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Buprenorphine

Pronunciation

(byoo pre NOR feen)

Index Terms

  • Buprenorphine HCl
  • Buprenorphine Hydrochloride
  • Subutex

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Film, Buccal:

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

Implant, Subcutaneous:

Probuphine Implant Kit: 74.2 mg (4 ea)

Patch Weekly, Transdermal:

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

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

Solution, Injection:

Buprenex: 0.3 mg/mL (1 mL)

Generic: 0.3 mg/mL (1 mL)

Tablet Sublingual, Sublingual:

Generic: 2 mg, 8 mg

Brand Names: U.S.

  • Belbuca
  • Buprenex
  • Butrans
  • Probuphine Implant Kit

Pharmacologic Category

  • Analgesic, Opioid
  • Analgesic, Opioid Partial Agonist

Pharmacology

Buprenorphine exerts its analgesic effect via high-affinity binding to mu opiate receptors in the CNS; displays partial mu agonist and weak kappa antagonist activity. Due to it being a partial mu agonist, its analgesic effects plateau at higher doses and it then behaves like an antagonist.

Absorption

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

Distribution

CSF concentrations are ~15% to 25% of plasma concentrations

Vd:

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

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

Adults: 97 to 187 L/kg

Metabolism

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

Excretion

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

Clearance: Related to hepatic blood flow

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

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

Adults: 0.78 to 1.32 L/hour/kg

Onset of Action

Analgesic: IM: ≥15 minutes; Peak effect: IM: ~1 hour

Time to Peak

Plasma: Buccal film: 2.5 to 3 hours; Subdermal implant: 12 hours after insertion, with steady state achieved by week 4; Sublingual: 30 minutes to 1 hour (Kuhlman 1996); Transdermal patch: Steady state achieved by day 3

Duration of Action

IM: ≥6 hours

Half-Life Elimination

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

Children 4 to 7 years: IV: ~1 hour (Olkkola 1989)

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

Protein Binding

High (~96%, primarily to alpha- and beta globulin)

Special Populations: Hepatic Function Impairment

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

Special Populations: Elderly

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

Use: Labeled Indications

Opioid dependence:

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

Sublingual tablet: Treatment of opioid dependence

Pain management:

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

Injection: Management of pain severe enough to require an opioid analgesic and for which treatments are inadequate

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

Off Label Uses

Opioid withdrawal in heroin-dependent hospitalized patients (Injection)

Data from a limited number of patients studied who received buprenorphine parenterally for opioid withdrawal during hospitalization for an acute medical problem suggests that buprenorphine is safe when used in this setting [Umbricht 2003], [Welsh 2002]. In a systematic review of trials evaluating the use of buprenorphine for managing opioid withdrawal, the use of buprenorphine was shown to be more effective than clonidine or lofexidine (not available in the US) and equally effective to methadone (limited data) [Gowing 2017]. Additional data may be necessary to further define the role of buprenorphine in the management of patients with opioid withdrawal while being hospitalized for an acute medical problem.

Perineural anesthesia

In a metaanalysis of trials evaluating the use of buprenorphine in peripheral nerve blocks, the use of buprenorphine in this manner was shown to be safe and effective [Schnabel 2017]. Buprenoprhine prolongs the duration of postoperative analgesia and may reduce opioid consumption when administered as a nerve block [Bailard 2014], [Kosel 2015], [Krishnan 2016]; Additional data may be necessary to further define the role of buprenorphine in the management of postoperative pain as a perineural adjunct.

Contraindications

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

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

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

Canadian labeling: Transdermal patch and buccal film (Additional contraindications; not in US labeling): Hypersensitivity to other opioids; suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild, intermittent or short duration pain that can otherwise be managed; management of acute pain, including use in outpatient or day surgeries; management of perioperative pain relief, or in other situations characterized by rapidly varying analgesic requirements; acute respiratory depression; hypercapnia; cor pulmonale; obstructive airway (other than asthma); status asthmaticus; acute alcoholism or alcohol dependence; delirium tremens; convulsive disorders; severe CNS depression; increased cerebrospinal or intracranial pressure; head injury; concurrent use or use within 14 days of MAOIs; myasthenia gravis; severe hepatic insufficiency; opioid dependent patients and for opioid withdrawal treatment; pregnancy or during labor and delivery; breastfeeding; known or suspected oral mucositis (buccal film only)

Dosing: Adult

Acute pain (moderate to severe): Note: Long-term use is not recommended. The following recommendations are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention. Buprenorphine has an analgesic ceiling.

