Brand names: Belbuca, Buprenex, Butrans, Probuphine, Sublocade
Drug class: Opiate Partial Agonists
VA class: CN101
Chemical name: 6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-, [5α,7α,(S)]
Molecular formula: C₂₉H₄₁NO₄C₂₉H₄₁NO₄•HCl
CAS number: 52485-79-7

Medically reviewed by Drugs.com on Apr 19, 2023. Written by ASHP.

Introduction

Analgesic; opiate partial agonist.

Uses for Buprenorphine

Pain

Used parenterally for relief of pain that is severe enough to require opiate analgesia and for which alternative treatment options (e.g., nonopiate analgesics, opiate-containing fixed combinations) have not been, or are not expected to be, adequate or tolerated.

Has been used parenterally for management of pain such as that associated with acute and chronic medical disorders including cancer, trigeminal neuralgia, accidental trauma, ureteral calculi, and MI.

Used parenterally for management of postoperative pain in patients who have undergone various types of surgery, including neurologic, cardiovascular (e.g., CABG, valve replacement), cesarean section, gynecologic, abdominal (e.g., cholecystectomy, bowel resection), urologic, general (e.g., head and neck, breast), and orthopedic (e.g., total hip replacement, spinal fusion).

Used transdermally or buccally for management of pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate. Do not use on an as-needed (“prn”) basis.

Has been used parenterally for preoperative sedation and analgesia^{† [off-label]} and as an adjunct to surgical anesthesia^{† [off-label]}.

Do not use oral transmucosal formulations that are intended for use in the treatment of opiate dependence for analgesia. Fatal overdosage reported with such use in opiate-naive individuals.

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated. Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain. Optimize concomitant use of other appropriate therapies.

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose).

Opiate Dependence

Used sublingually or buccally for treatment of opiate dependence (OUD) in an office-based outpatient setting (designated an orphan drug by FDA for this use); used alone and in fixed combination with naloxone (buprenorphine/naloxone).

Although buprenorphine traditionally has been preferred for the initial (i.e., induction) phase of treatment, additional experience indicates that either buprenorphine or buprenorphine/naloxone may be used for induction therapy in patients dependent on heroin or other short-acting opiates. The manufacturers and some experts recommend use of buprenorphine alone for induction in patients dependent on long-acting opiates; adequate and well-controlled studies of buprenorphine/naloxone are lacking in this population.

Generic buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Suboxone sublingual tablets; branded formulation no longer commercially available in US) are labeled in US only for maintenance treatment, but have been used (similarly to other oral transmucosal buprenorphine/naloxone preparations) for induction^{† [off-label]}.

Following induction, buprenorphine/naloxone is preferred for maintenance treatment when use includes unsupervised administration since the presence of naloxone (an opiate antagonist) in the formulation should discourage parenteral misuse. Limit use of buprenorphine alone in an unsupervised setting to pregnant women and patients who cannot tolerate naloxone.

Buprenorphine extended-release sub-Q injection used for the treatment of moderate to severe opiate dependence in patients who have initiated treatment with an oral transmucosal buprenorphine-containing preparation followed by dosage adjustment for ≥7 days.

Buprenorphine subdermal implants used for maintenance treatment of opiate dependence in patients who have achieved and maintained prolonged clinical stability on a low to moderate dosage of an oral transmucosal buprenorphine-containing preparation (i.e., a transmucosal dosage that provides blood buprenorphine concentrations comparable to or lower than those provided by the subdermal implants).

Safety and efficacy of transdermal buprenorphine for treatment of opiate dependence not established.

Related/similar drugs

gabapentin, acetaminophen, cyclobenzaprine, tramadol, naproxen, oxycodone, Tylenol

Buprenorphine Dosage and Administration

General

REMS: Opiate Analgesics Used in Outpatient Setting

• FDA has approved a REMS for opiate analgesics, including buprenorphine transdermal system (Butrans) and buprenorphine buccally dissolving strips (Belbuca), used in the outpatient setting and not covered by other REMS programs. (See REMS.)

• The goals are to reduce the occurrence of addiction, unintentional overdosage, and death resulting from inappropriate prescribing, misuse, and abuse of opiate analgesics.

• The program consists of educational programs for health professionals, a patient counseling guide, and a product-specific medication guide for patients.

• Additional information available at [Web].

REMS: Buprenorphine-containing Oral Transmucosal Preparations

• FDA has approved REMS program (Buprenorphine-containing Transmucosal Products for Opioid Dependence [BTOD] REMS) for buprenorphine-containing oral transmucosal preparations (i.e., sublingual tablets and sublingually or buccally dissolving strips) used for the treatment of opiate dependence. (See REMS.)

• The goals are to reduce the risk of accidental overdosage, misuse, and abuse and to inform prescribers, pharmacists, and patients of the serious risks associated with these preparations.

• The REMS includes a medication guide requirement and outlines steps to ensure documentation of safe use conditions and proper monitoring for each patient receiving the drug.

• REMS requirement does not apply when buprenorphine-containing oral transmsucosal preparations are dispensed to patients admitted to an opiate treatment program.

• Additional information about buprenorphine-containing oral transmucosal preparations available at [Web].

REMS: Buprenorphine Extended-release Sub-Q Injection

• FDA has approved a REMS for buprenorphine extended-release sub-Q injection (Sublocade REMS). (See REMS.)

• The goals are to reduce the risk of serious harm or death that could result from IV self-administration by ensuring that the injection is dispensed by certified health care settings and pharmacies directly to health care providers for administration by a health care professional.

• The REMS includes a redistricted distribution program.

• Additional information available at [Web].

REMS: Buprenorphine Subdermal Implants

• FDA has approved a REMS for buprenorphine subdermal implants (Probuphine REMS). (See REMS.)

• The goals are to reduce the risks of complications of implant migration, protrusion, or expulsion; nerve damage associated with implant insertion and removal; and accidental overdosage, misuse, and abuse if an implant is expelled or protrudes from the skin.

• The REMS requires certification of pharmacies that dispense the implant, clinicians who prescribe the implant, and clinicians who insert the implants; monitoring and documentation of implant removal; restriction of distribution to settings with a certified prescriber; and a medication guide for patients.

• Additional information available at [Web].

Restricted Distribution Program for Buprenorphine Treatment of Opiate Dependence

• The Drug Addiction Treatment Act of 2000 (DATA 2000) allows qualifying physicians to prescribe and dispense opiates in schedules III, IV, and V of the Federal Controlled Substances Act that have been approved by FDA for detoxification or maintenance treatment of opiate dependence. The Comprehensive Addiction and Recovery Act of 2016 (CARA 2016) expands the practitioner categories through October 1, 2021, to include qualifying nurse practitioners and physician assistants. Prior to passage of DATA 2000, opiate dependence treatment could be provided only at specially registered clinics.

• Under DATA 2000 and CARA 2016, prescription use of buprenorphine and buprenorphine/naloxone in the treatment of opiate dependence is limited to practitioners who meet certain requirements, have notified the Secretary of the US Department of Health and Human Services (HHS) of their intent to prescribe these preparations for this indication, and have been assigned a unique identification number that must be included on each prescription for the drug. Additional information available at HHS Substance Abuse and Mental Health Services Administration (SAMHSA) website ([Web]).

• Limits are placed on number of patients a qualifying practitioner may treat at one time: initial upper limit is 30, but regulations allow qualifying practitioners to subsequently apply to increase number of patients to 100 and ultimately to 275.

• Pharmacists may utilize SAMHSA's online look-up tool (at [Web]) or contact 866-287-2728 to verify whether a prescriber is in compliance with the provisions of DATA 2000; pharmacists also may contact SAMHSA at infobuprenorphine@samhsa.hhs.gov.

• Patient-identifying information pertaining to treatment of substance abuse must be handled with greater confidentiality than patients' general medical information.

Opiate Dependence

• Prior to induction, consider type of opiate dependence (i.e., long- or short-acting opiate), time since last opiate use, and degree of opiate dependence. Abuse of long-acting formulations by manipulation of the dosage form (e.g., crushing and snorting or injecting extended-release oral dosage forms) may cause these formulations to act as short-acting drugs.

• To avoid precipitating withdrawal, give the first dose of buprenorphine or buprenorphine/naloxone when clear, objective signs of opiate withdrawal are evident. Some experts recommend use of an opiate withdrawal scale (e.g., Clinical Opioid Withdrawal Scale [COWS] score of approximately 11–12 or higher) to establish that withdrawal is sufficient to allow for safe and comfortable induction.

• Individuals dependent on heroin or other short-acting opiates: Manufacturers recommend administering the first dose of buprenorphine or buprenorphine/naloxone ≥4 or ≥6 hours, respectively, after last opiate use. Some experts recommend waiting at least 6–12 hours after last use of short-acting opiates and recommend using an opiate withdrawal scale to determine whether withdrawal is adequate for initiating induction therapy.

• Controlled experience with the transfer of patients from methadone maintenance to buprenorphine is limited. Withdrawal symptoms may be more likely in those receiving higher methadone hydrochloride dosages (>30 mg daily) and when the first buprenorphine dose is given shortly after the last methadone dose.

• Individuals dependent on methadone or other long-acting opiates: May be more susceptible to precipitated and prolonged withdrawal during induction. Administer first dose of buprenorphine generally not less than 24 hours after last opiate use. Taper methadone hydrochloride dosage to approximately 30–40 mg daily, or less, and maintain at this level for ≥1 week prior to buprenorphine induction. Experts state that the first buprenorphine dose may be administered at least 24–72 hours or longer after last use of long-acting opiates (e.g., methadone) and recommend using an opiate withdrawal scale to determine whether withdrawal is adequate for initiating induction therapy.

• Induction in prescribing clinician's office is recommended to reduce the risk of precipitated withdrawal; unsupervised administration may then be initiated as the patient's clinical stability allows. Although large, randomized, controlled studies are lacking, experts state that at-home induction (with early in-office follow-up) by patients dependent on short-acting opiates may be considered depending on the patient's circumstances if the patient and/or clinician is experienced with buprenorphine use and the patient can rate withdrawal symptoms, fully understand induction dosing instructions, and can and will contact the clinician as needed.

• Patients receiving maintenance treatment should be seen at reasonable intervals based on the individual's circumstances (e.g., at least weekly during the first months of therapy, monthly visits may be reasonable when receiving stable dosage and progressing toward treatment goals).

• Consider patient's clinical stability, home situation, and ability to manage take-home medication when establishing prescription quantities for unsupervised administration. Authorization of multiple refills is not advised early in treatment or without appropriate follow-up visits.

• Review of state prescription drug monitoring program (PDMP) data, urine drug testing, and recall visits for “pill” counts are recommended.

• If treatment goals not achieved, reevaluate appropriateness of the current therapy. Unstable patients (e.g., those who are abusing or are dependent on various drugs or are unresponsive to psychosocial interventions) may require referral for more intensive treatment.

• Strongly consider prescribing naloxone concomitantly for all patients receiving medications for treatment of OUD. Also consider prescribing naloxone when patients receiving opiates (e.g., buprenorphine) for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.

Managing Opiate Therapy for Acute Pain

• Optimize concomitant use of other appropriate therapies.

• When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.

• When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days). Do not prescribe larger quantities for use in case pain continues longer than expected; instead, reevaluate patient if severe acute pain does not remit.

• For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.

• Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.

• Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery. When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.

Managing Opiate Therapy for Chronic Noncancer Pain

• Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.

• Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction; establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.

• Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.

• Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.

• Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage. Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.

• Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase and reevaluate on ongoing basis (e.g., at least every 3 months ) throughout therapy. Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies. Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment). If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.

• When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks. Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.

• Higher dosages require particular caution, including more frequent and intensive monitoring or referral to specialist. Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, OUD).

• CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and should avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily. Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended) or have mandated risk-management strategies (e.g., review of state PDMP data prior to prescribing).

• Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.

• Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion. Offer or arrange treatment for patients with OUD.

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.

Administration

Administer by IM or IV injection for relief of pain. Administer transdermally or buccally for management of chronic pain only (see Pain under Uses).

Administer sublingually as a single agent or sublingually or buccally in fixed combination with naloxone for management of opiate dependence. May administer buprenorphine as subdermal implants or as extended-release sub-Q injection following initial induction and stabilization on an oral transmucosal buprenorphine-containing preparation.

Also administered by continuous IV infusion^{† [off-label]}, by IM or IV injection using a patient-controlled infusion device^{† [off-label]}, and by epidural injection^† for pain relief.

For solution and drug compatibility information, see Compatibility under Stability.

Sublingual Administration

Buprenorphine or Buprenorphine/Naloxone Sublingual Tablets for Opiate Dependence (Generic equivalents of Suboxone or Subutex tablets, Zubsolv)

Place tablets under the tongue and allow to dissolve. Drinking warm fluids prior to administration may aid dissolution.

For doses requiring multiple tablets, all the tablets may be placed under the tongue at once. Alternatively, patients may place 2 tablets under the tongue at a time if they are unable to place >2 tablets comfortably.

To ensure consistent bioavailability, patients should adhere to the same manner of dosing with continued use.

Administer tablet whole; do not cut. Patient should not eat or drink until the tablet is completely dissolved. Patient should not chew or swallow the tablet and should not talk while the tablet is dissolving; these activities may affect absorption.

Median dissolution time for buprenorphine/naloxone (Zubsolv) sublingual tablets is 5 minutes.

Demonstrate proper administration technique to the patient.

Buprenorphine/Naloxone Sublingually Dissolving Strips for Opiate Dependence (Suboxone)

Administer sublingually during induction therapy to minimize exposure to naloxone and reduce the risk of precipitated withdrawal; administer either sublingually or buccally during maintenance treatment. Buprenorphine exposure is similar following buccal or sublingual administration, but naloxone exposure is somewhat higher after buccal administration.

Follow a consistent manner of administration to ensure consistency in bioavailability.

Place up to 2 strips under the tongue (on either side near the base of the tongue) in a way that minimizes overlapping, and allow to dissolve. Administer strips whole; do not cut. Patient should not move the strips after placement. Patient should drink water prior to administration to aid dissolution.

For doses requiring >2 strips, place additional strip(s) under the tongue after the first 2 strips have completely dissolved.

Patient should not chew or swallow the strip and should not talk while the strip is dissolving; these activities may alter absorption.

Demonstrate proper administration technique to the patient.

Buccal Administration

Buprenorphine Buccally Dissolving Strips for Pain Management (Belbuca)

For buccal administration only.

Administer every 12 hours.

Immediately before administration, patient must wet the inside of the cheek with the tongue or rinse the mouth with water to wet the area for placement. Apply strip immediately after removal from the individually sealed package. Do not use if package seal is broken or strip is cut, damaged, or altered in any way. Place yellow side of the strip against the inside of the cheek, where it will adhere to the moist mucosa. Hold entire strip in place with clean, dry fingers for 5 seconds; then leave in place until fully dissolved (usually ≤30 minutes).

Do not apply to areas of the mouth with open sores or lesions. (See Buccal Buprenorphine in Cancer Patients with Mucositis under Cautions.)

Patient should not manipulate the strip with the tongue or fingers and should not eat or drink until the strip has dissolved. Chewing or swallowing the strip may result in lower peak plasma concentrations and reduced bioavailability.

Demonstrate proper administration technique to the patient.

Buprenorphine/Naloxone Buccally Dissolving Strips for Opiate Dependence (Bunavail)

Immediately prior to administration, patient should wet the inside of the cheek with the tongue or rinse the mouth with water to moisten the area for placement. Apply strip immediately after removal from the individually sealed package. Administer the strip whole; do not cut or tear. Use clean, dry fingers to hold the strip with the text facing up and then place it against the inside of the cheek with the text side against the cheek; press in place for 5 seconds.

Place a second strip (if required to complete the dose) on the inside of the other cheek immediately after administering the first strip. When multiple strips are required, apply no more than 2 strips to the inside of one cheek at a time.

Patient should not manipulate the strip with the tongue or fingers, eat or drink until the strip has dissolved, or chew or swallow the strip. Chewing or swallowing the strip may alter absorption.

Buprenorphine/Naloxone Sublingually Dissolving Strips for Opiate Dependence (Suboxone)

Administer either buccally or sublingually during maintenance treatment. Sublingual administration is recommended during induction to minimize exposure to naloxone and reduce the risk of precipitated withdrawal. Buprenorphine exposure is similar following buccal or sublingual administration, but naloxone exposure is somewhat higher after buccal administration.

Follow a consistent manner of administration to ensure consistency in bioavailability.

Place 1 strip on the inside of the right or left cheek. Administer strip whole; do not cut. Strip should not be moved after placement. Patient should drink water prior to administration to aid dissolution.

Place a second strip, if required to complete the dose, on the inside of the opposite cheek. If a third strip is required, place it on the inside of the right or left cheek after the first 2 strips have dissolved.

Patient should not or chew or swallow the strip and should not talk while the strip is dissolving; these activities may alter absorption.

Demonstrate proper administration technique to the patient.

IV Injection

Rate of Administration of Conventional Injection for Pain Management

Administer over ≥2 minutes.

Continuous IV Infusion

Dilution of Conventional Injection

Dilute to a concentration of 15 mcg/mL in 0.9% sodium chloride.

Rate of Administration of Conventional Injection for Pain Management

Administer via a controlled-infusion device.

Sub-Q Administration

Buprenorphine Extended-release Sub-Q Injection for Opiate Dependence (Sublocade)

A clinician must prepare and administer the injection.

For sub-Q injection only. Do not administer IV or IM.

Administer at monthly intervals (minimum of 26 days between injections).

Remove injection from refrigerator and allow to reach room temperature (over ≥15 minutes) prior to administration. Do not open foil pouch containing the prefilled syringe until the patient arrives for the injection. Administer using the manufacturer-provided syringe and safety needle. Attach the safety needle just prior to administration. Injection should appear clear, viscous, and colorless to yellow to amber.

Make injections into the abdomen between the transpyloric and transtubercular planes at a site with adequate sub-Q tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigmentation). Do not inject into areas that are irritated, reddened, bruised, infected, or scarred. Rotate injection sites. Manufacturer recommends that patient be in the supine position to receive the injection.

Discard injection if stored at room temperature for >7 days.

A solid depot from which buprenorphine is gradually released forms at the injection site. A depot can be excised surgically, if necessary, under local anesthesia within 14 days of injection.

Monitor injection site for infection and evidence of tampering or attempted depot removal.

Subdermal Administration

Buprenorphine Subdermal Implants for Opiate Dependence (Probuphine)

Clinicians must successfully complete required training and become certified prior to prescribing buprenorphine implant therapy; those performing implant insertion or removal procedures must successfully complete training on these procedures and be certified to perform implant insertion. Patients must be monitored to ensure that buprenorphine implants are removed by a clinician with appropriate certification; clinicians must maintain documentation of implant insertion and removal in each patient's medical record.

Each dose consists of 4 implants inserted subdermally in the inner aspect of the upper arm; inserts are intended to be left in place for 6 months and removed by the end of the sixth month.

If continued implant therapy is desired at the time the initial implants are removed, insert new implants in the contralateral arm. After one insertion in each arm, most patients should be transitioned back to oral transmucosal buprenorphine therapy; experience is lacking with insertion of implants into other sites in the arm or with insertion of new implants at prior administration sites.

Consult manufacturer's prescribing information for proper methods of implant insertion and removal and associated precautions. Always verify the presence of each implant by palpation or, if necessary, by ultrasound or magnetic resonance imaging (MRI) immediately after insertion and prior to attempted removal.

Proper implant placement is essential to avoid serious complications and to facilitate removal.

Examine implant site one week following insertion for infection, adequacy of wound healing, and evidence of implant extrusion.

If an implant is expelled spontaneously, measure the expelled portion to ensure that it is intact. Remove any partial remaining implant, and examine the incision site for infection and to determine whether the remaining implants should be removed. A replacement for the expelled implant may be inserted in the same arm medially or laterally to the existing implants or, alternatively, in the contralateral arm.

A surgical specialist consulted to assist with a difficult implant removal does not require certification.

Epidural Injection†

Dilution of Conventional Injection

Has been diluted to a concentration of 6–30 mcg/mL in 0.9% sodium chloride.

Transdermal Administration

Buprenorphine Transdermal System for Pain Management

To expose the adhesive surface of the system, peel off and discard the protective-liner covering just prior to application.

Apply the transdermal system to a dry, intact, nonirritated, hairless or nearly hairless surface at 1 of 8 recommended application sites (upper chest, upper back, side of chest, or upper outer arm on either side of the body) by firmly pressing the system by hand for 15 seconds with the adhesive side touching the skin; ensure that contact is complete, particularly around the edges.

Patients or caregivers should always wash their hands after applying or handling the systems. If the drug-containing adhesive matrix contacts the skin, wash affected area with water; do not use soap, alcohol, or other solvents.

Clip, not shave, hair at the application site prior to application if needed.

Only water should be used if the site must be cleaned before transdermal application; do not use soaps, oils, lotions, alcohol, or abrasive devices that could alter absorption of the drug.

Do not use transdermal system if the seal of the package is broken or if the system is altered in any way (e.g., cut, damaged).

Each transdermal system is intended to be worn continuously for 7 days; apply subsequent systems to a different site after removal of the previous system. Rotation among the 8 recommended application sites is advised. At least 21 days should elapse before reusing any single application site.

If 2 systems are applied for a single dose, apply the systems adjacently at the same site; always apply and remove the systems at the same time.

If a system should inadvertently come off during the period of use, apply a new system to a different skin site and leave in place for 7 days. The edges of the system may be taped in place with first-aid tape if the patient experiences difficulty with system adhesion. If adhesion problems persist, a waterproof or semipermeable adhesive film dressing that is suitable for 7 days of wear (e.g., Bioclusive, Tegaderm) may be applied over the system.

Incidental exposure to water (e.g., while showering or bathing) is acceptable; do not expose system to external heat sources, hot water, or prolonged direct sunlight during period of use. (See Bioavailability under Pharmacokinetics.)

Carefully instruct patient on proper use.

Dosage

Available as buprenorphine (transdermal systems, extended-release sub-Q injection) and buprenorphine hydrochloride (conventional injection, buccally dissolving strips, subdermal implants, sublingual tablets); dosage generally expressed in terms of buprenorphine. Dosage of implants may be expressed as the salt or base.

Also available as fixed combination of buprenorphine hydrochloride and naloxone hydrochloride (sublingual tablets, sublingually or buccally dissolving strips); dosage expressed in terms of buprenorphine and naloxone content.

Pediatric Patients

Pain

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

Individualize initial dosage according to severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy.

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Monitor closely for respiratory depression, especially during the first 24–72 hours of therapy and following any increase in dosage. Adjust dosage accordingly.

IV or IM

Infants <2 years of age: Manufacturer states data are insufficient to recommend a dosage.

Children 2–12 years of age: 2–6 mcg/kg every 4–6 hours; however, longer dosing intervals (e.g., every 6–8 hours) may be sufficient. Do not use a fixed around-the-clock dosing interval until an adequate dosing interval has been established by clinical observation of the patient.

Children ≥13 years of age: 0.3 mg given at intervals of up to every 6 hours as necessary. Repeat initial dose (up to 0.3 mg) once in 30–60 minutes, if needed.

Exercise particular caution with IV administration, especially with initial doses.

