The FDA is warning about the risks of dental problems associated with transmucosal (buccal, sublingual) buprenorphine-containing medicines. Dental adverse events, including tooth decay, cavities, dental abscesses/infection, tooth erosion, and in some cases total tooth loss, have been reported even in patients with no history of dental issues. The FDA will require that a new warning about the risk of dental problems be added to the prescribing information and the patient Medication Guide for all transmucosal buprenorphine-containing medicines. Prescribers should advise patients to see a dentist soon after starting the medicine and during treatment.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-dental-problems-buprenorphine-medicines-dissolved-mouth-treat-opioid-use-disorder.
Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.
Note: Bunavail (buccal film) has been discontinued in the United States for >1 year.
Note: Buprenorphine 8 mg sublingual tablet = buprenorphine/naloxone 8 mg/2 mg sublingual film = buprenorphine/naloxone 4.2 mg/0.7 mg buccal film = buprenorphine/naloxone 5.7 mg/1.4 mg sublingual tablet (SAMHSA 2021).
Opioid use disorder: Note: Prior to induction, consider type of opioid use (ie, long- or short-acting opioid) and time since last use of opioid.
Patients on heroin or short-acting prescription opioids should initiate buprenorphine/naloxone when signs of opioid withdrawal occur, but no sooner than 12 hours after the last opioid use (ASAM 2020; SAMHSA 2021). See dosing section below on "Switching therapies" for guidance on transitioning from methadone to buprenorphine.
Despite the manufacturer's recommendation to use buprenorphine instead of buprenorphine/naloxone during the induction period for long-acting opioid dependence due to the risk of withdrawal caused by naloxone, some experts recommend the combination product or buprenorphine for induction for long- and short-acting opioids (SAMHSA 2021).
US labeling:
Induction:
Note:
Titrate induction dose carefully to control acute withdrawal symptoms while avoiding sedation and monitoring for onset of precipitated withdrawal symptoms. Consider lower initial doses in patients with a history of opioid use disorder with a high risk of relapse but not currently dependent on opioids; titration in these patients should occur much more slowly than tolerant patients to avoid oversedation/overdose (SAMHSA 2021).
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):
Day 1 induction dose: Initial: Buccal: Buprenorphine 2.1 mg/naloxone 0.3 mg; consider an initial dose of buprenorphine ~1 mg and naloxone 0.15 mg in patients with a history of opioid use disorder with a high risk of relapse but not currently dependent on opioids (SAMHSA 2021; manufacturer’s labeling). May repeat dose after ~2 hours, based on control of acute withdrawal symptoms; maximum total dose: buprenorphine 4.2 mg/naloxone 0.7 mg (manufacturer’s labeling).
Day 2 induction dose: Up to buprenorphine 8.4 mg/naloxone 1.4 mg as a single dose.
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; consider an initial dose of buprenorphine 1 mg and naloxone 0.25 mg in patients with a history of opioid use disorder with a high risk of relapse but not currently dependent on opioids (SAMHSA 2021; manufacturer’s labeling). 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 (manufacturer’s labeling).
Day 2 induction dose: Sublingual: Up to buprenorphine 16 mg/naloxone 4 mg as a single dose.
Sublingual tablet (Zubsolv: Buprenorphine 0.7 mg/naloxone 0.18 mg, 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: Sublingual: Start with an initial dose of buprenorphine 1.4 mg/naloxone 0.36 mg; based on control of acute withdrawal symptoms, may administer additional doses in increments of 1 to 2 buprenorphine 1.4 mg/naloxone 0.36 mg tablets 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: Sublingual: Up to buprenorphine 11.4 mg/naloxone 2.9 mg as a single dose.
Maintenance: Note: In patients with pain, temporarily increasing the dose by 20% to 25% or dosing frequency (eg, divide total daily dose over 3 to 4 times per day) may maximize the analgesic properties for pain management (ASAM 2020). Buprenorphine may be safely dosed 2 or 3 times a week instead of once daily when more convenient dosing schedules are needed; divide the total weekly dose over 2 or 3 days per week (Marsch 2005).
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: Target 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. Buprenorphine doses ≥16 mg/day have been associated with greater efficacy; limited evidence exists for doses >24 mg/day.
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. Buprenorphine doses ≥16 mg/day have been associated with greater efficacy; limited evidence exists for doses >24 mg/day.
