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Buprenorphine

Pronunciation

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)

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 μ 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: Within 15 minutes; Peak effect: IM: ~1 hour; Transdermal patch: Steady state achieved by day 3

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

Buccal film, transdermal patch: Management of pain severe enough to require around-the-clock, long-term, opioid treatment and for which alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are inadequate.

Limitations of use: Not indicated as an as-needed analgesic.

Injection: Management of moderate to severe pain

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

Use: Unlabeled

Injection: Management of opioid withdrawal in heroin-dependent hospitalized patients

Contraindications

Hypersensitivity to buprenorphine or any component of the formulation

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

Documentation of allergenic cross-reactivity for morphine and related drugs in this class 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 (Additional contraindications; not in US labeling): 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 out-patient or day surgeries; management of peri-operative 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 monoamine oxidase inhibitors (MAOIs); myasthenia gravis; severe hepatic insufficiency; opioid dependent patients and for narcotic withdrawal treatment; pregnancy or during labor and delivery; breast-feeding

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. In high-risk patients (eg, elderly, debilitated, presence of respiratory disease) and/or concurrent CNS depressant use, reduce dose by one-half. Buprenorphine has an analgesic ceiling.

IM: Initial: Opioid-naive: 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; usual dosage range: 0.15 to 0.6 mg every 4 to 8 hours as needed

Slow IV: Initial: Opioid-naive: 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: 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): 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 naïve 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: (US labeling) or Adults ≥40 kg (Canadian labeling):

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.

US labeling:

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.

Canadian labeling: Patients who were receiving daily dose of ≤80 mg of oral morphine equivalents: Initial: 5 or 10 mcg/hour applied once every 7 days

Dose titration (opioid-naive or opioid-experienced patients):

US labeling: 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).

Canadian labeling: May increase dose in 5 mcg/hour or 10 mcg/hour increments (using no more than 2 patches) every 7 days or by a minimum interval of 72 hours (maximum dose: 20 mcg/hour applied once every 7 days). Individualize therapy using lowest effective dose with adequate rescue medication as required (Note: Fentanyl is not recommended as rescue medication). Once an effective dose is achieved, a single patch containing that dose should be prescribed. If adequate pain relief is not attained with maximum patch dose (20 mcg/hour every 7 days) convert to an alternative around-the-clock mu opioid agonist.

Discontinuation of therapy: Taper dose gradually every 7 days to prevent withdrawal in the physically dependent patient; consider initiating immediate-release opioids, if needed. Due to the gradual decrease in buprenorphine plasma concentrations following patch removal, the Canadian labeling recommends avoiding use of an opioid within 24 hours of patch removal; appropriate rescue medication and/or close monitoring during this period is recommended.

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: 16 mg; usual induction dosage range: 12 to 16 mg/day (induction usually accomplished over 3 to 4 days). Treatment should begin at least 4 hours after last use of heroin or other short-acting opioids, preferably when first signs of withdrawal appear. 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. There is little controlled experience with induction in patients on methadone or other long-acting opioids; consult expert physician experienced with this procedure.

Maintenance: Target dose: 16 mg/day; in some patients 12 mg/day may be effective; 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.

Dosing: Geriatric

Acute pain (moderate to severe): IM, slow IV: 0.15 mg every 6 hours; elderly patients are more likely to suffer from confusion and drowsiness compared to younger patients. Long-term use is not recommended.

Chronic pain (moderate to severe): Buccal film, transdermal patch: No specific dosage adjustments required; use caution 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

Children ≥13 years: Refer to adult dosing.

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

Dosing: Renal Impairment

Buccal film, injection, subdermal implant, sublingual: There are no dosage adjustments provided in the manufacturer’s labeling (has not been adequately studied); use with caution.

Transdermal:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been adequately studied); use with caution.

Canadian labeling: No dosage adjustment necessary.

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 patients with mild or moderate impairment was similar to that observed in healthy subjects (Butrans prescribing information 2014). Undergoes extensive hepatic metabolism; use with caution.

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 US labeling; however, need for dosage adjustment is unlikely as systemic exposure following IV buprenorphine in patients with mild or moderate impairment was similar to that observed in healthy subjects. Undergoes extensive hepatic metabolism; use with caution.

Severe impairment:

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

Canadian labeling: Use is contraindicated.

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. Liquids and food can be consumed after 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 swallowed. 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. For patients wearing 2 patches and when 1 patch falls off, the Canadian labeling recommends that the remaining patch be removed and 2 new patches be reapplied at a different 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 takeback program is recommended; trash disposal is not advised.

Compatibility

Injection:

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, doxorubicin liposome.

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.

Film, patch, 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: Analgesics (Opioid) 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 Analgesics (Opioid). Monitor therapy

Analgesics (Opioid): Mixed Agonist / Antagonist Opioids may diminish the analgesic effect of Analgesics (Opioid). 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

Anticholinergic Agents: May enhance the adverse/toxic effect of Analgesics (Opioid). 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. 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. 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

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. Avoid combination

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

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

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

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

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

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

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

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

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

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

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. 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 enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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

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

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

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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

Nalmefene: May diminish the therapeutic effect of Analgesics (Opioid). 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 Analgesics (Opioid). 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. 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

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Pegvisomant: Analgesics (Opioid) 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 [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

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

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ramosetron: Analgesics (Opioid) 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

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: Analgesics (Opioid) 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. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. 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. 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. 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 Analgesics (Opioid). 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