Limit dose to the minimum amount required in high-risk patients and those receiving other CNS depressants, including patients in the immediate postoperative period. (See Respiratory Depression under Cautions.)

Circumcision-related Pain

IM

Children 9 months to 9 years of age^† undergoing circumcision: Initial dosage of 3 mcg/kg as an adjunct to surgical anesthesia, followed by additional 3-mcg/kg doses as necessary to provide analgesia postoperatively, has been used.

Adults

Pain

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.

Individualize initial dosage according to severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy. (See Specific Drugs under Interactions.)

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Monitor closely for respiratory depression, especially during the first 24–72 hours of therapy and following any increase in dosage. Adjust dosage accordingly.

IV or IM

0.3 mg given at intervals of up to every 6 hours as necessary. Repeat initial dose (up to 0.3 mg) once in 30–60 minutes, if needed. A dosing interval longer than 6 hours may be adequate in some patients.

It may be necessary to administer single doses of up to 0.6 mg, but the manufacturer recommends that such relatively high doses only be administered IM and only to adults who are not considered high-risk patients.

A regimen including an initial dose of 0.3 mg followed by another 0.3-mg dose repeated in 3 hours is as effective as a single 0.6-mg dose in relieving postoperative pain.

Exercise particular caution with IV administration, especially with initial doses.

Limit dose to the minimum amount required in high-risk patients and those receiving other CNS depressants, including patients in the immediate postoperative period.

Continuous IV Infusion†

Dosages of 25–250 mcg/hour have been used for the management of postoperative pain.

Epidural Injection†

Dosages of 0.15–0.3 mg have been administered in the management of severe, chronic pain (e.g., in terminally ill patients) as frequently as every 6 hours, up to a mean total daily dosage of 0.86 mg (range: 0.15–7.2 mg).

60 mcg as a single dose, up to a mean total dose of 180 mcg administered over a 48-hour period, has been used for the management of postoperative pain.

Supplement to Surgical Anesthesia

Epidural Injection^†

Dosage of 0.3 mg has been used as a supplement to surgical anesthesia with a local anesthetic.

Chronic Pain

Buprenorphine may precipitate withdrawal in patients who have been receiving opiate agonists. Taper current opiate regimen to <30 mg daily of oral morphine sulfate (or equivalent) before initiating buprenorphine.

Overestimation of buprenorphine dosage when transferring patients from other opiate therapy to buprenorphine therapy can result in fatal overdosage with the first dose. Monitor closely, particularly when switching from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.

Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.

Titrate dosage to a level that provides adequate analgesia and minimizes adverse effects. Patients may receive supplemental short-acting analgesics as needed until adequate analgesia is attained. If unacceptable adverse effects are observed, consider dosage reduction.

Continually assess adequacy of pain control and reevaluate for adverse effects, as well as for development of addiction, abuse, or misuse. During long-term therapy, periodically reevaluate continued need for opiate analgesics.

Patients who experience episodes of breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., “rescue” therapy with an immediate-release analgesic). If level of pain increases after dosage stabilization, attempt to identify source of increased pain before increasing the dosage.

Transdermal and buccal buprenorphine should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.

Buccal

Opiate-naive or non-tolerant patients: Initiate with 75 mcg once daily or, if tolerated, 75 mcg every 12 hours. After ≥4 days at this dosage, may increase dosage to 150 mcg every 12 hours.

Patients previously receiving <30 mg daily of oral morphine sulfate (or equivalent): Initiate with 75 mcg once daily or 75 mcg every 12 hours.

Patients previously receiving 30–89 mg daily of oral morphine sulfate (or equivalent): Taper current opiate regimen to <30 mg daily of morphine sulfate (or equivalent) and initiate with 150 mcg every 12 hours.

Patients previously receiving 90–160 mg daily of oral morphine sulfate (or equivalent): Taper current opiate regimen to <30 mg daily of morphine sulfate (or equivalent) and initiate with 300 mcg every 12 hours.

Patients previously receiving >160 mg daily of oral morphine sulfate (or equivalent): Buccally dissolving strips may not provide adequate analgesia; consider alternative analgesic.

Discontinue all other around-the-clock opiate analgesics when therapy with buprenorphine buccally dissolving strips is initiated.

Titration: Increase at minimum intervals of 4 days in increments of no more than 150 mcg every 12 hours to a level that provides adequate analgesia and minimizes adverse effects. Maximum dosage is 900 mcg every 12 hours (see QT-interval Prolongation under Cautions). If this dosage is inadequate, consider an alternative analgesic.

Use doses of 600, 750, and 900 mcg only following titration from lower buccal dosages.

In patients with known or suspected mucositis, reduce usual initial dosage and each incremental dosage during titration by one-half because of potential for higher peak concentrations and systemic exposure to the drug.

Discontinuance: When discontinuing therapy, gradually taper dosage to prevent manifestations of withdrawal. Do not abruptly discontinue therapy. If manifestations of withdrawal occur, increase dosage to the prior level and taper more slowly by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose.

Transdermal

Reserve dosages of 7.5, 10, 15, and 20 mcg/hour for patients who are opiate experienced (i.e., have been receiving oral morphine sulfate dosages of up to 80 mg or more daily [or equivalent] for 1 week or longer) and have developed tolerance to an opiate of comparable potency.

Opiate-naive patients: Initiate with buprenorphine 5 mcg/hour.

Patients previously receiving <30 mg daily of oral morphine sulfate (or equivalent): Initiate with buprenorphine 5 mcg/hour.

Patients previously receiving 30–80 mg daily of oral morphine sulfate (or equivalent): Taper current opiate regimen for up to 7 days to a total 24-hour dosage of ≤30 mg of morphine sulfate (or equivalent) and initiate with buprenorphine 10 mcg/hour.

Patients previously receiving >80 mg daily of oral morphine sulfate (or equivalent): Buprenorphine 20 mcg/hour may not provide adequate analgesia; consider alternative analgesic.

Discontinue all other around-the-clock opiate analgesics when therapy with transdermal buprenorphine is initiated. Initiate buprenorphine at the next dosing interval following discontinuance of the current opiate regimen.

Titration: Increase at minimum intervals of 72 hours to a level that provides adequate analgesia and minimizes adverse effects. Adjust dosage in increments of 5, 7.5, or 10 mcg/hour by simultaneously applying no more than two 5-, 7.5-, or 10-mcg/hour systems. Maximum transdermal dosage is 20 mcg/hour (see QT-interval Prolongation under Cautions).

Discontinuance: When discontinuing therapy, taper dosage every 7 days to prevent manifestations of withdrawal. Consider use of a short-acting opiate during tapering process. Do not abruptly discontinue therapy.

Opiate Dependence

All oral transmucosal formulations are not bioequivalent. (See Bioavailability under Pharmacokinetics.)

Recommended dosage ranges (based on buprenorphine component) are the same for generic buprenorphine sublingual tablets (i.e., generic equivalents of Subutex sublingual tablets [branded formulation no longer commercially available in US]), generic buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Suboxone sublingual tablets [branded formulation no longer commercially available in US]), and buprenorphine/naloxone sublingually dissolving strips (Suboxone), although some strengths and dose combinations of these preparations are not bioequivalent.

Dosage ranges for certain other oral transmucosal buprenorphine/naloxone preparations (i.e., Bunavail buccally dissolving strips, Zubsolv sublingual tablets) are lower, reflecting greater bioavailability.

Induction

To reduce the risk of precipitated withdrawal, use a low initial induction dose and give the first dose when clear, objective signs of opiate withdrawal are evident.

After establishing that the initial dose is well tolerated, achieve an adequate treatment dosage (titrated to clinical effectiveness) as rapidly as possible, since gradual dosage titration over several days has been associated with a high dropout rate during induction therapy.

Use of an opiate withdrawal scale (e.g., COWS) can be helpful in establishing that withdrawal is sufficient to allow for safe and comfortable induction and in assessing the effects of induction doses.

Sublingual (Generic equivalents of Suboxone or Subutex sublingual tablets, Suboxone sublingually dissolving strips)

Day 1: Total dosage of up to 8 mg of buprenorphine (alone or in fixed combination with up to 2 mg of naloxone). Administer initial buprenorphine dose of 2 or 4 mg (alone or in fixed combination with naloxone 0.5 or 1 mg, respectively); administer additional doses of 2 or 4 mg at approximately 2-hour intervals if withdrawal symptoms continue and sedation is not observed.

Day 2: Single dose of up to 16 mg of buprenorphine (alone or in fixed combination with up to 4 mg of naloxone).

Other induction regimens that employ a low initial dose with rapid titration to an effective maintenance dosage also have been used.

Sublingual (Zubsolv sublingual tablets)

Day 1: Total dosage of up to 5.7 mg of buprenorphine (in fixed combination with up to 1.4 mg of naloxone). Administer initial buprenorphine dose of 1.4 mg (with naloxone 0.36 mg); administer remainder of day 1 dosage (up to 4.2 mg of buprenorphine and up to 1.08 mg of naloxone) in divided doses as 1 or 2 tablets containing buprenorphine 1.4 mg and naloxone 0.36 mg at intervals of 1.5–2 hours. Some patients (e.g., those who recently received buprenorphine) may tolerate up to 3 tablets containing buprenorphine 1.4 mg and naloxone 0.36 mg as a single second dose.

Day 2: Single dose of up to 11.4 mg of buprenorphine (with up to 2.9 mg of naloxone).

Buccal (Bunavail buccally dissolving strips)

Day 1: Total dosage of up to 4.2 mg of buprenorphine (in fixed combination with up to 0.7 mg of naloxone). Administer initial buprenorphine dose of 2.1 mg (with naloxone 0.3 mg); administer second dose (same strength) approximately 2 hours later based on control of acute withdrawal symptoms.

Day 2: Single dose of up to 8.4 mg of buprenorphine (with up to 1.4 mg of naloxone).

Maintenance

For maintenance treatment, oral transmucosal buprenorphine/naloxone preparations are labeled only for once-daily administration; however, other dosage regimens (i.e., administration every other day^† or 3 times weekly^† at a dose higher than the individually titrated daily dose) have been used once satisfactory stabilization achieved.

Sublingual (Generic equivalents of Suboxone sublingual tablets, Suboxone sublingually dissolving strips)

From day 3 onward, adjust buprenorphine dosage in increments/decrements of 2 or 4 mg daily (in fixed combination with naloxone 0.5 or 1 mg, respectively) to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues treatment.

Target dosage: Buprenorphine 16 mg (with naloxone 4 mg) once daily.

Usual dosage range: Buprenorphine 4–24 mg (with naloxone 1–6 mg) daily.

If switching between generic equivalents of Suboxone sublingual tablets and Suboxone sublingually dissolving strips, continue same dosage. However, not all strengths and dose combinations are bioequivalent; because of potentially greater bioavailability with the strips relative to the tablets, monitor for underdosage or overdosage and adjust dosage if needed. (See Bioavailability under Pharmacokinetics.)

Switching between various combinations of lower- and higher-strength Suboxone strips to obtain the same total dose may alter systemic exposure to buprenorphine and naloxone and require monitoring for underdosage or overdosage. Do not substitute strip strengths without prescriber's approval.

Sublingual (Zubsolv sublingual tablets)

From day 3 onward, adjust buprenorphine dosage in increments/decrements of no more than 2.9 mg (in fixed combination with naloxone 0.71 mg) to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues treatment.

Target dosage: Buprenorphine 11.4 mg (with naloxone 2.9 mg) once daily.

Usual dosage range: Buprenorphine 2.9–17.2 mg (with naloxone 0.71–4.2 mg) daily.