Sublingual tablet (Zubsolv: Buprenorphine 0.7 mg/naloxone 0.18 mg, 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 2.9 mg/naloxone 0.71 mg or lower 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. Doses higher than buprenorphine 17.2 mg/naloxone 4.2 mg have not been demonstrated to provide any clinical advantage.
Switching therapies:
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.
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).
Buprenorphine to naltrexone: Taper the buprenorphine dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone. A naloxone challenge may be used to demonstrate an absence of physical dependence (ASAM 2020).
Buprenorphine to methadone: No time delay is required (ASAM 2020).
Methadone to buprenorphine : Taper the methadone dose gradually to 30 to 40 mg per day and remain on that dose for ≥7 days. The patient should be in mild withdrawal before starting buprenorphine; this is typically 24 to 48 hours after the last dose of methadone. Initiating buprenorphine at lower doses (eg, 2 mg) decreases risk of precipitated methadone withdrawal (ASAM 2020; SAMHSA 2021).
Naltrexone to buprenorphine: Begin buprenorphine ~1 day following last dose of oral naltrexone and ~28 days following last dose of IM naltrexone (ASAM 2020).
Canadian labeling: Sublingual tablet: Note: Dose based on buprenorphine content.
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.
Discontinuation of therapy: When discontinuing buprenorphine/naloxone for long-term treatment of opioid use disorder, gradually decrease the dose over several months to prevent withdrawal; do not abruptly discontinue (ASAM 2020; SAMHSA 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been adequately studied); use with caution.
Mild impairment: No dosage adjustment necessary.
Moderate impairment: Use for induction is not recommended due to risk of precipitating withdrawal. Use with caution during maintenance treatment (due to reduced clearance of buprenorphine and naloxone, use may not be appropriate) in patients inducted with buprenorphine monotherapy; monitor for buprenorphine toxicity or overdose (SAMHSA 2021).
Severe impairment: Avoid use (SAMHSA 2021).
(For additional information see "Buprenorphine and naloxone: Pediatric drug information")
Note: Bunavail (buccal film) has been discontinued in the United States for >1 year. Sublingual tablets and film contain a free-base ratio of buprenorphine:naloxone of 4:1. Not all sublingual dosage forms are bioequivalent and dosing adjustment or additional monitoring may be necessary when switching products. Buprenorphine 8 mg sublingual tablet = buprenorphine 8 mg/naloxone 2 mg sublingual film = buprenorphine 5.7 mg/naloxone 1.4 mg sublingual tablet (SAMHSA 2021); refer to specific dosing sections below.
Doses based on buprenorphine content; titrate to appropriate effect.
Opioid dependence, maintenance treatment (heroin or short-acting opioid) (ASAM [Kampman 2015]): Note: Buprenorphine alone (without naloxone) is preferred over the combination product for use during the induction period for long-acting opioids or methadone.
Adolescents: Limited data available: Sublingual: Tablets or Film:
Induction: Note: Combination products should only be administered for induction in patients dependent on short-acting opioids (eg, heroin, oxycodone) who have begun to show mild to moderate opioid withdrawal signs (to avoid precipitated withdrawal) and whose last dose of opioids was at least 6 to 12 hours prior to induction.
Initial: 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.
After induction and titration, daily doses usually ≥8 mg/day are necessary. 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. Maximum daily dose: 24 mg/day.
Switching between sublingual tablets and sublingual film: The same dosage should be used as the previous administered product with close patient monitoring. 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 (ASAM [Kampman 2015]).
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 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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments are provided in manufacturer's labeling.