IM: Initial: 0.3 mg every 6 to 8 hours as needed; initial dose (up to 0.3 mg) may be repeated once in 30 to 60 minutes after the initial dose if needed

Slow IV: Initial: 0.3 mg every 6 to 8 hours as needed; initial dose (up to 0.3 mg) may be repeated once in 30 to 60 minutes after the initial dose if needed

Chronic pain (moderate to severe):

Buccal film: Note: Buprenorphine buccal film doses of 600, 750, and 900 mcg are only for use following titration from lower doses (maximum dose: 900 mcg every 12 hours).

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

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

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

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

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

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

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

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

Discontinuation of therapy: Use a gradual downward titration of the dose to prevent withdrawal; do not abruptly discontinue.

Patients with oral mucositis: Reduce the starting dose and titration incremental dose by 50%.

Transdermal patch:

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

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

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

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

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

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

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

Opioid withdrawal in heroin-dependent hospitalized patients (off-label use): IV infusion: 0.3 to 0.9 mg (diluted in 50 to 100 mL of NS) over 20 to 30 minutes every 6 to 12 hours (Welsh 2002)

Opioid dependence:

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

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

Sublingual tablet: Note: The combination product, buprenorphine and naloxone, is preferred therapy over buprenorphine monotherapy for induction treatment (and stabilization/maintenance treatment) for short-acting opioid dependence (US Department of Health and Human Services 2005).

Manufacturer's labeling:

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

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

Alternate dosing (Kampman [ASAM 2015]):

Induction: 2 to 4 mg; if no signs of precipitated withdrawal after 60 to 90 minutes, may increase in increments of 2 to 4 mg. Once initial dose is tolerated, may increase to a dose that is clinically effective and provides 24 hours of stabilization. Buprenorphine treatment initiation should begin after mild to moderate opioid withdrawal signs appear (to avoid precipitated withdrawal), which is generally at least 6 to 12 hours after last use of short-acting opioids (eg. heroin, oxycodone) and 24 to 72 hours after last use of long-acting opioids (methadone).

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

Perineural anesthesia (off-label use): Perineural injection: 200 to 300 mcg added to local anesthetic (eg, bupivacaine, mepivacaine, tetracaine) with or without epinephrine and administered as a single injection (Kosel 2015; Krishnan 2016).

Dosing: Geriatric

Acute pain (moderate to severe): IM, slow IV: Refer to adult dosing; use with caution.

Chronic pain (moderate to severe): Buccal film, transdermal patch: No specific dosage adjustments required; use caution and titrate slowly due to potential for increased risk of adverse events.

Opioid dependence: Subdermal implant: No specific dosage adjustments required; use caution due to potential for increased risk of adverse events and inability to adjust dosage.

Dosing: Pediatric

Acute pain (moderate to severe):

Children 2 to 12 years: IM, slow IV: 2 to 6 mcg/kg every 4 to 6 hours

Adolescents ≥13 years: Refer to adult dosing.

Opioid dependence: Adolescents ≥16 years: Refer to adult dosing.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

Buccal film:

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

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

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

Injection:

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

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

Subdermal implant:

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

Moderate or severe impairment: Use is not recommended.

Sublingual:

Mild impairment: No dosage adjustment necessary.