If switching between Zubsolv and Suboxone (or generic equivalent) sublingual tablets, use corresponding strength (see Table 1) and monitor for underdosage or overdosage. Dosage adjustment may be necessary. Systemic buprenorphine exposure following administration of one Suboxone sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg is equivalent to that achieved following administration of one Zubsolv sublingual tablet containing buprenorphine 5.7 mg and naloxone 1.4 mg. (See Bioavailability under Pharmacokinetics.)

Buccal (Bunavail buccally dissolving strips)

From day 3 onward, adjust buprenorphine dosage in increments/decrements of 2.1 mg (in fixed combination with naloxone 0.3 mg) to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues treatment.

Target dosage: Buprenorphine 8.4 mg (with naloxone 1.4 mg) once daily.

Usual dosage range: Buprenorphine 2.1–12.6 mg (with naloxone 0.3–2.1 mg) daily.

If switching between Bunavail and Suboxone (or generic equivalent) sublingual tablets, use corresponding strength (see Table 2) and monitor for underdosage or overdosage. Dosage adjustments may be necessary. Systemic buprenorphine exposure following administration of one Suboxone sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg is equivalent to that achieved following administration of one Bunavail buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7 mg. (See Bioavailability under Pharmacokinetics.)

Buccal (Suboxone sublingually dissolving strips)

Once induction is complete, can switch between buccal and sublingual administration of the sublingually dissolving strips without substantial risk of underdosage or overdosage.

From day 3 onward, adjust buprenorphine dosage in increments/decrements of 2 or 4 mg daily (in fixed combination with naloxone 0.5 or 1 mg, respectively) to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues treatment.

Target dosage: Buprenorphine 16 mg (with naloxone 4 mg) once daily.

Usual dosage range: Buprenorphine 4–24 mg (with naloxone 1–6 mg) daily.

Sub-Q (Sublocade extended-release injection)

Initiate following induction with an oral transmucosal buprenorphine-containing preparation and dosage adjustment over ≥7 days to an oral transmucosal buprenorphine dosage of 8–24 mg daily (as Subutex or Suboxone [or equivalent generic buprenorphine or buprenorphine/naloxone preparation]) or a dosage of another oral transmucosal preparation that provides equivalent buprenorphine exposure. The following formulations and strengths provide equivalent buprenorphine exposure as one Suboxone sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg: one Bunavail buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7 mg, one Zubsolv sublingual tablet containing buprenorphine 5.7 mg and naloxone 1.4 mg, and one Subutex sublingual tablet containing buprenorphine 8 mg.

300 mg monthly for the first 2 months, followed by maintenance dosage of 100 mg monthly. May increase maintenance dosage to 300 mg monthly in patients who tolerate the 100-mg monthly dosage but do not achieve a satisfactory response as evidenced by self-reports or urine drug test results indicating illicit opiate use.

If a dose is missed, administer the missed dose as soon as possible and administer the following dose no less than 26 days later. Occasional dosing delays of up to 2 weeks are not expected to substantially alter the treatment effect.

If a sub-Q depot of the drug must be surgically excised, monitor for withdrawal manifestations and institute appropriate treatment (e.g., an oral transmucosal preparation of the drug) as clinically indicated.

Subdermal (Probuphine implants)

Initiate implant therapy in patients who have achieved and maintained prolonged clinical stability on oral transmucosal buprenorphine therapy; are currently receiving an oral transmucosal buprenorphine maintenance dosage of ≤8 mg daily (as Subutex or Suboxone [or equivalent generic buprenorphine or buprenorphine/naloxone preparations] or a dosage of another oral transmucosal preparation that provides comparable blood buprenorphine concentrations [e.g., Bunavail buccally dissolving strips at a dosage of buprenorphine 4.2 mg and naloxone 0.7 mg daily or less, Zubsolv sublingual tablets at a dosage of buprenorphine 5.7 mg and naloxone 1.4 mg daily or less]); and have received a stable oral transmucosal buprenorphine maintenance dosage of ≤8 mg daily for ≥3 months without the need for supplemental doses or dosage adjustments. The 8-mg oral transmucosal dosage provides blood buprenorphine concentrations that are similar to or less than those provided by the recommended implant dosage. Do not taper the oral transmucosal buprenorphine dosage to this dosage level solely for the purpose of transitioning to implant therapy.

Each dose consists of 4 implants (each containing 80 mg of buprenorphine hydrochloride [equivalent to 74.2 mg of the base]) intended to be left in place for 6 months and then removed by the end of the sixth month.

New implants may be inserted in the contralateral arm when the initial inserts are removed. After one insertion in each arm, most patients should be transitioned back to oral transmucosal buprenorphine therapy.

If new implants are not inserted on the same day that the current ones are removed, administer oral transmucosal buprenorphine at the previous (pre-implant therapy) dosage prior to additional implant therapy.

Although some patients may require occasional supplemental buprenorphine dosing, the manufacturer states that patients should not receive prescriptions for oral transmucosal buprenorphine-containing preparations for as-needed use. Promptly evaluate patients who feel the need for supplemental dosing. An ongoing need for supplemental dosing indicates that the implant dosage is inadequate for stable treatment; consider use of an alternate buprenorphine preparation for maintenance treatment.

If an implant is spontaneously expelled, carefully monitor the patient until the implant is replaced for withdrawal manifestations or other indications that supplemental oral transmucosal dosing may be required.

Discontinuance

The decision to discontinue therapy after a period of maintenance or brief stabilization should be made as part of a comprehensive treatment plan.

Sublingual or Buccal

Taper dosage to reduce the occurrence of withdrawal manifestations. Dosage generally tapered over several months with close monitoring and a plan for sustaining recovery.

Sub-Q (Sublocade extended-release injection)

If therapy is discontinued, monitor for several months for withdrawal manifestations since onset of withdrawal may be delayed; if treatment is required, consider use of an oral transmucosal preparation.

Plasma concentrations of buprenorphine may be detectable for ≥12 months if therapy with this formulation is discontinued after steady state has been achieved (4–6 months of treatment); the correlation between plasma and detectable urine concentrations is not known.

Subdermal (Probuphine implants)

If therapy is discontinued, monitor for withdrawal manifestations and consider use of a tapering dosage of an oral transmucosal preparation.

Prescribing Limits

Pediatric Patients

Pain

IV or IM

Children 2–12 years of age: Manufacturer states that there is insufficient evidence to recommend doses >6 mcg/kg or administration of a repeat dose within 30–60 minutes of the initial dose.

Adults

Pain

For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).

CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to ≥50 mg of morphine sulfate daily for chronic pain and avoid dosages equivalent to ≥90 mg of morphine sulfate daily or carefully justify their decision to prescribe such dosages. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80–120 mg of morphine sulfate daily.

Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).

IM

There are insufficient clinical data to recommend single doses >0.6 mg for long-term use.

Chronic Pain

Buccal

Maximum 900 mcg every 12 hours.

Transdermal

Maximum 20 mcg/hour.

Opiate Dependence

Maintenance

Sublingual (Generic equivalents of Suboxone sublingual tablets, Suboxone sublingually dissolving strips)

Dosages exceeding buprenorphine 24 mg (with naloxone 6 mg) daily not shown to provide any additional clinical advantage.

Sublingual (Zubsolv sublingual tablets)

Dosages exceeding buprenorphine 17.2 mg (with naloxone 4.2 mg) not shown to provide any additional clinical advantage.

Buccal (Bunavail buccally dissolving strips)

Dosages exceeding buprenorphine 12.6 mg (with naloxone 2.1 mg) not shown to provide any additional clinical advantage.

Special Populations

Hepatic Impairment

Pain

Chronic Pain

Buccal

Moderate hepatic impairment (Child-Pugh class B): No dosage adjustment required, but monitor for overdosage and toxicity.

Severe hepatic impairment (Child-Pugh class C): Reduce usual initial dosage and reduce each incremental change in dosage during titration by one-half (i.e., from 150 mcg to 75 mcg); monitor for overdosage and toxicity.

Transdermal

Severe hepatic impairment: Transdermal buprenorphine not studied in this population; consider an alternative analgesic regimen that allows for greater dosing flexibility.

Opiate Dependence

Sublingual or Buccal

Moderate hepatic impairment: Buprenorphine/naloxone not recommended for induction therapy but may be used with caution and careful monitoring for maintenance treatment following induction with buprenorphine alone. (See Hepatic Impairment under Cautions and also see Absorption: Special Populations and Elimination: Special Populations, under Pharmacokinetics.)

Severe hepatic impairment: Reduce initial dose and titration increments of buprenorphine by one-half; monitor for overdosage or toxicity. Avoid use of buprenorphine/naloxone.

Sub-Q (Extended-release Injection)

Moderate to severe hepatic impairment: Use not recommended since formulation does not allow for rapid adjustment of plasma buprenorphine concentrations.

Subdermal (Implant)

Moderate to severe hepatic impairment: Use not recommended since dosage cannot be titrated.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

Pain

Limit parenteral dosage to minimum amount required. Select parenteral dosage with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease or drug therapy.

While specific transdermal or buccal dosage adjustments are not necessary based on age, use caution to ensure safe use. (See Geriatric Use under Cautions.)

Cautions for Buprenorphine

Contraindications

• Known hypersensitivity to buprenorphine or any ingredient (e.g., naloxone) or component of the formulation.

Buprenorphine (Analgesic Use)

• Known or suspected GI obstruction (including paralytic ileus).

• Substantial respiratory depression.

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

Risk of addiction, abuse, and misuse; addiction can occur at recommended dosages or with misuse or abuse. Abuse of buprenorphine can result in overdosage and death; concurrent abuse of alcohol or other CNS depressants increases risk of toxicity.

Assess each patient’s risk for addiction, abuse, and misuse prior to prescribing for analgesia. Monitor all patients for development of these behaviors or conditions. Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk. The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for signs of addiction, abuse, and misuse.

Extended-release opiates (e.g., buprenorphine transdermal system) are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit. Abuse or misuse of the transdermal system by placing it in the mouth, chewing it, swallowing it, or using it in other unintended ways may cause choking, overdosage, and death.

Abuse or misuse of buprenorphine buccally dissolving strips by swallowing the strips may cause choking, overdosage, and death.

Buprenorphine subdermal implants that protrude from the skin or have been expelled are subject to misuse and abuse.

Prescribe for analgesic use in the smallest appropriate quantity; instruct patient on secure storage and proper disposal to prevent theft.

When used for treatment of opiate dependence, prescribe and dispense with appropriate precautions to minimize risk of misuse, abuse, or diversion, and to ensure appropriate protection from theft, including in the patient's home. Monitor for progression of OUD and addictive behaviors. Clinical monitoring must be appropriate to patient’s level of stability. Do not authorize multiple refills during early stages of treatment or without appropriate follow-up visits.

Respiratory Depression

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression. Large initial doses in nontolerant patients, overestimation of the initial buprenorphine dosage when transferring patients from another opiate analgesic, or accidental exposure to buprenorphine, especially by a child, can result in respiratory depression and death.

Serious, life-threatening, or fatal respiratory depression can occur with use of opiates, including buprenorphine, even when used as recommended; can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases. Monitor for respiratory depression, especially during first 24–72 hours of therapy and following any dosage increase.

Carbon dioxide retention from opiate-induced respiratory depression can exacerbate the drug's sedative effects and, in certain patients, can lead to elevated intracranial pressure. (See Head Injury and Increased Intracranial Pressure under Cautions.)

Geriatric, cachectic, or debilitated patients are at increased risk for life-threatening respiratory depression. Closely monitor such patients, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants. Consider use of nonopiate analgesics.

Even recommended doses of buprenorphine may decrease respiratory drive to the point of apnea in patients with COPD or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. Closely monitor such patients, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants. Consider use of nonopiate analgesics. (See Contraindications.)