There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment is suggested.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Film, Buccal:
Bunavail: Buprenorphine 6.3 mg and naloxone 1 mg (1 ea [DSC], 30 ea [DSC]); Buprenorphine 2.1 mg and naloxone 0.3 mg (1 ea [DSC], 30 ea [DSC]); Buprenorphine 4.2 mg and naloxone 0.7 mg (1 ea [DSC], 30 ea [DSC]) [contains fd&c blue #1 (brilliant blue), methylparaben, propylparaben, saccharin sodium, sodium benzoate]
Film, Sublingual:
Suboxone: Buprenorphine 4 mg and naloxone 1 mg (1 ea, 30 ea); Buprenorphine 8 mg and naloxone 2 mg (1 ea, 30 ea); Buprenorphine 12 mg and naloxone 3 mg (1 ea, 30 ea); Buprenorphine 2 mg and naloxone 0.5 mg (1 ea, 30 ea) [contains fd&c yellow #6 (sunset yellow); lime flavor]
Generic: Buprenorphine 12 mg and naloxone 3 mg (1 ea, 30 ea); Buprenorphine 2 mg and naloxone 0.5 mg (1 ea, 30 ea); Buprenorphine 4 mg and naloxone 1 mg (1 ea, 30 ea); Buprenorphine 8 mg and naloxone 2 mg (1 ea, 30 ea)
Tablet Sublingual, Sublingual:
Zubsolv: Buprenorphine 5.7 mg and naloxone 1.4 mg, Buprenorphine 8.6 mg and naloxone 2.1 mg, Buprenorphine 0.7 mg and naloxone 0.18 mg, Buprenorphine 1.4 mg and naloxone 0.36 mg, Buprenorphine 11.4 mg and naloxone 2.9 mg, Buprenorphine 2.9 mg and naloxone 0.71 mg [contains menthol; menthol flavor]
Generic: Buprenorphine 2 mg and naloxone 0.5 mg, Buprenorphine 8 mg and naloxone 2 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Film, Sublingual:
Suboxone: Buprenorphine 4 mg and naloxone 1 mg (30 ea); Buprenorphine 8 mg and naloxone 2 mg (30 ea); Buprenorphine 12 mg and naloxone 3 mg (30 ea); Buprenorphine 2 mg and naloxone 0.5 mg (30 ea) [contains fd&c yellow #6 (sunset yellow)]
Tablet Sublingual, Sublingual:
Suboxone: Buprenorphine 8 mg and naloxone 2 mg, Buprenorphine 12 mg and naloxone 3 mg, Buprenorphine 16 mg and naloxone 4 mg, Buprenorphine 2 mg and naloxone 0.5 mg [contains corn starch]
Generic: Buprenorphine 2 mg and naloxone 0.5 mg, Buprenorphine 8 mg and naloxone 2 mg
Bunavail (buccal film) has been discontinued in the United States for >1 year.
C-III
In the US prescribing of tablets for opioid dependence is limited to physicians who have met the qualification criteria and have received a DEA number specific to prescribing this product. Tablets will be available through pharmacies and wholesalers which normally provide controlled substances.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Bunavail buccal film:https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/205637s023s024lbl.pdf#page=33
Buprenorphine and naloxone sublingual film for sublingual or buccal administration: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022410s033,020732s019,020733s023lbl.pdf#page=32
Cassipa sublingual film:https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208042s005s007lbl.pdf#page=30
Suboxone sublingual film:https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022410s046s047lbl.pdf#page=35
Suboxone sublingual tablet:https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020733s031s032lbl.pdf#page=32
Zubsolv sublingual tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204242s021s023lbl.pdf#page=20
Film:
Bunavail: Buccal: Although the manufacturer recommends administering the film whole without cutting, chewing, or swallowing, one stability study (using Suboxone brand) suggested that films split in half have uniform content and maintain stability for up to 7 days (Reindel 2019). Immediately before 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. Once film is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth. 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.
Suboxone: May be used buccally or sublingually.
Buccal: Although the manufacturer recommends administering the film whole without cutting, chewing, or swallowing, one stability study suggested that films split in half have uniform content and maintain stability for up to 7 days (Reindel 2019). 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. Once film is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth. 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 2 films have dissolved.
Sublingual film: Although the manufacturer recommends administering the film whole without cutting, chewing, or swallowing, one stability study suggested that films split in half have uniform content and maintain stability for up to 7 days (Reindel 2019). 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. Once film is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth.
Sublingual tablet: Immediately after removal from blister pack, tablet should be placed under the tongue until dissolved (can take up to 10 minutes to fully dissolve [SAMHSA 2021]). If 2 or more tablets are needed per dose, all may be placed under the tongue at once, or 2 at a time. In patients requiring more than one 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. Do not chew or swallow sublingual tablets. Once tablet(s) are completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth.
Sublingual film:
Suboxone: Although the manufacturer recommends administering the film whole without cutting, chewing, or swallowing, one stability study suggested that films split in half have uniform content and maintain stability for up to 7 days (Reindel 2019). Place one film under the tongue 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 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. Once film is completely dissolved, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth. Do not eat or drink until film is completely dissolved.