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

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

Transdermal patch:

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

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

Extemporaneously Prepared

A 0.075 mg/mL solution can be made using the 0.3 mg/mL injection, 95% ethanol, and simple syrup. Add 1.26 mL of 95% ethanol to 0.3 mg buprenorphine obtained from an 0.3 mg/1 mL ampule, mix well, and add quantity of simple syrup sufficient to obtain 4 mL (final volume). Solution is stable under refrigeration and at room temperature for 30 days when stored in amber glass bottles and for 7 days when stored in oral syringes (Anagnostis 2011; Anagnostis 2013).

Anagnostis EA, Sadaka RE, Sailor LA, et al, "Formulation of Buprenorphine for Sublingual Use in Neonates," J Pediatr Pharmacol Ther, 2011, 16(4):281-4.22768012Anagnostis EA, personal communication, March 2013.

Administration

IM: Administer via deep IM injection

IV: Administer slowly, over at least 2 minutes. Administration over 20 to 30 minutes preferred when managing opioid withdrawal in heroin-dependent hospitalized patients (Welsh 2002).

Oral:

Buccal film: Prior to placing the film, moisten inside of cheek with tongue or water. Apply film with a dry finger immediately after removing it from packaging. Place yellow side of film against the inside of the moistened cheek; press and hold the film in place for 5 seconds with finger (film should stay in place after this period). Keep film in place until it dissolves completely (usually within 30 minutes of application). Do not chew, swallow, touch, or move film after placement. Avoid eating or drinking until film dissolves. Do not cut or tear the film. Avoid application to areas of the mouth with any open sores or lesions. To dispose of film; remove foil overwrap from any unused, unneeded films and dispose by flushing down the toilet.

Sublingual tablet: Tablet should be placed under the tongue until dissolved; should not be chewed or swallowed (swallowing tablets before dissolved reduces bioavailability). If two or more tablets are needed per dose, all may be placed under the tongue at once, or two at a time. To ensure consistent bioavailability, subsequent doses should always be taken the same way.

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

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

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from prolonged exposure to light.

Buccal film, transdermal patch, sublingual tablet: Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Subdermal implant: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

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

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

Amphetamines: May enhance the analgesic effect of Opioid Analgesics. Monitor therapy

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

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

Atazanavir: Buprenorphine may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Buprenorphine. Management: Avoid this combination in patients un-boosted atazanavir due to possible decreased atazanavir concentrations. This combination is not contraindicated in patients also receiving ritonavir, but monitoring for buprenorphine toxicity is recommended. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: May decrease the serum concentration of Buprenorphine. Boceprevir may increase the serum concentration of Buprenorphine. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy

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

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

CNS Depressants: May enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cobicistat: May increase the serum concentration of Buprenorphine. Monitor therapy

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

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

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

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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Desmopressin: Opioid Analgesics may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

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

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Efavirenz: May decrease serum concentrations of the active metabolite(s) of Buprenorphine. Efavirenz may decrease the serum concentration of Buprenorphine. Monitor therapy

Eluxadoline: Opioid Analgesics may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Buprenorphine. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

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

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

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

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

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

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

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

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

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

Naltrexone: May diminish the therapeutic effect of Opioid Analgesics. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

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

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of Buprenorphine. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Buprenorphine. Monitor therapy

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

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

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

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

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

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

Pegvisomant: Opioid Analgesics may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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

QTc-Prolonging Agents (Highest Risk): Buprenorphine may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Monitor therapy

Ramosetron: Opioid Analgesics may enhance the constipating effect of Ramosetron. Monitor therapy

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

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

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: Opioid Analgesics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Analgesics. Monitor therapy

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

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Adverse Reactions

Buccal film:

1% to 10%:

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

Central nervous system: Fatigue (≥5%), anxiety (≥1% to <5%), depression (≥1% to <5%), falling (≥1% to <5%), insomnia (≥1% to <5%), withdrawal syndrome (≥1% to <5%), headache (4%), dizziness (2%), drowsiness (1%)

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

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

Gastrointestinal: Nausea (9% to 10%; incidence may be increased during dose titration), diarrhea (≥5%), xerostomia (≥5%), vomiting (4% to 5%), abdominal pain (≥1% to <5%), decreased appetite (≥1% to <5%), gastroenteritis (≥1% to <5%), constipation (3% to 4%)