Risk of respiratory depression is increased when used concomitantly with other respiratory depressants. Many postmarketing reports of coma and death have involved misuse of buprenorphine by self-injection or concomitant use with benzodiazepines or other CNS depressants (e.g., alcohol). (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions.)

If buprenorphine extended-release sub-Q injection is discontinued because of compromised respiratory function, monitor patient for continued buprenorphine effects for several months.

Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized opiate prescriptions for pain management or new or reauthorized prescriptions for medications for treatment of OUD.

Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose); strongly consider prescribing naloxone for all patients receiving medications for treatment of OUD. Also consider prescribing naloxone when patients receiving opiates for pain management or for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage. Even if patients are not receiving an opiate for pain management or medication for treatment of OUD, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).

If respiratory depression occurs, follow usual guidelines for management of opiate agonist-induced respiratory depression.

Naloxone and doxapram may be only partially effective in reversing buprenorphine-induced respiratory depression; use of assisted or controlled respiration may be necessary and should be considered the principal method of management. If decision is made to treat serious respiratory depression in a physically dependent patient with an opiate antagonist, initiate therapy carefully and titrate with smaller than usual doses.

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiate agonists or opiate partial agonists, including buprenorphine, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use. (See Respiratory Depression under Cautions.)

Reserve concomitant use of buprenorphine for analgesia and other CNS depressants for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

Morbidity and mortality associated with untreated opiate addiction can outweigh the serious risks associated with concomitant use of opiate agonists or partial agonists and benzodiazepines or other CNS depressants. Buprenorphine treatment for opiate addiction (i.e., medication-assisted treatment [MAT]) should not be categorically withheld from patients receiving benzodiazepines or other CNS depressants. Taper and discontinue these drugs, if possible; however, excluding or discharging patients from MAT because of benzodiazepine or CNS depressant use is not likely to prevent such concomitant use and may lead to use outside the treatment setting, which could result in more severe outcomes.

Benzodiazepines are not the treatment of choice for anxiety or insomnia in patients receiving buprenorphine for opiate addiction; consider other pharmacologic or nonpharmacologic therapies.

Current evidence does not support dose limitations or other arbitrary limits on buprenorphine as a strategy for addressing concomitant benzodiazepine or other CNS depressant use in patients receiving MAT. However, if patient is sedated at the time of a scheduled buprenorphine dose, evaluate the cause of sedation; omission or reduction of the buprenorphine dose may be appropriate.

Precautions for minimizing risks associated with concomitant use of benzodiazepines or other CNS depressants in patients receiving MAT include:

• Educating patients upon initiation of MAT regarding risks associated with such concomitant use;

• Developing strategies upon initiation of MAT for managing any prescribed or illicit use of benzodiazepines or other CNS depressants;

• Verifying diagnosis in any patient receiving prescribed benzodiazepines or other CNS depressants for anxiety or insomnia, and considering other treatment options for these conditions;

• Adjusting induction procedures, if necessary, and providing more intensive monitoring;

• Recognizing that MAT may be required indefinitely and should be continued for as long as the patient benefits and MAT contributes to treatment goals;

• Coordinating care to minimize risks and ensure other prescribers are aware that patient is receiving buprenorphine;

• Taking measures to confirm that prescribed drugs are being used as intended and are not being diverted or supplemented with illicit drugs; and

• Performing toxicology tests for prescribed or illicit drug use.

Accidental Exposure

Accidental exposure to buprenorphine can cause severe, possibly fatal, respiratory depression in children. Store buprenorphine-containing preparations out of sight and reach of children.

A disproportionate share of unsupervised prescription drug and opiate ingestions by children <6 years of age involve buprenorphine-containing preparations (mostly buprenorphine/naloxone).

Properly dispose of any used transdermal systems and any buprenorphine-containing preparations that are no longer needed.

Keep any spontaneously expelled subdermal implants away from others, especially children.

Buprenorphine Subdermal Implant Complications

Improper insertion of implants may result in rare but serious complications including nerve damage and implant migration resulting in embolism and death. Local migration, protrusion, and expulsion of implants also may occur. Protrusion or expulsion may be caused by incomplete insertion or infection at the insertion site and may result in accidental exposure to the drug.

Insert implants in accordance with the manufacturer's instructions. It is essential for each implant to be inserted subdermally so that it is palpable following insertion and for proper placement to be confirmed by palpation immediately after insertion.

Neural or vascular injury may occur if implants are inserted into muscle or fascia. Removal may be complicated if an implant is inserted too deeply, cannot be palpated, or has migrated. Additional surgical procedures may be required to remove an implant that was inserted too deeply and cannot be readily localized. Removal of deeply inserted implants may result in injury to deeper neural or vascular structures.

Excessive palpation shortly after implant insertion or improper removal may increase risk of infection.

Available only through a restricted distribution program (Probuphine REMS) because of the risks associated with implant insertion and removal.

Extended-release Sub-Q Injection

Buprenorphine extended-release sub-Q injection forms a solid mass upon contact with body fluids; risk of death or serious complications (e.g., venous occlusion, local tissue damage, thromboembolic events including life-threatening PE) if the injection is administered IV.

Available only through a restricted distribution program (Sublocade REMS) because of the risks associated with IV self-administration.

Sensitivity Reactions

Hypersensitivity Reactions

Acute and chronic hypersensitivity reactions reported. Rash, urticaria, and pruritus are most common; bronchospasm, angioedema, and anaphylactic shock also have occurred.

Other Warnings and Precautions

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists. Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function. If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued. In some patients, switching to a different opiate improved symptoms.

QT-interval Prolongation

Prolongation of QT interval corrected for heart rate (QT_c) reported.

Prolongation of QT_c interval (corrected using Fridericia's formula) to 450–480 msec occurred in 2% of patients with chronic pain receiving buprenorphine buccally dissolving strips at dosages up to 900 mcg every 12 hours; do not exceed dosage of 900 mcg every 12 hours.

QT-interval prolongation observed with transdermal dosage of 40 mcg/hour in healthy adults; do not exceed dosage of 20 mcg/hour.

Take potential QT-interval prolongation into account when considering buprenorphine in patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease (e.g., unstable atrial fibrillation, symptomatic bradycardia, unstable CHF, active myocardial ischemia). Periodic ECG monitoring recommended in such patients.

Avoid use of buprenorphine in patients with a personal or family (i.e., immediate family member) history of long QT syndrome and in patients who are receiving class IA (e.g., disopyramide, procainamide, quinidine) or class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval.

Hypotensive Effects

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients, especially in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant use of certain CNS depressants (e.g., phenothiazines, general anesthetics). Monitor BP following initiation of therapy and dosage increases in such patients.

Vasodilation produced by the drug may further reduce cardiac output and BP in patients with circulatory shock. Avoid use in such patients.

Withdrawal Effects

Marked and intense opiate withdrawal symptoms are likely if buprenorphine/naloxone fixed combination is misused via parenteral injection by individuals who are physically dependent on opiates.

Buprenorphine may precipitate withdrawal in patients physically dependent on opiates (because of the drug’s antagonist activity) if administered before the agonistic effects of the full opiate agonist have subsided. To avoid precipitating withdrawal symptoms in patients currently receiving opiate analgesia, taper dosage of the current opiate analgesic to the equivalent of ≤30 mg daily of oral morphine sulfate prior to switching to buprenorphine.

To reduce the risk of precipitated withdrawal in patients initiating buprenorphine for treatment of opiate dependence, initiate induction therapy when clear, objective signs of opiate withdrawal are evident. Prior to initiating therapy with buprenorphine implants or buprenorphine extended-release sub-Q injection, stabilize patient on oral transmucosal buprenorphine.

Abrupt discontinuance or rapid reduction in buprenorphine dosage may result in withdrawal symptoms in patients who are physically dependent on the drug; gradually taper dosage when discontinuing therapy.

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome.

Hepatic Effects

Cytolytic hepatitis and hepatitis with jaundice reported in individuals receiving buprenorphine for opiate dependence.

Other serious adverse hepatic events (e.g., hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy) reported.

Some individuals had risk factors for such adverse events (i.e., preexisting hepatic enzyme abnormalities, HBV or HCV infection, concomitant use of potentially hepatotoxic drugs, ongoing illicit use of injectable drugs), but the possibility exists that buprenorphine had a causative or contributory role.

Evaluate liver function prior to initiation of buprenorphine for the management of opiate dependence and periodically during treatment. Manufacturer of buprenorphine extended-release sub-Q injection recommends monthly monitoring of liver function, particularly in patients receiving the 300-mg monthly dosage.

Evaluate liver function prior to initiation of buprenorphine for analgesia and periodically during treatment in patients at increased risk of hepatotoxicity (e.g., history of excessive alcohol use, IV drug abuse, or liver disease).

Evaluate carefully in the event of an adverse hepatic event.

Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis; in other patients, no dosage reduction was necessary. If decision is made to discontinue buprenorphine, discontinue carefully to prevent withdrawal symptoms and, in patients being treated for opiate dependence, the return to illicit drug use; initiate strict monitoring of the patient.

Dependence and Tolerance

Possible psychologic dependence to buprenorphine’s opiate agonist activity. Limited physical dependence may occur infrequently; the potential for tolerance to develop to the drug’s opiate agonist activity is limited.

Selection of an Appropriate Formulation

Do not use oral transmucosal preparations intended for use in the treatment of opiate dependence for analgesia. Fatal overdosage reported following administration of 2 mg of sublingual buprenorphine for analgesia in opiate-naive individuals.

Do not use buprenorphine extended-release sub-Q injection in opiate-naive individuals.

Transdermal buprenorphine not studied and not indicated for treatment of opiate dependence.

Anesthesia and Analgesia in Patients Receiving Extended-release Injection or Implant Therapy for Opiate Dependence

When anesthesia or analgesia for acute pain is required, use nonopiate analgesics whenever possible in patients with buprenorphine subdermal implants and those who received buprenorphine extended-release sub-Q injection within the prior 6 months.

Such patients requiring opiate analgesia may receive a high-affinity, full opiate agonist under clinician supervision, with particular attention given to respiratory function. Potential for toxicity is increased because higher doses may be required for analgesia.

If opiates are a required component of anesthesia, persons not involved in the conduct of the surgical or diagnostic procedure should continuously monitor the patient in an anesthesia care setting. Opiate therapy must be provided by individuals trained in the use of anesthetic drugs and the management of respiratory effects of potent opiates (i.e., establishment and maintenance of a patent airway, assisted ventilation).

Head Injury and Increased Intracranial Pressure

Potential for increased carbon dioxide retention and secondary elevation of intracranial pressure; in patients particularly susceptible to these effects (e.g., those with evidence of elevated intracranial pressure or brain tumors), monitor closely for sedation and respiratory depression, particularly during initiation of therapy.

Opiates may obscure the clinical course in patients with head injuries.

Avoid use in patients with impaired consciousness or coma.

Dermatologic Effects Following Transdermal Administration

Application site reactions (e.g., pruritus, erythema, rash) reported with transdermal administration; severe reactions with marked inflammation (e.g., burning, discharge, vesicles) reported rarely. Reported days to months following initiation of therapy.

Effects of Fever or High Temperatures on Transdermal Absorption

Drug absorption from buprenorphine transdermal systems depends in part on the temperature of the skin and increases with increasing temperature.

Monitor patients who develop a fever or whose core body temperature increases following strenuous exercise for manifestations of opiate toxicity and adjust dosage if respiratory or CNS depression occurs.

Exposure of the application site or surrounding area to direct external heat sources (e.g., heating pads, electric blankets, heat or tanning lamps, saunas, hot tubs, hot baths, heated water beds, prolonged direct sunlight, hot water) may increase percutaneous absorption of buprenorphine; potential for overdosage and death. Avoid such exposure.

Seizures

May aggravate preexisting seizure disorder. Monitor for worsened seizure control.