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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%), 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% (Limited to important or life-threatening): Abdominal discomfort, abnormal dreams, abnormal hepatic function tests, acute sinusitis, amblyopia, anaphylactic shock, angina pectoris, apnea, application site dermatitis, bradycardia, cellulitis, coma, constipation, contact dermatitis, cough, cyanosis, decreased appetite, decreased serum testosterone, depression, diplopia, diverticulitis, dyspepsia, dysphoria, dyspnea, exacerbation of asthma, excoriation, fatigue, hallucination, hepatic encephalopathy, hepatic failure, hepatic necrosis, hepatitis (including cytolytic), hepatorenal syndrome, hypersensitivity reaction, hypertension, hyperventilation, hypoesthesia, hypogonadism (Brennan 2013; Debono 2011), hypotension, hypoventilation, increased serum ALT, increased serum AST, injection site reaction, intestinal obstruction, jaundice, laceration, loss of consciousness, memory impairment, mental deficiency, mental status changes, migraine, miosis, musculoskeletal pain, nasal congestion, neck pain, orthostatic hypotension, paresthesia, prolonged Q-T interval on ECG, psychosis, respiratory distress, rhinorrhea, seizure, skin rash, slurred speech, syncope, tachycardia, tooth abscess, toothache, tremor, urinary incontinence, urinary retention, vasodilatation, visual disturbance, weakness, Wenckebach period on ECG, withdrawal syndrome

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse (buccal film, 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, 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.

Neonatal opioid withdrawal syndrome (buccal film, 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.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Cases of adrenal insufficiency have occurred with opioid use, more often following greater than one month of use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness and low blood pressure. If adrenal insufficiency is diagnosed, treat with corticosteroids and wean the patient off of opioids to allow adrenal function to recover. Use with caution in patients with adrenal insufficiency, including Addison's disease.

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

• Hepatic events: Hepatitis has been reported with buprenorphine use; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic dysfunction. 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.

• Hypogonadism: Chronic opioid use may cause secondary hypogonadism, although this may not occur with buprenorphine (Aurilio 2001; Bliesener 2005; Brennan 2013).

• Hypotension: May cause severe hypotension, including orthostatic hypotension and syncope; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).

• 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, transdermal patch: [US Boxed Warning]: May cause potentially life-threatening respiratory depression; monitor 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. Accidental exposure to even one dose, especially in children, can result in a fatal overdose.

Disease-related concerns:

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

• Acute alcoholism: Use with caution in patients with acute alcoholism or delirium tremens.

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

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

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

• Circulatory shock: Avoid use in patients with circulatory shock; may cause vasodilation that can further reduce cardiac output and blood pressure.

• CNS depression/coma: Avoid use of buprenorphine in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention. The Canadian labeling contraindicates use in patients with severe CNS depression.

• Dermatological conditions: 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; exaggerated elevation of ICP may occur. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. The Canadian labeling contraindicates use in patients with head injury or elevated cerebrospinal or intracranial pressure.

• Hepatic impairment: Use buccal film and sublingual tablet with caution in patients with moderate hepatic impairment; dosage adjustment recommended in severe hepatic impairment. Buprenorphine subdermal implants should not be used in patients with pre-existing moderate to severe hepatic impairment. The Canadian labeling contraindicates use in severe hepatic insufficiency.

• 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 extreme caution in patients with preexisting respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages. The Canadian labeling contraindicates use in patients with hypercapnia, cor pulmonale, obstructive airway (other than asthma) or status asthmaticus.

• Seizure: Opioid therapy may lower seizure threshold; use caution in patients with a history of seizure disorders. The Canadian labeling contraindicates use in patients with convulsive disorders.

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

Concurrent drug therapy issues:

• 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:

• Debilitated patients: Use with caution in debilitated or cachectic patients; there is a greater potential for life-threatening respiratory depression, even at therapeutic dosages.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects (eg, life-threatening respiratory depression).

• Low body weight (adults): The Canadian labeling does not recommend use of transdermal buprenorphine in patients <40 kg (may alter pharmacokinetics due to poor fat stores, altered clearance, or muscle wasting.

• Neonates: Buccal film, transdermal patch: [US Boxed Warning]: Prolonged use during pregnancy may result in neonatal opioid withdrawal syndrome in neonates. If not recognized and treated, this may be life-threatening and require management according to protocols developed by neonatology experts. Monitor neonate closely. 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 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.

• 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. In Canada, disposal via a pharmacy take back program is recommended; disposal in the trash is not advised. 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, or 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 central nervous system 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, transdermal patch: [US Boxed Warning]: Abuse, misuse, and addiction, which can lead to overdose and death, may occur. Risk of opioid abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness (eg, major depression). Assess each patient’s risk before prescribing, and monitor all patients for the development of these behaviors or conditions. 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. The Canadian labeling contraindicates use in patients with acute alcoholism, alcohol dependence, or delirium tremens.

• 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.

• 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 or less.

• 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]). The Canadian labeling contraindicates use of the transdermal patch in the perioperative setting and recommends withholding patch for at least 48 hours prior to chordotomy or other pain-relieving procedures and in the immediate postoperative period. If transdermal buprenorphine therapy is resumed after postoperative recovery, a dosage adjustment may be required based on pain relief needs.

• 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 effects of 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]).

Pregnancy Risk Factor

C

Pregnancy Considerations

The Canadian labeling contraindicates use during pregnancy and during labor and delivery.

Adverse effects have been observed in some animal reproduction studies. 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. [US Boxed Warning]: Prolonged use can result in neonatal opioid withdrawal syndrome. If not recognized and treated, this may be life-threatening and require management according to protocols developed by neonatology experts. 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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