse events in the mother and breastfeeding infant. When opioid is needed to treat maternal pain following surgery, use of buprenorphine can be considered (AAP [Sachs 2013]; ABM [Martin 2018]; ABM [Reece-Stremtan 2017]).

Monitor infants exposed to opioids via breast milk for drowsiness, sedation, feeding difficulties, or limpness (ACOG 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); signs or symptoms of infection or evidence of tampering or attempts to remove the depot at the injection site (ER injection [Brixadi]).

Additional monitoring parameters with use for subacute or 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. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2022]).

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 ER Sublocade formulation is injected SUBQ as a liquid; subsequent precipitation following injection results in a solid depot which will gradually release buprenorphine via diffusion and biodegradation of the depot. The ER Brixadi formulation is injected SUBQ as a low viscous solution and transforms into a liquid crystalline gel depot that will gradually release buprenorphine via diffusion and biodegradation of the depot.

Pharmacokinetics (Adult Data Unless Noted)

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: IV: ~218 to 806 L (Huestis 2013; Kuhlman 1996; manufacturer's labeling).

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:

Buccal film: 27.6 ± 11.2 hours.

ER SUBQ: Apparent terminal half-life: 3 to 5 days (weekly Brixadi), 19 to 26 days (monthly Brixadi), or 43 to 60 days (Sublocade).

IV: 2.2 hours (range: 1.2 to 7.2 hours) after IV administration of buprenorphine 0.3 mg (manufacturer's labeling). Note: Variable half-lives have been reported ranging from 8.6 to 32.1 hours for doses from 0.3 to 16 mg but may be due to analytical methods utilized (Harris 2000; Huestis 2013; Kalluri 2017).

Sublingual tablet: Apparent terminal half-life: ~37 hours. Note: Extended elimination half-life for sublingual administration may be due to depot effect (Kuhlman 1996).

Transdermal patch: Apparent terminal half-life: ~26 hours.

Time to peak, plasma:

Buccal film: 2.5 to 3 hours.

ER SUBQ: ~24 hours (weekly Brixadi), 6 to 10 hours (monthly Brixadi), or 24 hours (Sublocade), with steady state achieved after the 4th weekly or monthly dose (Brixadi) or 4 to 6 months (Sublocade). Injection in the arm site is associated with ~10% lower plasma levels from other sites (Brixadi).

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 (Adult Data Unless Noted)