May increase risk of seizures in other settings associated with seizures.

Buccal Buprenorphine in Cancer Patients with Mucositis

Cancer patients with oral mucositis may absorb buprenorphine from buccally dissolving strips (Belbuca) more rapidly than intended; likely to result in higher plasma concentrations.

Reduce buccal dosage in patients with known or suspected mucositis; carefully monitor for toxicity or overdosage.

CNS Depression

May cause somnolence, dizziness, alterations in judgment, or alteration in level of consciousness, including coma. Avoid use in comatose patients and patients with impaired consciousness.

May impair mental alertness and/or physical coordination needed to perform potentially hazardous activities such as driving or operating machinery; warn patient about possible adverse CNS effects of opiate agonists.

Concurrent use of other CNS depressants may potentiate CNS depression and may result in profound sedation, respiratory depression, coma, or death.

Many postmarketing reports of coma and death have involved misuse of buprenorphine by self-injection or were associated with concomitant use of buprenorphine and benzodiazepines or other CNS depressants (e.g., alcohol).

Dental Complications Associated with Transmucosal Buprenorphine Preparations

Adverse dental events, sometimes severe, reported following use of transmucosal buprenorphine-containing preparations (i.e., tablets and films dissolved under the tongue or placed against the inside of the cheek available as single-ingredient products or in combination with naloxone). FDA has issued a drug safety communication about this risk.

Reported events included cavities/tooth decay, including rampant caries; dental abscesses/infection; tooth erosion; fillings falling out; and, in some cases, total tooth loss. Occurred in patients with or without prior dental issues. Tooth extraction or removal was required in most cases; other dental interventions included root canals, dental surgery, crowns, and implants.

Screen patients for oral disease and assess oral health history prior to prescribing transmucosal buprenorphine.

Counsel patients about the potential for dental problems and the importance of taking extra steps after the drug has completely dissolved to reduce this risk, including gently rinsing teeth and gums with water and then swallowing. Advise patients to wait at least 1 hour before brushing their teeth.

Refer patients to a dentist as soon as possible after starting transmucosal buprenorphine for a baseline dental evaluation and caries risk assessment and preventive plan; encourage regular dental checkups while taking the drug.

Advise patients to not stop taking buprenorphine without first discussing with their health care professional as it could lead to serious consequences, including relapse to opioid misuse or abuse that could result in overdose and death. The benefits of buprenorphine clearly outweigh its risks.

GI Conditions

May cause spasm of the sphincter of Oddi and increase serum amylase concentrations; monitor patients with biliary disease, including acute pancreatitis, for worsening symptoms.

May obscure the diagnosis and/or clinical course of acute abdominal conditions.

Buprenorphine analgesics contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.

Hypothyroidism

Use with caution in patients with hypothyroidism.

Addison’s Disease

Use with caution in patients with Addison’s disease.

Prostatic Hypertrophy or Urethral Stricture

Use with caution in patients with prostatic hypertrophy or urethral stricture.

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy; causality not established. Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility. Perform appropriate laboratory testing in patients with manifestations of hypogonadism.

Other Special Risk Patients

Use with caution in debilitated patients and in those with toxic psychoses, acute alcoholism, or delirium tremens.

Fixed-combination Preparations

When buprenorphine is used in fixed combination with naloxone, consider the cautions, precautions, and contraindications associated with naloxone.

Specific Populations

Pregnancy

Crosses the placenta. The limited data on buprenorphine use during pregnancy do not indicate an increased risk of major malformations specifically due to the drug; however, maternal factors (e.g., illicit drug use, late presentation for prenatal care, poor nutritional status, presence of infections, poor compliance, psychosocial circumstances) and lack of comparative data for untreated opiate-dependent pregnant women complicate interpretation of the data.

Reproduction studies in animals have not revealed evidence of teratogenicity, although increased skeletal abnormalities (e.g., extra rib formation) observed. Increased preimplantation and postimplantation pregnancy losses observed in animals.

The recommended treatment of opiate dependence in pregnant women is maintenance treatment with buprenorphine or methadone. Untreated opiate addiction is associated with adverse obstetrical outcomes (e.g., preeclampsia, fetal growth restriction, preterm birth, spontaneous abortion, fetal death) and often results in continued or relapsing illicit opiate use and engagement in high-risk behaviors.

In a controlled trial (Maternal Opioid Treatment: Human Experimental Research [MOTHER]) comparing neonatal outcomes following maternal use of either buprenorphine or methadone for treatment of opiate dependence during pregnancy (from average gestational age of 18.7 weeks until delivery), similar neonatal outcomes observed with maternal use of either drug, but buprenorphine-exposed neonates received a lower total morphine dosage for treatment of withdrawal, had shorter hospital stays, and required shorter duration of treatment for withdrawal compared with methadone-exposed neonates. However, rate of treatment discontinuance prior to delivery was higher for buprenorphine-treated women; this complicates interpretation of results.

Single-entity buprenorphine recommended during pregnancy to protect the fetus from any potential naloxone exposure, especially if the fixed combination is injected IV, and to avoid precipitated withdrawal in the event of IV injection. However, recent studies suggest neonatal outcomes are similar with either buprenorphine/naloxone or buprenorphine; if additional data confirm these findings, buprenorphine/naloxone use may increase, since single-entity buprenorphine has a higher risk for misuse and diversion. Manufacturers of buprenorphine/naloxone state that data on sublingual naloxone exposure during pregnancy are insufficient to evaluate risk.

No adequate and well-controlled studies to date with buprenorphine subdermal implants in pregnant women.

Manufacturer states buprenorphine extended-release sub-Q injection should be used during pregnancy only if potential benefits justify potential risks to the fetus. Animal studies suggest some adverse embryofetal effects may be attributable to a solvent (N-methyl-2-pyrrolidone [NMP]) in the formulation. Advise pregnant women of potential risk to the fetus.

Buprenorphine dosage adjustments may be required during pregnancy, even in women receiving a stable dosage prior to pregnancy. Closely monitor for withdrawal manifestations and adjust dosage as necessary.

Opiate-dependent women receiving buprenorphine maintenance therapy may require additional analgesia during labor. When opiates required, higher than usual dosages generally needed for adequate analgesia.

Use of opiates in pregnant women during labor can result in neonatal respiratory depression. Monitor neonates exposed to opiates during labor for respiratory depression; an opiate antagonist must be readily available for reversal of opiate-induced respiratory depression.

Manufacturer states safety of buprenorphine injection during labor and delivery not established. Transdermal buprenorphine and buprenorphine buccally dissolving strips not recommended for pain relief immediately before or during labor; use of shorter-acting analgesics or other analgesic techniques is more appropriate.

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts. Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity vary depending on the specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate. Onset in neonates exposed to buprenorphine generally occurs in first 1–2 days after birth. Closely monitor neonates whose mothers used opiates chronically during pregnancy for withdrawal.

Lactation

Distributes into milk.

In 2 studies including 13 nursing women receiving maintenance treatment with sublingual buprenorphine (2.4–24 mg daily) for opiate dependence, breast-fed infants were exposed to <1% of the maternal daily dosage; no adverse reactions observed in nursing infants.

Experts recommend that women who are stable on buprenorphine or buprenorphine/naloxone treatment for opiate dependence, are not using other illicit drugs, and have no contraindications to nursing be encouraged to breast-feed their infants; to lower the risk of return to substance use, women receiving buprenorphine should be encouraged to continue treatment during the postpartum period. Breast-feeding has been associated with decreased severity of neonatal opiate withdrawal syndrome, decreased need for pharmacotherapy, and shorter hospital stays for the neonate.

Manufacturers of buprenorphine-containing preparations used for treatment of opiate dependence recommend considering developmental and health benefits of breast-feeding along with the mother's clinical need for buprenorphine or buprenorphine/naloxone and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

Manufacturers of buprenorphine preparations used as analgesics state that women should not nurse while receiving the drug because of the potential for serious adverse reactions (e.g., excess sedation, respiratory depression) in nursing infants. Monitor infants exposed to buprenorphine through breast milk for excess sedation and respiratory depression.

Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.

Pediatric Use

Buprenorphine conventional injection: Safety and efficacy as an analgesic not established in children <2 years of age. Safety and efficacy in children 2–12 years of age is supported by adequate and well-controlled trials in adults, with additional data from studies including 960 patients 9 months to 18 years of age (pharmacokinetic study, several controlled clinical trials, several large postmarketing studies and case series).

Transdermal buprenorphine: Safety and efficacy as an analgesic not established in patients <18 years of age.

Buprenorphine buccally dissolving strips: Safety and efficacy as an analgesic not established in pediatric patients.

Buprenorphine sublingual tablets, buprenorphine/naloxone sublingual tablets, and buprenorphine/naloxone buccally or sublingually dissolving strips: Safety and efficacy for the treatment of opiate dependence not established in pediatric patients. Naloxone-containing preparations are not appropriate for management of neonatal opiate withdrawal syndrome.

Buprenorphine extended-release sub-Q injection: Safety and efficacy for treatment of opiate dependence not established in pediatric patients.

Buprenorphine subdermal implants: Safety and efficacy for treatment of opiate dependence not established in pediatric patients <16 years of age.

Geriatric Use

Respiratory depression is the chief risk for geriatric patients receiving opiate analgesics. Titrate dosage slowly and monitor closely for CNS and respiratory depression.

Buprenorphine conventional injection for pain relief: Possible increased sensitivity to the drug. Select dosage with caution, usually starting at the low end of the dosing range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy.

Transdermal buprenorphine for pain relief: Specific dosage adjustments not necessary. Pharmacokinetic profile similar to that in younger adults. Use with caution. Safety profile in healthy geriatric adults similar to that in younger adults, but constipation and urinary retention may occur more frequently.

Buprenorphine buccally dissolving strips for pain relief: Specific dosage adjustments not necessary. Pharmacokinetic profile similar to that in younger adults. Use with caution; some adverse effects reported more frequently in geriatric patients.

Because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy, use caution when deciding to use buprenorphine or buprenorphine/naloxone for treatment of opiate dependence in patients ≥65 years of age; monitor for toxicity or overdosage.

Buprenorphine sublingual tablets, buprenorphine/naloxone sublingual tablets, buprenorphine/naloxone buccally or sublingually dissolving strips, and buprenorphine extended-release sub-Q injection for opiate dependence: Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Buprenorphine subdermal implants for opiate dependence: Clinical studies did not include patients >65 years of age.

Other experience with buprenorphine has not identified differences in responses between geriatric and younger adults.

Hepatic Impairment

Metabolized in the liver; therefore, activity of the drug may be increased and/or prolonged in patients with hepatic impairment.

Buprenorphine conventional injection for pain relief: Use with caution in patients with severe hepatic impairment.

Buprenorphine buccally dissolving strips for pain relief: Dosage adjustment recommended in patients with severe hepatic impairment; monitor patients with moderate or severe hepatic impairment for toxicity or overdosage.

Transdermal buprenorphine for pain relief: Transdermal system is intended for 7-day application; consider use of an alternative analgesic with greater dosing flexibility in patients with severe hepatic impairment.

Oral transmucosal preparations of buprenorphine or buprenorphine/naloxone for opiate dependence: Plasma concentrations of buprenorphine and naloxone are increased and half-lives of the drugs are prolonged in patients with moderate or severe hepatic impairment. Naloxone is affected to a greater degree than buprenorphine, and the magnitude of the difference in effect is greater in individuals with severe hepatic impairment than in those with moderate hepatic impairment. This may increase risk of precipitated withdrawal during induction therapy and interfere with buprenorphine's efficacy throughout treatment.

Sublingual buprenorphine for opiate dependence: Dosage adjustment recommended in patients with severe hepatic impairment; monitor patients with either moderate or severe hepatic impairment for toxicity or overdosage.

