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Buprenorphine and Naloxone

Pronunciation

(byoo pre NOR feen & nal OKS one)

Index Terms

  • Buprenorphine HCl/Naloxone HCl
  • Buprenorphine Hydrochloride and Naloxone Hydrochloride Dihydrate
  • Naloxone and Buprenorphine
  • Naloxone Hydrochloride Dihydrate and Buprenorphine Hydrochloride

Dosage Forms

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

Film, buccal:

Bunavail: Buprenorphine 2.1 mg and naloxone 0.3 mg (30s); buprenorphine 4.2 mg and naloxone 0.7 mg (30s); buprenorphine 6.3 mg and naloxone 1 mg (30s) [citrus flavor]

Film, sublingual:

Suboxone: Buprenorphine 2 mg and naloxone 0.5 mg (30s); buprenorphine 4 mg and naloxone 1 mg (30s); buprenorphine 8 mg and naloxone 2 mg (30s); buprenorphine 12 mg and naloxone 3 mg (30s) [lime flavor]

Tablet, sublingual: Buprenorphine 2 mg and naloxone 0.5 mg; buprenorphine 8 mg and naloxone 2 mg

Zubsolv: Buprenorphine 1.4 mg and naloxone 0.36 mg; buprenorphine 2.9 mg and naloxone 0.71 mg; buprenorphine 5.7 mg and naloxone 1.4 mg; buprenorphine 8.6 mg and naloxone 2.1 mg; buprenorphine 11.4 mg and naloxone 2.9 mg [menthol flavor]

Brand Names: U.S.

  • Bunavail
  • Suboxone
  • Zubsolv

Pharmacologic Category

  • Analgesic, Opioid
  • Analgesic, Opioid Partial Agonist

Pharmacology

Buprenorphine: 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

Naloxone: Pure opioid antagonist that competes and displaces opioids at opioid receptor sites

Absorption

Absorption widely is variable among patients following sublingual and buccal use, but variability within each individual patient is low.

Half-Life Elimination

Suboxone: Buprenorphine 24 to 42 hours; Naloxone 2 to 12 hours; Bunavail: Buprenorphine 16.4 to 27.5 hours; Naloxone 1.9 to 2.4 hours

Special Populations: Hepatic Function Impairment

Because both drugs are extensively metabolized, the plasma levels will be expected to be higher and the half-life values have been shown to be longer in patients with moderate and severe hepatic impairment; the significance of the effects are greater for naloxone compared to buprenorphine and for patients with severe hepatic impairment compared to patients with moderate hepatic impairment.

Use: Labeled Indications

Opioid dependence: Treatment of opioid dependence.

General information: Buprenorphine/naloxone should be used as part of a complete treatment plan to include counseling and psychosocial support

Contraindications

Hypersensitivity (eg, anaphylactic shock) to buprenorphine, naloxone, or any component of the formulation

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 (sublingual tablets): Additional contraindications (not in US labeling): Opioid naïve patients; severe respiratory insufficiency; severe hepatic impairment; acute alcoholism; delirium tremens

Dosing: Adult

Opioid dependence:

US labeling:

Induction: Heroin or other short-acting opioid dependency: Sublingual:

Notes:

Buprenorphine/naloxone is not recommended for use during the induction period for long-acting opioids or methadone; initial treatment should begin using buprenorphine monotherapy under supervision. Patients should be switched to the combination product for maintenance and unsupervised therapy.

Initiate treatment with sublingual buprenorphine/naloxone or buprenorphine monotherapy during the induction period for short-acting opioids or heroin; initiate treatment when signs of moderate opioid withdrawal appear and not less than 6 hours after last opioid use. Titrate to adequate maintenance dose as rapidly as possible based on control of acute withdrawal symptoms.

Sublingual film (Suboxone: Buprenorphine 2 mg/naloxone 0.5 mg; buprenorphine 4 mg/naloxone 1 mg; buprenorphine 8 mg/naloxone 2 mg; buprenorphine 12 mg/naloxone 3 mg):

Day 1 induction dose: Initial: Sublingual: Buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg; may titrate dose, based on control of acute withdrawal symptoms, in buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg increments approximately every 2 hours up to a total dose of buprenorphine 8 mg/naloxone 2 mg.