Sublingual tablets: Administer sublingual tablets whole; do not cut, chew, or swallow whole. Immediately after removal from blister pack, tablet should be placed under the tongue until dissolved. If 2 or more tablets are needed per dose, all may be placed under the tongue at once, or 2 at a time. In patients requiring more than one 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. Once tablet is completely dissolved along oral mucosa, swish a sip of water around the teeth and gums and swallow; wait at least 1 hour after administration to brush teeth. 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.
Opioid use disorder: Treatment of opioid use disorder.
General information: Buprenorphine/naloxone should be used as part of a complete treatment plan to include counseling and psychosocial support.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
KIDs List: Naloxone, when used in neonates for postpartum resuscitation, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided due to risk of seizure (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).
Potential for over- or underdosing when switching among various formulations and between strengths of the sublingual films: Not all strengths of sublingual tablets and films are bioequivalent to one another. In addition, systemic exposure between the various strengths of sublingual films may be different; pharmacists should not substitute one or more film strengths for another (eg, dispense three 4 mg films for one 12 mg film, or vice-versa) without physician approval. Any patient switching between sublingual tablet and sublingual film formulation or between one or more strengths of the sublingual films should be monitored for over- or underdosing.
Use of sublingual buprenorphine products (tablets and films) may result in dental adverse events (eg, tooth decay, dental caries, dental abscesses/infection, tooth erosion, fillings falling out, total tooth loss) (Ref). Cases may be severe and have occurred in patients without prior dental problems (Ref). Tooth extraction, root canal, dental surgery, and other restorative procedures (eg, fillings, crowns, implants, dentures) may be required for treatment.
Mechanism: Not clearly established; a potential factor may include the acidity of buprenorphine and naloxone in combination with prolonged contact with tooth surfaces during dissolution (Ref).
Onset: Delayed; worsening dental health was seen after an average of ~4 years of treatment with sublingual or buccal products (range: ~1.5 to 6.5 years) (Ref).
Risk factors:
• Etiologic factors known to exist in patients with opioid dependence that increase the risk of dental problems include (Ref):
- Poor personal hygiene
- Consumption of high sugar foods and beverages
- Xerostomia
- Opioid-induced immunosuppression
- Teeth clenching, bruxism
Opioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction, which is a broader term that encompasses additional GI opioid-induced adverse reactions including nausea, vomiting, and gastroesophageal reflux. Tolerance does not develop to OIC (Ref). Constipation due to opioids may decrease quality of life, contribute to nonadherence, and result in treatment failure (Ref). However, buprenorphine exhibits a lower incidence of constipation compared to full agonist opioids and does not cause spasm of the sphincter of Oddi (Ref). The rate of OIC has been shown to proportionately increase with buprenorphine dose (Ref). The risk of constipation may also be higher with sublingual administration of buprenorphine tablets or films as compared to buccal administration of bilayered films (Bunavail [discontinued]) (Ref). While constipation is common following use of buprenorphine/naloxone, use of this combination as a treatment option in a patient with narcotic bowel syndrome who required continued opioid analgesic therapy has been described (Ref).
Mechanism: Time-related; activity in both the central and enteric nervous systems (predominantly via the mu-opioid receptor) delays gastric emptying, inhibits peristalsis, impairs enzyme release, and produces antisecretory effects (Ref).
Onset: Varied; changes in peristalsis has been reported to occur 5 to 25 minutes after administration of opioids (Ref). However, OIC is defined based on a 7-day period of change (Ref).
Risk factors:
• Chronic opioid administration (Ref)
Serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of buprenorphine, especially during dose escalation or with misuse (Ref). Because buprenorphine is a partial agonist at the mu-opioid receptor, there is a dose-response ceiling with regards to respiratory depression (Ref); however, clinically significant respiratory depression can occur. If OIRD secondary to buprenorphine occurs, high dose naloxone given as a continuous infusion and/or mechanical ventilation may be required due to the slow receptor kinetics and high receptor affinity of buprenorphine at the mu-opioid receptor (Ref).
Patients who have been treated with buprenorphine and naloxone may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication, including OIRD. Patients should be aware that they may be more sensitive to lower doses of opioids after treatment with buprenorphine and naloxone is discontinued, after a missed dose, or near the end of the dosing interval (Ref).
Mechanism: Dose-related; mediated predominately via the mu-opioid receptor. Activates specific CNS sites (ie, pre-Bötzinger complex and Kölliker-Fuse nucleus) that control respiratory rhythms (Ref).