Buprenorphine/naloxone for opiate dependence: Avoid use in patients with severe hepatic impairment; may not be appropriate for those with moderate hepatic impairment. In patients with moderate hepatic impairment, buprenorphine/naloxone is not recommended for induction therapy but may be used with caution and careful monitoring for maintenance treatment following induction with buprenorphine alone.

Buprenorphine extended-release sub-Q injection for opiate dependence: Use not recommended in patients with moderate to severe hepatic impairment since plasma buprenorphine concentrations cannot be rapidly adjusted. If moderate or severe hepatic impairment develops during therapy, monitor for several months for toxicity or overdosage. If manifestations of overdosage or toxicity occur within 2 weeks following an injection, the depot containing buprenorphine may be surgically excised, if necessary.

Buprenorphine subdermal implants for opiate dependence: Use not recommended in patients with moderate to severe hepatic impairment since implant dosage cannot be titrated. If moderate or severe hepatic impairment develops during therapy, monitor for toxicity or overdosage; implant removal may be required.

Renal Impairment

No substantial relationship between estimated Cl_cr and steady-state buprenorphine concentrations.

Common Adverse Effects

Conventional parenteral injection for pain relief: Sedation (e.g., drowsiness), dizziness, vertigo, nausea.

Transdermal system for pain relief: Nausea, headache, application site reactions (pruritus, erythema, rash), dizziness, constipation, somnolence, vomiting, dry mouth.

Buccally dissolving strips for pain relief: Nausea, constipation, headache, vomiting, dizziness, somnolence.

Oral transmucosal formulations for opiate dependence: Oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, manifestations of withdrawal, insomnia, pain, peripheral edema. Adverse effects similar following administration as buprenorphine or buprenorphine/naloxone.

Extended-release sub-Q injection for opiate dependence: Constipation, headache, nausea, injection site reactions (pain, pruritus), vomiting, increased hepatic enzymes concentrations, fatigue.

Subdermal implants for opiate dependence: Implant site reactions (pain, pruritus, erythema), headache, depression, constipation, nausea, vomiting, back pain, toothache, oropharyngeal pain.

Drug Interactions

Metabolized principally by CYP3A4. Buprenorphine and its metabolite norbuprenorphine are conjugated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes, mainly by UGT 1A1 and 2B7 and by UGT 1A3, respectively.

Buprenorphine inhibits CYP2D6 and CYP3A4 in vitro; norbuprenorphine is a moderate CYP2D6 inhibitor.

CYP3A4 Inhibitors

Potential pharmacokinetic interaction (increased plasma buprenorphine concentrations); may result in increased or prolonged opiate effects. If concomitant therapy is required, monitor closely for respiratory depression and sedation, and consider adjusting buprenorphine dosage until drug effects are stable. If CYP3A4 inhibitor is discontinued, monitor for opiate withdrawal and consider adjusting buprenorphine dosage until drug effects are stable.

In patients switching to buprenorphine implants or extended-release sub-Q injection after stabilization on oral transmucosal buprenorphine given concomitantly with a CYP3A4 inhibitor, monitor to ensure that buprenorphine concentrations are adequate.

If dosage from subdermal implants or extended-release sub-Q injection is excessive following initiation of a CYP3A4 inhibitor (and dosage reduction or discontinuance of the CYP3A4 inhibitor is not feasible) or if dosage is inadequate following discontinuance of a CYP3A4 inhibitor, switch to an alternative buprenorphine formulation that permits dosage adjustment. In case of toxicity or overdosage, removal of the implants or sub-Q drug depot may be necessary.

CYP3A4 Inducers

Potential pharmacokinetic interaction (decreased plasma buprenorphine concentrations); may reduce efficacy or precipitate opiate withdrawal. If concomitant therapy is required, monitor for opiate withdrawal and consider adjusting buprenorphine dosage until drug effects are stable. If CYP3A4 inducer is discontinued, monitor for respiratory depression and adjust buprenorphine dosage as necessary.

In patients switching to buprenorphine implants or extended-release sub-Q injection after stabilization on oral transmucosal buprenorphine given concomitantly with a CYP3A4 inducer, monitor to ensure that buprenorphine concentrations provided by implants or extended-release injection are adequate but not excessive.

If dosage from subdermal implants or extended-release sub-Q injection is inadequate following initiation of a CYP3A4 inducer (and dosage reduction or discontinuance of the CYP3A4 inducer is not feasible) or if dosage is excessive following discontinuance of a CYP3A4 inducer, switch to an alternative buprenorphine formulation that permits dosage adjustment. In case of toxicity or overdosage, removal of the implants or sub-Q drug depot may be necessary.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6 or CYP3A4: Interactions are unlikely.

Drugs Affecting Hepatic Blood Flow

Drugs that reduce hepatic blood flow may decrease the rate of hepatic elimination of buprenorphine. Use with caution; reduce dosage of at least one of the drugs.

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased risk of QT-interval prolongation). Avoid concomitant use. (See QT-interval Prolongation under Cautions.)

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs. May occur at usual dosages. Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases. (See Advice to Patients.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.

If serotonin syndrome is suspected, discontinue buprenorphine, other opiate therapy, and/or any concurrently administered serotonergic agents.

Specific Drugs

Buprenorphine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, buprenorphine undergoes extensive first-pass metabolism in the GI mucosa and liver.

Buprenorphine conventional injection: Approximately 40–90% absorbed following IM administration. Following a single IV dose, mean peak plasma concentrations occurred within 2 minutes. Following IM administration of a dose 3 hours after an initial IV dose, mean peak plasma concentrations occurred within 2–5 minutes. Approximately 10 minutes after administration, plasma buprenorphine concentrations are similar following IV or IM injection.

Buprenorphine transdermal system: Absolute bioavailability is about 15%. Buprenorphine is quantifiable in plasma about 17 hours after application of a 10-mcg/hour transdermal system; steady-state concentrations attained by day 3 of treatment.

Application of heat to a 10-mcg/hour transdermal system increased blood buprenorphine concentrations by 26–55%; concentrations returned to normal within 5 hours after removal of heat source.

Buprenorphine buccally dissolving strips (Belbuca) for analgesia: Absolute bioavailability is 46–65%. Peak plasma concentrations and AUC increase in linear manner. Following single doses of 75, 300, or 1200 mcg, peak plasma concentrations average 0.17, 0.47, or 1.43 ng/mL, respectively, and are achieved at a median of 2.5–3 hours. Following repeated administration (60–240 mcg every 12 hours), steady-state concentrations are attained prior to the sixth dose, and steady-state peak plasma concentrations and AUC are proportional to dose.

Ingestion of cold, hot, or room-temperature water during buccal administration of Belbuca strips decreased AUC by 23–27%; a low-pH liquid (e.g., decaffeinated cola) decreased AUC by about 37%.

Buprenorphine and buprenorphine/naloxone oral transmucosal formulations for opiate dependence: Not all formulations, strengths, or dose combinations are bioequivalent.

Concomitant administration of naloxone and buprenorphine does not affect pharmacokinetics of buprenorphine.

Generic buprenorphine or buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Subutex or Suboxone sublingual tablets [branded formulations no longer commercially available in US]): Exhibit substantial interindividual variability in absorption, but low intraindividual variability. Buprenorphine peak plasma concentrations and AUC increase with increasing dose (over the range of 4–16 mg), but the increase is not directly proportional to dose. (See Table 3.) Naloxone generally cannot be quantified in plasma beyond 2 hours after sublingual administration of buprenorphine/naloxone at naloxone doses of 1–4 mg; mean peak plasma concentrations of naloxone at these doses range from 0.11–0.28 ng/mL.

Buprenorphine/naloxone (Suboxone) sublingually dissolving strips: Not all strengths and combinations of the strips are bioequivalent to Suboxone sublingual tablets at the same total dose. (See Table 4.) Pharmacokinetic parameters and systemic exposures are generally comparable following either buccal or sublingual administration of the strips, but naloxone exposure may be somewhat higher after buccal administration. (See Dosage: Opiate Dependence, under Dosage and Administration.)

Buprenorphine/naloxone (Zubsolv) sublingual tablets: Not bioequivalent to Suboxone sublingual tablets. One sublingual tablet containing buprenorphine 5.7 mg and naloxone 1.4 mg provides 12% lower naloxone exposure and equivalent buprenorphine exposure as one Suboxone sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg. Exhibits substantial interindividual variability in absorption, but low intraindividual variability. Buprenorphine peak plasma concentrations and AUC increase with increasing dose (over the range of 1.4–11.4 mg), but the increase is not directly proportional to dose.

Buprenorphine/naloxone (Bunavail) buccally dissolving strips: Not bioequivalent to Suboxone sublingual tablets. One strip containing buprenorphine 4.2 mg and naloxone 0.7 mg provides 33% lower naloxone exposure and equivalent buprenorphine exposure as one sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg. Exhibits substantial interindividual variability in absorption, but low intraindividual variability. Buprenorphine peak plasma concentrations and AUC increase with increasing dose (over the range of 0.875–6.3 mg), but the increase is not directly proportional to dose. Administration of liquids with the strips decreases buprenorphine and naloxone exposure by as much as 59 and 76%, respectively, depending on the pH of the liquid.

Buprenorphine extended-release sub-Q injection: Solid depot forms after sub-Q injection and drug is released via diffusion from and biodegradation of the depot. Following administration of single doses of 50–200 mg and repeated doses of 50–300 mg at 28-day intervals, initial peak plasma concentrations attained at a median of 24 hours after injection; concentrations decreased slowly to a plateau, and steady-state concentrations achieved at 4–6 months.

Mean steady-state plasma concentrations attained following 6 doses (series of two 300-mg doses followed by four 100-mg doses or series of six 300-mg doses) were 3.21 or 6.54 ng/mL, respectively, compared with 2.91 ng/mL following stabilization on a sublingual tablet dosage of 24 mg daily. At steady state, mean trough plasma concentrations achieved with both sub-Q dosages and the mean peak concentration achieved with the higher-dosage sub-Q regimen exceeded those attained with the sublingual dosage; the peak concentration attained with the lower-dosage sub-Q regimen was approximately 59% of that attained with the sublingual dosage. Simulations suggest therapeutic concentrations persist for 2–5 months, depending on dosage (100 or 300 mg), following the last injection.

Buprenorphine subdermal implants: Initial peak plasma concentrations attained at a median of 12 hours after insertion; concentrations decreased slowly, and steady-state concentrations achieved by approximately week 4. Mean steady-state plasma concentrations of approximately 0.5–1 ng/mL were maintained for approximately 20 weeks (weeks 4–24) and were comparable to the steady-state trough concentrations attained with a sublingual dosage of 8 mg daily.

In patients who received sublingual buprenorphine (16 mg daily for ≥5 days) followed by insertion of 4 implants (total buprenorphine hydrochloride dose of 320 mg), peak plasma concentrations were markedly lower after implant insertion compared with the lead-in sublingual dosing period. On day 28 of implant therapy, steady-state AUC was 31% of the steady-state AUC achieved with the sublingual dosage, and mean steady-state concentration was approximately 0.82 ng/mL (8% of the peak concentration and 52% of the trough concentration achieved at steady state with the sublingual dosage).

Onset

Following parenteral administration of single doses in postoperative patients, the onset of analgesia usually occurs within 10–30 minutes. Peak analgesia usually occurs within 60 minutes but may occur within 15 minutes in some patients.

Duration

Analgesia generally persists for 6 hours following single IM or IV doses, but has persisted for 4–10 hours following single IM doses and 2–24 hours following single IV doses.

Special Populations

In cancer patients with grade 3 mucositis receiving buprenorphine buccally dissolving strips (Belbuca), absorption was more rapid, and peak plasma concentrations and AUC were approximately 79 and 56%, respectively, higher compared with healthy controls.