Day 2 induction dose: Up to buprenorphine 16 mg/naloxone 4 mg once daily.

Sublingual tablet (Zubsolv: Buprenorphine 1.4 mg/naloxone 0.36 mg, buprenorphine 2.9 mg/naloxone 0.71 mg, buprenorphine 5.7 mg/naloxone 1.4 mg, buprenorphine 8.6 mg/naloxone 2.1 mg, or buprenorphine 11.4 mg/naloxone 2.9 mg):

Day 1 induction dose: Initial: Sublingual: Buprenorphine 1.4 mg/naloxone 0.36 mg: May titrate dose, based on control of acute withdrawal symptoms in increments of buprenorphine 1.4 mg/naloxone 0.36 mg or buprenorphine 2.9 mg/naloxone 0.71 mg every 1.5 to 2 hours to a total day 1 dose up to buprenorphine 5.7 mg/naloxone 1.4 mg. Some patients (eg, those with recent exposure to buprenorphine) may tolerate up to buprenorphine 4.2 mg/naloxone 1.08 mg as a single, second dose.

Day 2 induction dose: Up to buprenorphine 11.4 mg/naloxone 2.9 mg once daily.

Maintenance:

Buccal film (Bunavail: Buprenorphine 2.1 mg/naloxone 0.3 mg, buprenorphine 4.2 mg/naloxone 0.7 mg, buprenorphine 6.3 mg/naloxone 1 mg): Buccal: Usual dose: Buprenorphine 8.4 mg/naloxone 1.4 mg once daily; dosage should be adjusted in increments/decrements of buprenorphine 2.1 mg/naloxone 0.3 mg to a level that maintains treatment and suppresses opioid withdrawal symptoms; usual range: Buprenorphine 2.1 to 12.6 mg/naloxone 0.3 to 2.1 mg once daily.

Sublingual film (Suboxone: Buprenorphine 2 mg/naloxone 0.5 mg; buprenorphine 4 mg/naloxone 1 mg; buprenorphine 8 mg/naloxone 2 mg; buprenorphine 12 mg/naloxone 3 mg): Sublingual or buccal: Target dose: Buprenorphine 16 mg/naloxone 4 mg once daily; dosage should be adjusted in increments/decrements of buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg to a level that maintains treatment and suppresses opioid withdrawal symptoms; usual range: Buprenorphine 4 to 24 mg/naloxone 1 to 6 mg once daily.

Sublingual tablet (buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 8 mg/naloxone 2 mg): Sublingual: Target dose: Buprenorphine 16 mg/naloxone 4 mg once daily; dosage should be adjusted in increments/decrements of buprenorphine 2 mg/naloxone 0.5 mg or buprenorphine 4 mg/naloxone 1 mg to a level that maintains treatment and suppresses opioid withdrawal symptoms; usual range: Buprenorphine 4 to 24 mg/naloxone 1 to 6 mg once daily.

Sublingual tablet (Zubsolv: Buprenorphine 1.4 mg/naloxone 0.36 mg, buprenorphine 2.9 mg/naloxone 0.71 mg, buprenorphine 5.7 mg/naloxone 1.4 mg, buprenorphine 8.6 mg/naloxone 2.1 mg, or buprenorphine 11.4 mg/naloxone 2.9 mg): Sublingual: Target dose: Buprenorphine 11.4 mg/naloxone 2.9 mg once daily; dosage should be adjusted in increments/decrements of buprenorphine 1.4 mg/naloxone 0.36 or buprenorphine 2.9 mg/naloxone 0.71 mg to a level that maintains treatment and suppresses opioid withdrawal symptoms; usual range: Buprenorphine 2.9 to 17.2 mg/naloxone 0.71 to 4.2 mg once daily.

Off-label dosing recommendations (U.S. Department of Health and Human Services, 2004): Doses provided based on buprenorphine content.

Induction (only administer combination product for induction in patients who are dependent on short-acting opioids and whose last dose of opioids was >12 to 24 hours prior to induction):

Day 1 induction dose: Initial: 4 mg; may repeat dose after >2 hours if withdrawal symptoms not relieved; maximum daily dose on day 1: 8 mg daily.