Onset: Rapid; OIRD has been reported from 5 minutes to 1.2 hours after administration of morphine (Ref).
Risk factors:
• Overdose (may also occur at therapeutic doses) ·
• Initiation or dose escalation
• Opioid naive (Ref)
• Opioid misuse/abuse (Ref)
• Respiratory disease (eg, chronic obstructive pulmonary disease, obstructive sleep apnea, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression) (Ref)
• Cardiac disease (Ref)
• Morbid obesity (Ref)
• Older adults (Ref)
• Kidney and/or liver impairment (Ref)
• Cachectic or debilitated patients
• Concurrent benzodiazepines or other CNS depressants, including alcohol
• Concurrent use with cytochrome P450 3A4 inhibitors
Initiation of buprenorphine may precipitate withdrawal symptoms in patients currently or recently taking full mu-opioid agonists (prescribed and/or non-prescribed) for a prolonged period (Ref); treatment initiation should be done in consultation with a healthcare professional experienced in pain management and/or opioid use disorder. Abrupt discontinuation or dose reduction of buprenorphine and naloxone in patients who are physically dependent on opioids may lead to opioid-induced withdrawal syndrome (OIW). Reversal of analgesia, irritability, nausea, vomiting, abdominal cramping, tachycardia, restlessness, and sweating are common symptoms of OIW. OIW symptoms typically resolve within 5 to 14 days; symptoms may cause significant distress but are rarely life-threatening (Ref).
Mechanism: Withdrawal; noradrenergic hyperactivity resulting from an abrupt discontinuation of opioids in patients who are physically dependent on opioids (OIW) (Ref) or initiation of a partial agonist (eg, buprenorphine) in a patient currently or recently taking a full mu-opioid agonist for a prolonged period (precipitated withdrawal) (Ref). This hyperactivity occurs due to abrupt reversal of adaptive mechanisms related to cAMP, locus coeruleus firing rate, and norepinephrine levels that occur with prolonged exposure to opioids (Ref).
Onset: Rapid; varies based on half-life of opioid. For short-acting opioids, symptoms of OIW typically occur within 12 hours after discontinuation and peak at 36 to 72 hours; OIW symptoms occur within 3 to 5 days following abrupt discontinuation of long-term buprenorphine treatment (Ref). Precipitated withdrawal may occur suddenly and in accordance with the onset of action of buprenorphine (eg, within 30 to 60 minutes) (Ref).
Risk factors:
• Prolonged exposure to opioids (Ref)
• Opioid use disorder (Ref)
• Abrupt discontinuation or dose reduction (Ref)
• Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics
• Discontinuation of concurrent cytochrome P450 3A4 inhibitors
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported for the sublingual tablet in adults unless otherwise indicated. Also see individual agents.
>10%:
Dermatologic: Diaphoresis (14%)
Gastrointestinal: Abdominal pain (11%), constipation (12%) (table 1), nausea (5% to 15%) (table 2)
|
Drug (Buprenorphine and Naloxone) |
Comparator (Buprenorphine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Buprenorphine and Naloxone) |
Number of Patients (Buprenorphine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
12% |
8% |
3% |
16 mg buprenorphine/4 mg naloxone per day |
Sublingual tablets |
107 |
103 |
107 |
|
Drug (Buprenorphine and Naloxone) |
Comparator (Buprenorphine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Buprenorphine and Naloxone) |
Number of Patients (Buprenorphine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
15% |
14% |
11% |
16 mg buprenorphine/4 mg naloxone per day |
Sublingual tablets |
107 |
103 |
107 |
|
5% |
7% |
N/A |
Initial dose of 1.4 mg buprenorphine/0.36 mg naloxone followed by 4.2 mg buprenorphine/1.08 mg naloxone 1.5 hours later |
Sublingual tablets |
538 |
530 |
N/A |
Nervous system: Headache (7% to 37%), pain (22%), withdrawal syndrome (25%) (table 3)
|
Drug (Buprenorphine and Naloxone) |
Comparator (Buprenorphine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Buprenorphine and Naloxone) |
Number of Patients (Buprenorphine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
25% |
18% |
37% |
16 mg buprenorphine/4 mg naloxone per day |
Sublingual tablets |
107 |
103 |
107 |
1% to 10%:
Cardiovascular: Vasodilation (9%)
Gastrointestinal: Oral hypoesthesia (sublingual film: >1%), vomiting (5% to 8%)
Frequency not defined:
Cardiovascular: Palpitations (sublingual film)
Dermatologic: Hyperhidrosis (sublingual film), piloerection
Gastrointestinal: Glossalgia (sublingual film), oral mucosal erythema (sublingual film), stomach discomfort
Nervous system: Anxiety, disturbance in attention (sublingual film), insomnia (sublingual film), intoxicated feeling (sublingual film), irritability, restlessness
Neuromuscular & skeletal: Arthralgia
Ophthalmic: Blurred vision (sublingual film), increased lacrimation
Respiratory: Rhinorrhea
Postmarketing (any route):
Cardiovascular: Peripheral edema