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

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

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

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

Miscellaneous: Fever (≥1% to <5%)

Implant:

>10%:

Central nervous system: Headache (13%)

Dermatologic: Pruritus (12%; at implant site)

Miscellaneous: Pain at medication pump site (4% to 13%)

1% to 10%:

Cardiovascular: Edema (5%; at implant site), chest pain (1%)

Central nervous system: Depression (6%), dizziness (4%), drowsiness (3%), fatigue (3%), chills (2%), migraine (2%), paresthesia (1%), sedation (1%), sensation of cold (1%)

Dermatologic: Erythema (10%; at implant site), skin rash (2%), excoriation (1% to 2%; including scratch), skin lesion (1%)

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

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

Local: Local swelling (1%)

Neuromuscular & skeletal: Back pain (6%), limb pain (3%), weakness (2%)

Respiratory: Oropharyngeal pain (5%), cough (3%), dyspnea (1%)

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

Injection:

>10%: Central nervous system: Sedation (≤66%)

1% to 10%:

Cardiovascular: Hypotension (1% to 5%)

Central nervous system: Dizziness (5% to 10%), vertigo (5% to 10%), headache (1% to 5%)

Dermatologic: Diaphoresis (1% to 5%)

Gastrointestinal: Nausea (5% to 10%), vomiting (1% to 5%)

Ophthalmic: Miosis (1% to 5%)

Respiratory: Hypoventilation (1% to 5%)

Sublingual tablet:

>10%:

Central nervous system: Headache (29%), insomnia (21%)

Dermatologic: Diaphoresis (13%)

Gastrointestinal: Nausea (14%), abdominal pain (12%), constipation (8%)

Infection: Infection (12%)

1% to 10%: Gastrointestinal: Vomiting (8%)

Transdermal patch:

>10%:

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

Gastrointestinal: Nausea (6% to 23%), constipation (3% to 13%)

Local: Local pruritus (4% to 15%)

1% to 10%:

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

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

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

Gastrointestinal: Vomiting (4% to 9%), xerostomia (6%), anorexia (1% to <5%), diarrhea (1% to <5%), dyspepsia (1% to <5%), upper abdominal pain (1% to <5%), abdominal distress (2%)

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

Local: Application site erythema (3% to 10%), application site rash (3% to 8%), application site irritation (1% to 6%)

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

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

Miscellaneous: Fever (1% to <5%)

<1%, postmarketing, and/or case reports: Abdominal discomfort, abdominal distention, abnormal dreams, abnormal hepatic function tests, acute sinusitis, agitation, amblyopia, anaphylactic shock, angina pectoris, angioedema, apathy, apnea, application site dermatitis, ataxia, blurred vision, bradycardia, bronchospasm, cellulitis, chills, coma, confusion, conjunctivitis, constipation, contact dermatitis, cough, cyanosis, decreased appetite, decreased libido, decreased serum testosterone, dehydration, depersonalization, depression, diarrhea, diplopia, disorientation, diverticulitis, dry eye syndrome, dysarthria, dysgeusia, dyspepsia, dysphagia, dysphoria, dyspnea, emotional lability, euphoria, exacerbation of asthma, excoriation, facial edema, fatigue, flatulence, flushing, hallucination, hepatic encephalopathy, hepatic failure, hepatic necrosis, hepatitis (including cytolytic), hepatorenal syndrome, hiccups, hot flash, hypersensitivity reaction, hypertension, hyperventilation, hypoesthesia, hypogonadism (Brennan 2013; Debono 2011), hypotension, hypoventilation, increased blood pressure, increased serum ALT, increased serum AST, increased serum transaminases, injection site reaction, intestinal obstruction, jaundice, laceration, lack of concentration, lethargy, loss of consciousness, malaise, memory impairment, mental deficiency, mental status changes, migraine, miosis, musculoskeletal pain, myasthenia, nasal congestion, neck pain, nervousness, nightmares, orthostatic hypotension, pallor, palpitations, paresthesia, prolonged Q-T interval on ECG, pruritus, psychosis, respiratory depression, respiratory distress, restlessness, rhinitis, rhinorrhea, sedation, seizure, sexual disorder, skin rash, slurred speech, syncope, tachycardia, tinnitus, tooth abscess, toothache, tremor, unsteady gait, urinary hesitancy, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, visual disturbance, weakness, weight loss, Wenckebach period on ECG, wheezing, withdrawal syndrome, xeroderma