Day 2 induction dose: Previous dose from day 1 if no withdrawal symptoms present; if symptoms of withdrawal present, increase day 1 dose by 4 mg. If withdrawal symptoms not relieved after >2 hours, may administer 4 mg; maximum daily dose on day 2: 16 mg daily.

Subsequent induction days: If withdrawal symptoms are not present, daily dose is established. If withdrawal symptoms are present, increase dose in increments of 2 mg or 4 mg each day as needed for symptom relief. Target daily dose by the end of the first week: 12 mg or 16 mg daily; maximum daily dose: 32 mg daily.

Stabilization: Usual dose: 16 to 24 mg daily; maximum dose: 32 mg daily.

Switching between sublingual tablets and sublingual film: Same dosage should be used as the previous administered product. Note: Potential for greater bioavailability with certain sublingual film strengths compared to the same strength of the sublingual tablet; monitor closely for either over- or underdosing when switching patients from one formulation to another.

Switching between buccal film and sublingual tablets or films: Due to differences in the bioavailability of Bunavail buccal films compared to other buprenorphine/naloxone sublingual tablets, different strengths must be given to achieve equivalent doses. When switching between Bunavail and other sublingual tablets, corresponding dosage strengths are as follows:

Bunavail buprenorphine 2.1 mg/naloxone 0.3 mg = buprenorphine 4 mg/naloxone 1 mg sublingual tablets or films

Bunavail buprenorphine 4.2 mg/naloxone 0.7 mg = buprenorphine 8 mg/naloxone 2 mg sublingual tablets or films

Bunavail buprenorphine 6.3 mg/naloxone 1 mg = buprenorphine 12 mg/naloxone 3 mg sublingual tablets or films

Switching between sublingual film strengths: Systemic exposure may be different with various combinations of sublingual film strengths; pharmacists should not substitute one or more film strengths for another (eg, switching from three buprenorphine 4 mg/naloxone 1 mg films to a single buprenorphine 12 mg/naloxone 3 mg film, or vice-versa) without health care provider approval, and patients should be monitored closely for either over- or underdosing when switching between film strengths.

Switching between sublingual and buccal sites of administration (Suboxone): Systemic exposure between buccal and sublingual administration of buprenorphine/naloxone sublingual film is similar. Once induction is complete, patients can switch between buccal and sublingual administration without significant risk of under or overdosing.

Switching between sublingual tablet products: Due to differences in the bioavailability of Zubsolv sublingual tablets compared to other buprenorphine/naloxone sublingual tablets, different strengths must be given to achieve equivalent doses. When switching between Zubsolv and other sublingual tablets, corresponding dosage strengths are as follows:

Zubsolv buprenorphine 1.4 mg/naloxone 0.36 mg sublingual tablets = buprenorphine 2 mg/naloxone 0.5 mg sublingual tablets

Zubsolv buprenorphine 2.9 mg/naloxone 0.71 mg sublingual tablets = buprenorphine 4 mg/naloxone 1 mg (as two buprenorphine 2 mg/naloxone 0.5 mg sublingual tablets)

Zubsolv buprenorphine 5.7 mg/naloxone 1.4 mg sublingual tablets = buprenorphine 8 mg/naloxone 2 mg sublingual tablets

Zubsolv buprenorphine 8.6 mg/naloxone 2.1 mg sublingual tablet = buprenorphine 12 mg/naloxone 3 mg sublingual tablets (as one buprenorphine 8 mg/naloxone 2 mg sublingual tablets and two buprenorphine 2 mg/naloxone 0.5 mg sublingual tablets)

Zubsolv buprenorphine 11.4 mg/naloxone 2.9 mg sublingual tablet = buprenorphine 16 mg/naloxone 4 mg sublingual tablets (as two buprenorphine 8 mg/naloxone 2 mg sublingual tablets)

Canadian labeling: Sublingual tablet: Note: Dose based on buprenorphine content. Prior to induction, consider patient’s type of dependence (ie, long- or short-acting opiate), time since last use of opiate and extent of dependence. Initiate buprenorphine/naloxone when early signs of opiate withdrawal appear but no sooner than 6 hours after the last use of heroin or other short-acting opiates. Patients on methadone should have their methadone maintenance dose reduced to the minimum tolerable dose; initiate buprenorphine/naloxone only when early signs of withdrawal appear but no sooner than 24 hours after the last methadone dose.