Renal impairment: No substantial relationship between estimated Cl_cr and steady-state buprenorphine concentrations.

Mild hepatic impairment did not substantially alter peak plasma concentration or AUC of buprenorphine or naloxone following single sublingual dose of buprenorphine/naloxone.

Moderate hepatic impairment increased buprenorphine and naloxone peak plasma concentrations by 8 and 170%, respectively, and increased AUCs by 64 and 218%, respectively, following single sublingual dose of buprenorphine/naloxone.

Severe hepatic impairment increased buprenorphine and naloxone peak plasma concentrations by 72 and 1030%, respectively, and increased AUCs by 181 and 1302%, respectively, following single sublingual dose of buprenorphine/naloxone.

HCV-infection (without evidence of hepatic impairment) had no clinically important effect on peak plasma concentrations or systemic exposure to buprenorphine or naloxone.

Distribution

Extent

Rapidly (within several minutes) distributes into CSF following IV administration; CSF concentrations appear to be approximately 15–25% of concurrent plasma concentrations.

Crosses the placenta in humans.

Distributes into human milk.

Plasma Protein Binding

Approximately 96% (mainly α- and β-globulins.

Elimination

Metabolism

Almost completely metabolized in the liver, principally by N-dealkylation (mediated by CYP3A4) to form norbuprenorphine, which may have weak analgesic activity. Buprenorphine and norbuprenorphine undergo conjugation with glucuronic acid (mediated mainly by UGT 1A1 and 2B7 and by UGT 1A3, respectively).

Following transdermal administration, buprenorphine undergoes negligible metabolism in the skin.

Norbuprenorphine binds to opiate receptors in vitro; not known whether norbuprenorphine contributes to overall effects of the drug. The AUC ratio of norbuprenorphine to buprenorphine at steady state is 0.2–0.4 following administration as extended-release sub-Q injection and approximately 0.36–0.45 following sublingual administration as buprenorphine sublingual tablets.

Elimination Route

Eliminated principally in feces (about 69%) via biliary excretion and also in urine (about 30%) as unchanged drug and metabolites.

Half-life

Biphasic or triphasic elimination.

Following IV administration, terminal elimination half-life is approximately 2.2 hours (range: 1.2–7.2 hours).

Following sublingual administration as buprenorphine or buprenorphine/naloxone sublingual tablets, mean plasma elimination half-life of buprenorphine is 31–35 or 24–42 hours, respectively.

Following sublingual or buccal administration as buprenorphine/naloxone sublingually dissolving strips, mean plasma elimination half-life of buprenorphine is 24–42 hours.

Following buccal administration as buprenorphine or buprenorphine/naloxone buccally dissolving strips, mean elimination half-life of buprenorphine is 28 or 16–28 hours, respectively.

Following transdermal administration, terminal elimination half-life is approximately 26 hours.

Following administration as extended-release sub-Q injection, apparent elimination half-life is 43–60 days as a result of slow release from the sub-Q depot.

Norbuprenorphine half-life of 12–21 hours reported following sublingual administration as buprenorphine sublingual tablets.

Limited data suggest clearance may be higher in children than in adults.

Special Populations

Renal impairment does not substantially alter buprenorphine pharmacokinetics.

Hemodialysis does not substantially alter plasma concentrations of transdermally administered buprenorphine.

Mild hepatic impairment did not substantially alter half-life of buprenorphine or naloxone following single sublingual dose of buprenorphine/naloxone.

Moderate hepatic impairment increased buprenorphine and naloxone half-lives by 35 and 165%, respectively, and severe hepatic impairment increased half-lives by 57 and 122%, respectively, following single sublingual dose of buprenorphine/naloxone. (See Absorption: Special Populations, under Pharmacokinetics.)

In a limited number of patients with mild or moderate hepatic impairment (Child-Pugh class A or B), buprenorphine exposure following a 0.3-mg IV infusion was similar to that in patients with normal hepatic function; effect of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics not determined.

Effect of severe hepatic impairment on pharmacokinetics of buprenorphine transdermal system or buprenorphine buccally dissolving strips not established.

Effect of hepatic impairment on pharmacokinetics of buprenorphine subdermal implants or extended-release sub-Q injection not established.

In healthy geriatric adults, pharmacokinetic profile of transdermal buprenorphine generally is similar to that in younger adults.

In HCV-infected patients without evidence of hepatic impairment, no clinically important changes in buprenorphine or naloxone half-life.

Stability

Storage

Buccal

Buccally Dissolving Strips

Room temperature, generally 20–25°C (may be exposed to 15–30°C). Protect buprenorphine/naloxone (Bunavail) strips from freezing and moisture.

Sublingual

Sublingually Dissolving Strips

25°C (may be exposed to 15–30°C).

Sublingual Tablets

Room temperature, generally 20–25°C (may be exposed to 15–30°C).

Parenteral

Conventional Injection

20–25°C (may be exposed to 15–30°C); protect from prolonged exposure to light.

Extended-release Sub-Q Injection

2–8°C. May store in original package at 15–30°C for up to 7 days; discard if not used within 7 days.

Subdermal Implants

20–25°C (may be exposed to 15–30°C).

Topical

Transdermal System

25°C (may be exposed to 15–30°C).

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• Exhibits analgesic and opiate antagonist activities. Acts as a partial agonist at μ-opiate receptors in the CNS and peripheral tissues, an antagonist at κ-opiate receptors, and an agonist at δ-opiate receptors.

• Binds slowly with and dissociates slowly from the μ-receptor; may account for the prolonged duration of analgesia and possibly in part for the limited physical dependence potential observed.

• Single sublingual doses of buprenorphine produce physiologic and subjective effects that are similar to those produced by equivalent doses of the buprenorphine/naloxone fixed combination.

• Produces dose-related analgesia; appears to result from a high affinity of buprenorphine for μ- and possibly κ-opiate receptors in the CNS.

• Opiate agonist and antagonist activities appear to be dose related. At doses of ≤1 mg sub-Q, buprenorphine has a potent analgesic effect; at doses >1 mg sub-Q, the opiate agonist activity decreases and the opiate antagonist activity predominates. Following IM administration, opiate antagonist activity occurs principally at doses >0.8 mg.

• Usual parenteral doses potentially may depress respiration to the same degree as 10 mg of parenteral morphine sulfate; however, onset of buprenorphine-induced respiration depression is slower than that induced by morphine and appears to be more prolonged.

Advice to Patients

• Provide manufacturer’s patient information (medication guide and any instructions for use of the prescribed preparation) to the patient each time the drug is dispensed.

• Importance of instructing patients in proper techniques for administering oral transmucosal formulations and transdermal systems.

• Potential for addiction, abuse, and misuse, which can lead to overdosage or death, even when used as recommended. Protect from theft or misuse; properly dispose of any unused drug, and do not share buprenorphine with others.

• Risk of potentially fatal respiratory depression; most likely to occur following initiation of therapy and dosage increases; may occur at recommended dosages. Importance of seeking immediate medical attention if signs or symptoms of respiratory depression occur. Advise patients of the benefits of naloxone following opiate overdose and of their options for obtaining the drug.

• Accidental ingestion, especially by a child, may result in respiratory depression or death. Importance of keeping buprenorphine out of reach of children.

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly; avoid concomitant use unless such use is supervised by clinician. Advise patients that self-administration of benzodiazepines while taking buprenorphine is extremely dangerous. Advise patients that buprenorphine should not be combined with alcohol.

• Advise patients receiving maintenance treatment for opiate dependence that they should instruct family members to inform clinicians in the event of emergency that the patient is receiving an oral transmucosal or long-acting formulation of buprenorphine and is dependent on opiates.

• Importance of taking the drug exactly as prescribed; do not alter the dosage without consulting clinician.

• Advise patients receiving oral transmucosal buprenorphine or buprenorphine/naloxone for treatment of opiate dependence to take a missed dose as soon as it is remembered; however, if it is almost time for the next dose, omit the missed dose and resume the regular schedule with the next dose.

• Potential for buprenorphine to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.

• Advise patients that buprenorphine can cause physical dependence and that gradual tapering of the dosage may be required to prevent withdrawal symptoms when the drug is discontinued.

• Advise patients receiving buprenorphine or buprenorphine/naloxone for treatment of opiate dependence of the potential for relapse to illicit drug use upon discontinuance of maintenance treatment.

• Risk of orthostatic hypotension and syncope in ambulatory patients.

• Potential for severe constipation; advise patients on appropriate management.

• Potential risk of adrenal insufficiency. Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.

• Potential risk of serotonin syndrome with concurrent use of buprenorphine and other serotonergic agents. Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.

• Advise patients that buprenorphine should not be taken with or within 14 days of an MAO inhibitor.

• Advise patients receiving therapy with buprenorphine extended-release sub-Q injection that the drug may be detectable for a prolonged time after administration and that drug effects and other associated precautions and considerations (e.g., risk of drug interactions, risks associated with treatment of emergent acute pain) may persist for several months after the last injection.

• Inform patients receiving therapy with buprenorphine extended-release sub-Q injection that a lump (a solid depot containing the drug) may form at the injection site and that it will gradually diminish in size. Instruct patient not to rub or massage the injection site or allow belts or waistbands to rub the site. Instruct patients not to tamper with or attempt to remove the depot. Advise them that this preparation is available only under a restricted distribution program because of the risk of serious harm or death if the formulation is self-administered IV.

• Instruct patients receiving buprenorphine subdermal implants on appropriate care of the incision and advise them of potential complications resulting from insertion or removal procedures (e.g., neural or vascular injury, infection, implant migration with the potential for embolism or nerve damage). Inform patients that complications may be more likely during removal if the implants were inserted too deeply or if the patient manipulated the implants or gained substantial weight following insertion. Inform patients that implant removal carries risks inherent to other minor surgical procedures, improper removal may result in infection, and premature removal may induce withdrawal symptoms.

• Advise patients receiving implant therapy of the potential risk to others (accidental overdosage, misuse, abuse) if an implant protrudes from the skin or is expelled; instruct patient on safety precautions they must follow prior to seeing their clinician.

• Advise patients receiving implant therapy that the implants are available only under a restricted distribution program and must be inserted and removed in the facility of a certified prescriber.

• Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use. Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.

• Advise patients that severe hypersensitivity reactions (e.g., anaphylaxis) have occurred. Importance of promptly contacting a clinician if symptoms of a serious allergic reaction occur.

• Advise patients receiving transdermal buprenorphine to avoid exposing application site or surrounding area to external heat sources (e.g., heating pads, electric blankets, heat lamps, saunas, heated water bed, hot water, prolonged direct sunlight ) because of risk of increased buprenorphine exposure, overdosage, and death.

• Importance of informing clinician of any breakthrough pain or adverse effects that occur during analgesic therapy, so that therapy may be adjusted based on individual patient requirements.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Importance of discussing risks and benefits of buprenorphine therapy in the context of the intended use (pain management, treatment of opiate dependence) with pregnant and nursing women. Advise women of childbearing potential that prolonged use of opiates during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated. Advise nursing women who are receiving buprenorphine to monitor their infants for drowsiness or difficulty breathing.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.

Under the Drug Addiction Treatment Act of 2000 (DATA 2000) and Comprehensive Addiction and Recovery Act of 2016 (CARA 2016), use of buprenorphine and buprenorphine/naloxone for treatment of opiate dependence is restricted to physicians, nurse practitioners, and physician assistants who meet specific requirements. (See Restricted Distribution Program for Buprenorphine Treatment of Opiate Dependence under Dosage and Administration.)

Distribution of buprenorphine hydrochloride subdermal implants and buprenorphine extended-release sub-Q injection is further restricted under REMS programs. (See General under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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