Gastrointestinal: Dental caries (including tooth fracture, tooth loss) (Suzuki 2012), glossitis, oral bullae, oral mucosa ulcer, stomatitis
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-naive patients; severe respiratory insufficiency (eg, acute or severe bronchial asthma, chronic obstructive airway, status asthmaticus, acute respiratory depression, cor pulmonale); severe hepatic impairment; acute alcohol intoxication or delirium tremens; convulsive or seizure disorders; known or suspected mechanical GI obstruction or diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); severe CNS depression, increased cerebrospinal or intracranial pressure, or head injury; concurrent use or within 2 weeks of MAO inhibitors.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hepatic events: Hepatitis has been reported; hepatic events ranged from transient, asymptomatic transaminase elevations to hepatic failure; in many cases, patients had preexisting hepatic impairment. Monitor liver function tests in patients at increased risk for hepatotoxicity (eg, history of alcohol or IV drug abuse, preexisting hepatic dysfunction) prior to and during therapy.
• Hypersensitivity reactions: Hypersensitivity, including bronchospasm, angioneurotic edema, and anaphylactic shock, have been reported.
• Hypotension: May cause severe hypotension, including orthostatic hypotension and syncope; use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Use with caution in patients with circulatory shock.
• QT prolongation: Buprenorphine has been observed to cause QTc 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.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis.
• Bowel obstruction: Use with caution in patients with a history of ileus or bowel obstruction.
• CNS depression/coma: Use with caution in patients with impaired consciousness or coma because these patients are susceptible to intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• 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.
• 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.
• Obesity: Use with caution in patients who are morbidly obese (DeVido 2015).
• 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.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease, cor pulmonale, or kyphoscoliosis, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages.
• Seizure: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Benzodiazepines and other CNS depressants: Concomitant use of benzodiazepines or other CNS depressants, including alcohol and opioids, may result in profound sedation, respiratory depression, coma, and death. Prohibiting medication-based opioid use disorder treatment may increase the risk of morbidity and mortality, therefore, patients should be educated on the risks of concomitant use with benzodiazepines, sedatives, opioid analgesics, and alcohol. Strategies should be developed to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of or during treatment with buprenorphine; adjustments to induction procedures and additional monitoring may be required. If appropriate, delay or omit buprenorphine dose if a patient is sedated at time of buprenorphine dosing. Discontinuation of benzodiazepines or other CNS depressants is preferred; gradual tapering of benzodiazepine or other CNS depressant, decreasing to lowest effective dose, or monitoring in a higher level of care for taper may be appropriate. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids. Benzodiazepines are not the treatment of choice for anxiety or insomnia for patients in buprenorphine treatment; make sure patients are appropriately diagnosed and consider alternative medications for anxiety and insomnia prior to coadministration of benzodiazepines and buprenorphine.
Special populations:
• Older adult: Use with caution in older adults; may be more sensitive to adverse effects (eg, life-threatening respiratory depression).
• Neonates: Neonatal withdrawal syndrome: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant patient, advise the patient of the risk of neonatal withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
Special handling:
• Disposal: Dispose of unused buccal and sublingual films (if 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:
• Accidental ingestion: Accidental ingestion in children can result in severe respiratory depression (may be fatal); store buprenorphine-containing medications out of reach of children and dispose of unused medication appropriately.
• Acute pain: When using buprenorphine for treatment of opioid use disorder, treat acute pain with nonopioid analgesics whenever possible. Dividing buprenorphine daily dose into 3 divided doses may also provide sufficient pain relief (SAMHSA 2021). If treatment with a high-affinity full opioid analgesic is required, monitor closely for respiratory depression because high doses may be necessary to achieve pain relief.