Induction: Day 1: Initial: 4 mg as single dose; may repeat dose if necessary depending on patient’s requirement; target dose: 8 to 12 mg.

Maintenance: Day 2 and beyond: Titrate per response in increments or decrements of 2 to 8 mg; usual maintenance dose: 12 to 16 mg once daily (maximum: 24 mg/day). Upon stabilization, may consider less frequent administration of corresponding equivalent dose (eg, 16 mg every other day instead of 8 mg/day or 3 times/week dosing [eg, Monday-Wednesday-Friday] with twice the maintenance dose on Monday and Wednesday and three times the maintenance dose on Friday); continue to limit maximum dose to 24 mg/day on any single day. Note: When switching dosing to less than once daily, monitor all patients for at least 90 minutes following the initial dose of the new regimen. The less frequent dosing regimen is not recommended in patients dependent on concurrent CNS-active drugs, including ethanol.

Missed doses: Reassess patients who have missed multiple doses; initial induction doses may be required when resuming therapy.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Opioid dependence: Adolescents ≥16 years: Refer to adult dosing. Canadian labeling does not approve of use in patients <18 years.

Dosing: Renal Impairment

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

Canadian labeling:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Use with caution in severe impairment; dosage adjustment may be required.

Dosing: Hepatic Impairment

US labeling:

Mild hepatic impairment: No dosage adjustment necessary.

Moderate hepatic impairment: Use with caution during maintenance treatment (due to reduced clearance of naloxone and potential for reduced buprenorphine efficacy, use may not be appropriate). Suboxone use is not recommended during induction therapy.

Severe hepatic impairment: Use is not recommended.

Canadian labeling:

Mild to moderate impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a dosage adjustment may be considered. Because of extensive metabolism of buprenorphine and naloxone, use may not be appropriate in moderate impairment; use with caution and monitor closely.

Severe impairment: Use is contraindicated.

Administration

Film:

Bunavail:

Buccal: Prior to placing the film, moisten inside of cheek with tongue or water. Apply film with a dry finger immediately after removing it from packaging. Place film with the text (BN2, BN4, or BN6) 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. Do not chew, swallow or move film after placement. Liquids and food can be consumed after film dissolves. If using more than 1 film simultaneously, the additional film should be placed on the inside of the other cheek; no more than 2 films should be applied to the inside of one cheek at a time. Do not cut or tear the film.

Suboxone: May be used buccally or sublingually.

Buccal: Administer film whole; do not cut, chew, or swallow. Place one film on the inside of the right or left cheek. If more than one film is needed, the additional film should be placed on the inside of the opposite cheek. Keep the film on the inside of the cheek until completely dissolved. Do not move film after placement. If a third film is necessary, place it on the inside of the right or left cheek after the first two films have dissolved.

Sublingual film: Administer film whole; do not cut, chew, or swallow. Place one film under the tongue until the film completely dissolves, close to the base on the left or right side. If more than one film is needed, the additional film should be placed under the tongue on the opposite side from the first film. Place the film in a manner to minimize overlapping as much as possible. Do not move film after placement. If a third film is necessary to achieve the prescribed dose, place it under the tongue on either side after the first 2 films have dissolved.

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. In patients requiring more than one Zubsolv sublingual tablet, place all tablets in different places under the tongue at the same time. To ensure consistent bioavailability, subsequent doses should always be taken the same way. Patients should not eat or drink anything until the tablet(s) are completely dissolved. If a sequential mode of administration is preferred, patients should follow the same manner of dosing with continued use of the product, to ensure consistency in bioavailability.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from freezing and moisture.

Suboxone (Canadian labeling): Store at 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

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; 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

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: 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

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: 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

Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

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

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

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

Also see individual agents.