ALERT: U.S. Boxed Warning

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

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

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

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

Accidental exposure (buccal film, transdermal patch):

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

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

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

Risk associated with insertion and removal (Probuphine implant):

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

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

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

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

Warnings/Precautions

Concerns related to adverse effects:

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

• Hepatic events: Hepatitis has been reported; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic impairment. Monitor liver function tests in patients at increased risk for hepatotoxicity (eg, history of alcohol abuse, preexisting hepatic dysfunction, IV drug abusers) prior to and during therapy. Remove buprenorphine subdermal implant if signs and symptoms of buprenorphine toxicity develop concurrent with hepatic impairment.

• Hypersensitivity reactions: Hypersensitivity, including bronchospasm, angioneurotic edema, and anaphylactic shock, have been reported.

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

• Infection: Subdermal implant: Infection may occur at site of insertion or removal, with excessive palpation shortly after insertion and improper removal increasing the risk. Examine the insertion site 1 week following insertion for signs of infection or problems with wound healing.

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

• Respiratory depression: Buccal film, injection, transdermal patch: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Misuse or abuse by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film or transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

Disease-related concerns:

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

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

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

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

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

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

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

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

• Hepatic impairment: Use buccal film and sublingual tablet with caution in patients with moderate hepatic impairment; dosage adjustment recommended in severe hepatic impairment. Use injection with caution in patients with severe impairment. Subdermal implants should not be used in patients with preexisting moderate to severe hepatic impairment. Transdermal patch should not be used in patients with severe hepatic impairment; consider alternative therapy with more flexibility for dosing adjustments.

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

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

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

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

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

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

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

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

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

Concurrent drug therapy issues:

• Benzodiazepines and other CNS depressants: Buccal film, injection, transdermal patch: [US Boxed Warning]: Concomitant use of benzodiazepines or other CNS depressants, including alcohol and opioids, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of opioids and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

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

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

• Neonates: Neonatal withdrawal syndrome: Buccal film, injection, transdermal patch: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Subdermal implant: [US Boxed Warning]: Insertion and removal of implant are associated with the risk of implant migration, protrusion, and expulsion. Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion in the upper arm. Additional complications may include local migration, protrusion, and expulsion. Incomplete insertions or infections may lead to protrusion or expulsion. Because of the risks associated with insertion and removal, buprenorphine implant is available only through a restricted program. All health care providers must successfully complete a live training program on the insertion and removal procedures and become certified, prior to performing insertions or prescribing buprenorphine implants. Patients must be monitored to ensure that the implant is removed by a health care provider certified to perform insertions.

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

Special handling:

• Disposal: Subdermal implant: Handle the removed implants with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

Other warnings/precautions:

• Abuse/misuse/diversion: Buccal film, injection, transdermal patch: [US Boxed Warning]: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with an increased risk for misuse include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]). The misuse of buccal film by swallowing or of transdermal patch by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death.

• Accidental ingestion: Buccal film, transdermal patch: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of buprenorphine.

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

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

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

• Discontinuation of therapy: Sublingual tablet: There is no maximum recommended duration for maintenance treatment of opioid addiction; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-assisted treatment.

• Optimal pain regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention. When switching patients from buprenorphine to naltrexone, do not initiate naltrexone until 7 to 14 days after buprenorphine discontinuation. No time delay is required when switching patients from buprenorphine to methadone (Kampman [ASAM 2015]).