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.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Butrans | Buvidal;
  • (AR) Argentina: Buprenorfina teva | Magnogen | Restiva | Temgesic;
  • (AT) Austria: Astec | Bupensan | Buprenocan | Buprenorphin 1a pharma | Buprenorphin hexal | Buprenorphin ratiopharm | Buprenorphin stada | Bupretec | Buvidal | Norspan | Sixmo | Subutex | Temgesic | Transtec | Triquisic;
  • (AU) Australia: Bupredermal | Buprenorphine sandoz | Buvidal monthly | Buvidal weekly | Norspan | Sublocade | Subutex | Temgesic;
  • (BE) Belgium: Buprenorfine sandoz | Buprenorphine Teva Wekelijks | Buvidal | Subutex | Temgesic | Transtec;
  • (BG) Bulgaria: Buprenorphin G.L. | Buprenorphine | Buprenorphine actavis;
  • (BR) Brazil: Norpatch | Restiva | Temgesic | Transtec;
  • (CH) Switzerland: Buprenorphin mepha | Subutex | Transtec;
  • (CI) Côte d'Ivoire: Temgesic;
  • (CL) Chile: Brugesic | Norspan | Preqifin | Transtec;
  • (CN) China: Buprenorphine | Norspan | Sha fei | Shu mei fen;
  • (CO) Colombia: Norspan 7 | Transtec;
  • (CZ) Czech Republic: Addnok | Buprenorfin mylan | Buprenorfin stada | Buprenorphine actavis | Buprenorphine alkaloid | Buprenorphine sandoz | Bupretec | Noprex | Ravata | Sixmo | Subutex | Temgesic | Transtec;
  • (DE) Germany: Bup 4 Tagepflaster | Bupensan | Buplab | Bupre 1a pharma | Bupre hexal | Buprenaddict | Buprendo | Buprenor Mylan | Buprenorphin al | Buprenorphin AWD | Buprenorphin axunio | Buprenorphin beta | Buprenorphin dura | Buprenorphin ethypharm | Buprenorphin G.L. | Buprenorphin neuraxpharm | Buprenorphin puren | Buprenorphin ratiopharm | Buprenorphin Sanofi | Buprenorphine glenmark | Buprenorphine libra pharm | Butrans | Buvera | Buvidal | Cras | Norspan | Subutex | Temgesic | Transtec | Transtec pro;
  • (DK) Denmark: Norspan | Norvipren;
  • (DO) Dominican Republic: Temgesic | Transtec;
  • (EC) Ecuador: Norspan | Temgesic | Transtec;
  • (EE) Estonia: Norspan | Subutex;
  • (ES) Spain: Buprenorfina aristo | Buprenorfina ratiopharm | Buprenorfina Sandoz | Buprenorfina stada | Buprenorfina teva | Buprex | Buvidal | Feliben | Prefin | Subutex | Transtec;
  • (FI) Finland: Buprefarm | Bupremyl | Buprenorphine glenmark | Buprenorphine sandoz | Buprenorphine stada | Buvidal | Norspan | Sixmo | Subutex | Temgesic;
  • (FR) France: Buprenorphine arrow | Buprenorphine Biogaran | Buprenorphine cristers | Buprenorphine eg | Buprenorphine Sandoz | Buprenorphine Teva | Buvidal | Subutex | Temgesic;
  • (GB) United Kingdom: Bunov | Bupeaze | Buplast | Bupramyl | Buprenorphine | Buprenorphine Sandoz | Busiete | Butec | Buvidal | Carlosafine | Gabup | Hapoctasin | Natzon | Panitaz | Prefibin | Prenotrix | Rebrikel | Reletrans | Relevtec | Sevodyne | Sixmo | Subutex | Temgesic | Tephine | Transtec | Turgeon;
  • (GR) Greece: Buvera | Prenorvine | Subutex;
  • (HK) Hong Kong: Norspan | Subutex | Temgesic;
  • (HR) Croatia: Buprenorfin Alkaloid | Buprenorfin sandoz | Laribon | Subutex | Transtec;
  • (HU) Hungary: Bupren | Buprenorphine alkaloid | Norspan | Temgesic | Transtec;
  • (ID) Indonesia: Subutex;
  • (IE) Ireland: Butrans | Buvidal | Reletrans | Subutex | Temgesic | Transtec;
  • (IL) Israel: Nopan;
  • (IN) India: Addnok | Aquadol bp | Benergence | Bupatch | Buprenorphine | Bupreplast | Buprigesic | Buprinor | Buvalor | Norphin | Rupatch | Tidigesic | Zuprinor;
  • (IS) Iceland: Norspan;
  • (IT) Italy: Algesalona | Buprenorfina molteni | Buprenorfina Mylan Generics | Buprenorfina Sun | Busette | Durlevatec | Sixmo | Subutex | Temgesic | Transtec;
  • (JP) Japan: Lepetan | Norspan;
  • (KE) Kenya: Addnok;
  • (KR) Korea, Republic of: Norspan | Renolphan | Transtec;
  • (KW) Kuwait: Butrans | Buvidal;
  • (LT) Lithuania: Bunondol | Subutex | Temgesic;
  • (LU) Luxembourg: Subutex | Temgesic | Transtec;
  • (LV) Latvia: Bunondol | Buprenorphine g.l. pharma | Subutex | Temgesic;
  • (MA) Morocco: Temgesic;
  • (MX) Mexico: Binarius | Brospina | Buprenorfina | Cistersin | Dosfol | Herbane | Patox | Soloro 7 | Subutex | Tecnopren | Temgesic | Transtec;
  • (MY) Malaysia: Sovenor | Subutex | Temgesic | Transtec;
  • (NL) Netherlands: Buprenorfine CF | Buprenorfine glenmark | Buprenorfine Mylan | Buprenorfine sandoz | Buprenorfine teva | Buprenorphin acino | Butrans | Temgesic | Transtec;
  • (NO) Norway: Bugnanto | Buprefarm | Buprenorphine Orifarm | Buprenorphine Sandoz | Buvidal | Norspan | Sixmo | Subutex | Temgesic;
  • (NZ) New Zealand: Buprenorphine | Sublocade | Temgesic;
  • (PE) Peru: Buprex | Norspan | Transtec;
  • (PH) Philippines: Buprenorphine | Norspan | Transtec;
  • (PK) Pakistan: Benorine | Bnor | Bubrifen | Buepron | Bunex | Bunorfin | Bupregesic | Dorfene | Dorgesic | Gesnor | Loragesic | Mupregesic | Norpin | Orgesic | Prenor | Temfin | Temgesic | Zonor;
  • (PL) Poland: Bunondol | Bunorfin | Buprendal | Buprenorfina | Melodyn | Temgesic | Transtec;
  • (PR) Puerto Rico: Buprenex | Buprenorphine | Buprenorphine HCL | Butrans | Probuphine | Sublocade | Subutex;
  • (PT) Portugal: Buprenorfina | Buprenorfina actavis | Buprenorfina Azevedos | Buprenorfina ciclum | Buprenorfina generis | Buprenorfina Goldfarma | Buprenorfina Labesfal | Buprenorfina PLS | Buprenorfina ratiopharm | Buprenorphine ratiopharm | Buprex | Ramatrix | Subutex | Transtec | Triquisic;
  • (QA) Qatar: Butrans | Buvidal Weekly | Sublocade | Subutex;
  • (RU) Russian Federation: Addnok | Bupranal | Transtec;
  • (SA) Saudi Arabia: Butrans | Buvidal;
  • (SE) Sweden: Buprefarm | Bupremyl | Buprenorfin Actavis | Buprenorfin evolan | Buprenorphine 2care4 | Buprenorphine bluefish | Buprenorphine g.l. pharma | Buprenorphine glenmark | Buprenorphine Orifarm | Buprenorphine Sandoz | Buprenorphine sandoz | Buprenorphine stada | Buprenorphine Teva | Buprenorphine teva | Buprenotex | Buvidal | Norspan | Sixmo | Subutex | Temgesic;
  • (SG) Singapore: Sovenor | Subutex | Temgesic;
  • (SI) Slovenia: Buprenorfin Alkaloid | Buvidal | Subutex | Transtec;
  • (SK) Slovakia: Buprenorphine sandoz | Bupretec | Noprex | Norspan | Subutex | Temgesic | Transtec;
  • (TH) Thailand: Buprine | Temgesic;
  • (TW) Taiwan: Buprenorphine | Sovenor | Subutex | Temgesic | Transtec;
  • (UA) Ukraine: Addnok | Bupren ic | Buprenorphin | Buprenorphyn;
  • (UY) Uruguay: Temgesic;
  • (ZA) South Africa: Sovenor | Subutex | Temgesic
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