>10%:

Central nervous system: Headache (36%), withdrawal syndrome (25%; placebo 37%), pain (22%)

Dermatologic: Diaphoresis (14%)

Gastrointestinal: Glossodynia (film), oral hypoesthesia (film), oral mucosa erythema (film)

1% to 10%:

Cardiovascular: Vasodilatation (9%)

Gastrointestinal: Vomiting (8%)

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: Cytolytic hepatitis and hepatitis with jaundice has been reported with buprenorphine use; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy, and death. In many cases, preexisting hepatic dysfunction, preexisting liver enzyme abnormalities, hepatitis B or C virus infection, concomitant use of potentially hepatotoxic drugs, and ongoing drug use may have played a causative or contributory role. Monitor liver function tests in all patients prior to and periodically during therapy.

• 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 2011; Bliesener 2005; Brennan 2013).

• Orthostatic hypotension: May occur; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotension.

• Respiratory depression: Buprenorphine has been associated with significant respiratory depression and death, particularly when taken by IV route or in combination with other CNS and respiratory depressants.

Disease-related concerns:

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

• Adrenal insufficiency: Use buprenorphine with caution in patients with adrenal insufficiency, including Addison disease.

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

• Bowel obstruction: Use buprenorphine with caution in patients with a history of ileus or bowel obstruction.

• CNS depression/coma: Use buprenorphine with caution in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Ethanol abuse: Use buprenorphine with caution in patients with alcoholism or delirium tremens.

• Head trauma: Use buprenorphine with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.

• Hepatic impairment: Use is not recommended in patients with moderate hepatic impairment for induction therapy (Suboxone) or in patients with severe hepatic impairment. Use with caution in patients with moderate hepatic impairment for maintenance treatment; due to reduced clearance of naloxone and potential for reduced buprenorphine efficacy, use may not be appropriate.

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

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

• Respiratory disease: Use with caution in patients with preexisting respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve and kyphoscoliosis or other skeletal disorder that may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

• Thyroid dysfunction: Use buprenorphine with caution in patients with thyroid dysfunction (eg, myxedema, hypothyroidism).

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 patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Neonates: Neonatal opioid withdrawal syndrome (NOWS): May occur after chronic maternal exposure to opioids; 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. Opioid withdrawal syndrome in the neonate, unlike in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

Special handling:

• Disposal: Subcutaneous and buccal films: Dispose of unused films as long as they are no longer needed by removing from foil patch and flushing down the toilet. If multiple films are no longer needed, flush each film individually.

Other warnings/precautions:

• Abuse/misuse/diversion: Health care provider should be alert to problems of abuse, misuse, and diversion.

• Appropriate use: Buprenorphine/naloxone is not appropriate for pain management; deaths have been reported in opioid-naive patients receiving oral buprenorphine for analgesia.

• Withdrawal: Partial antagonist activity of buprenorphine may precipitate acute opioid withdrawal in opioid-dependent individuals upon rapid discontinuation or rapid taper. Naloxone may also precipitate intense withdrawal symptoms in patients addicted to opioids when administered before the opioid effects have subsided, or if misused and administered parenterally by opioid-dependent individuals. Abrupt discontinuation is not recommended; taper dose gradually when discontinuing.

Monitoring Parameters

Liver function tests (prior to initiation and periodically during therapy); respiratory status; mental status; CNS depression; symptoms of withdrawal; signs of addiction, abuse, or misuse. The Canadian labeling additionally recommends checking viral hepatitis status prior to initiation.

Pregnancy Considerations

Adverse reactions were observed in some animal reproduction studies. In the treatment of addiction involving opioid use in pregnant women, the buprenorphine/naloxone combination product is not recommended for use (insufficient evidence); however, the buprenorphine monoproduct is a reasonable and recommended option for use (Kampman [ASAM 2015]). Women who become pregnant while on this combination should generally be transitioned to the single agent (buprenorphine) product (ACOG 2012). See individual agents.

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, vomiting, headache, abdominal pain, insomnia, sweating a lot, flushing, numbness or tingling of mouth, or application site pain or irritation. 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), severe dizziness, passing out, difficulty breathing, slow breathing, shallow breathing, severe fatigue, confusion, severe constipation, vision changes, severe loss of strength and energy, anxiety, change in balance, mood changes, extra muscle movement, slow movements, or slurred speech (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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