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

• Surgery: In patients undergoing elective surgery (excluding caesarean section), discontinuation of buprenorphine 24 to 36 hours before anticipated need for surgical anesthesia may be considered. Short-acting opioids may be given during and/or after surgery. In patients unable to abruptly discontinue buprenorphine prior to surgery, full opioid agonists may be added to the buprenorphine to maintain proper anesthesia; however, increased doses may be required to overcome buprenorphine receptor blockade. The decision whether to discontinue buprenorphine prior to elective surgery should be made in consultation with the surgeon and anesthesiologist (Kampman [ASAM 2015]).

• Withdrawal: Concurrent use of opioid agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms and is not recommended; taper dose gradually when discontinuing. Tablets, which are used for induction treatment of opioid dependence, should not be started until objective and clear signs of moderate withdrawal are evident. If subdermal implants are not immediately replaced in contralateral arm after removal, maintain patients on their previous dosage of sublingual buprenorphine.

Monitoring Parameters

Pain relief, respiratory and mental status, CNS depression (especially in elderly, debilitated or cachectic patients particularly during treatment initiation or titration, or when using concomitant CNS depressants), blood pressure (monitor for hypotension during initiation and titration); LFTs (prior to initiation and during therapy); signs of addiction, abuse, or misuse; symptoms of withdrawal; patients with biliary tract disease for worsening symptoms; application site reactions (transdermal patch); signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs and symptoms of toxicity or overdose (especially in patients with hepatic impairment); signs of infection or problems with wound healing one week after insertion of subdermal implant.

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

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

Pregnancy Risk Factor

C

Pregnancy Considerations

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

Buprenorphine crosses the placenta; buprenorphine and norbuprenorphine can be detected in newborn serum, urine, and meconium following in utero exposure (CSAT 2004). Based on available data, an increased risk of major malformations has not been observed. Following chronic opioid therapy in pregnancy, adverse events in the newborn (including withdrawal) may occur; monitoring of the neonate is recommended. The minimum effective dose should be used if opioids are needed (Chou 2009). The onset of withdrawal in infants of women receiving buprenorphine during pregnancy ranged from day 1 to day 8 of life, most occurring on day 1. Symptoms of withdrawal may include agitation, apnea, bradycardia, convulsions, hypertonia, myoclonus, respiratory depression, and tremor. Based on available data, there does not appear to be a dose-response relationship with the incidence of neonatal abstinence syndrome.

Buprenorphine is currently considered an alternate treatment for pregnant women who need therapy for opioid addiction (CSAT 2004; Dow 2012; Kampman [ASAM 2015]); however, use in pregnancy for this purpose is increasing (ACOG 2012; Soyka 2013). Because dose adjustments cannot be made, it may not be appropriate to initiate use of the implant in pregnant women; women who become pregnant while using the implant should be closely monitored. Buprenorphine should not be used to treat pain during labor. Women receiving buprenorphine for the treatment of addiction should be maintained on their daily dose of buprenorphine in addition to receiving the same pain management options during labor and delivery as opioid-naive women; maintenance doses of buprenorphine will not provide adequate pain relief. Opioid agonist-antagonists should be avoided for the treatment of labor pain in women maintained on buprenorphine due to the risk of precipitating acute withdrawal. In addition, buprenorphine should not be given to women in labor taking methadone (ACOG 2012).

Amenorrhea may develop secondary to substance abuse; pregnancy may occur following the initiation of buprenorphine maintenance treatment. Contraception counseling is recommended to prevent unplanned pregnancies (Dow 2012). Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea or vomiting. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), slow breathing, shallow breathing, difficulty breathing, sexual dysfunction (males), amenorrhea, decreased libido, infertility, severe dizziness, passing out, sweating a lot, tachycardia, bradycardia, abnormal heartbeat, confusion, severe constipation, severe loss of strength and energy, anxiety, chills, pharyngitis, change in balance, mood changes, severe abdominal pain, abnormal movements, slurred speech, swelling of arms or legs, vision changes, burning or tingling feeling, difficulty speaking, angina, urinary retention, hallucinations, muscle pain, joint pain, memory impairment, seizures, severe headache, tremors, severe fatigue, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), injection site irritation, or severe skin irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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