• Addiction/abuse/misuse: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of substance use disorder; potential for opioid use disorder exists. Other factors associated with an increased risk for misuse include younger age and psychotropic medication use (Dowell [CDC 2016]).
• Appropriate use: Buprenorphine/naloxone is not appropriate for pain management; deaths have been reported in opioid-naive patients receiving oral buprenorphine for analgesia.
• Discontinuation of therapy: There is no maximum recommended duration for maintenance treatment of opioid use disorder; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-based opioid use disorder treatment.
• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of) or substance use disorder, and have higher opioid dosages (≥50 morphine milligram equivalents/day orally) (Dowell [CDC 2016]), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.
• Partial opioid agonist and mixed opioid agonist/antagonist overdose: Reversal of partial opioid agonists or mixed opioid agonist/antagonists (eg, buprenorphine, pentazocine) may be incomplete and higher than normal doses and repeated administration of naloxone may be required.
• Surgery: In patients undergoing elective surgery (excluding caesarean section), consider discontinuation of buprenorphine the day before or day of surgery. In patients unable to abruptly discontinue buprenorphine prior to surgery, full opioid agonists may be added to the buprenorphine to maintain proper analgesia. If opioid therapy is required as part of analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in in the conduct of the surgical or diagnostic procedure. The decision whether to discontinue buprenorphine prior to elective surgery should be made in consultation with the surgeon and anesthesiologist. If discontinued, buprenorphine can be resumed postoperatively when there is no longer a need for full opioid agonist therapy; in general, presurgery daily doses may be resumed if held for <2 to 3 days (ASAM 2020).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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. Risk D: Consider therapy modification
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Atazanavir: Buprenorphine may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Buprenorphine. Management: Buprenorphine is not recommended in patients taking atazanavir without ritonavir. In patients taking atazanavir with ritonavir or cobicistat, monitor for opioid excess if coadministered with buprenorphine and consider buprenorphine dose reductions. Risk X: Avoid combination
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Buprenorphine. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Buprenorphine. Risk C: Monitor therapy
Daclatasvir: May increase the serum concentration of Buprenorphine. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: Buprenorphine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination
Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification
Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Nefazodone: Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4). Management: If concomitant use of opioid agonists that are metabolized by CYP3A4 and nefazodone is necessary, consider dose reduction of the opioid until stable drug effects are achieved. Monitor for increased opioid effects and serotonin syndrome/serotonin toxicity. Risk D: Consider therapy modification
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: Opioids (Mixed Agonist / Antagonist) may diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination
Opioids (Mixed Agonist / Antagonist): May diminish the therapeutic effect of Buprenorphine. This combination may also induce opioid withdrawal. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
PHENobarbital: May enhance the CNS depressant effect of Buprenorphine. PHENobarbital may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider therapy modification
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Primidone: May enhance the CNS depressant effect of Buprenorphine. Primidone may decrease the serum concentration of Buprenorphine. Management: Avoid use of buprenorphine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased buprenorphine efficacy and withdrawal if combined. Risk D: Consider therapy modification
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination
Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Pregnancy testing is recommended prior to initiating therapy for opioid use disorders. Long-term opioid use and misuse may cause infertility, including erectile dysfunction, decreased sperm motility, menstrual disorders, and amenorrhea in patients of reproductive potential (SAMHSA 2021). Initiation of buprenorphine maintenance treatment may improve fertility resulting in unplanned pregnancy (Dow 2012). Contraception counseling is recommended (Dow 2012; SAMHSA 2021).
Buprenorphine and naloxone can be detected in cord blood following maternal use of sublingual tablets; cord blood concentrations of buprenorphine and naloxone correlate with maternal serum levels (Weigand 2016).
Prolonged use of opioids 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 patient, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure appropriate treatment will be available.
Opioid agonist pharmacotherapy is recommended when treating opioid use disorder in pregnancy (ACOG 2017; ASAM 2020; SAMHSA 2021). Treatment should begin as early in pregnancy as possible (ASAM 2020). Buprenorphine monotherapy is generally preferred when treatment is initiated during pregnancy (ACOG 2017; ASAM 2020; SAMHSA 2021). Based on available data, an increased risk of adverse pregnancy outcomes has not been observed when pregnancy occurs during treatment with buprenorphine/naloxone combination therapy, and continued use may be considered (Ecker [SMFM 2019]; Link 2020; Link 2021).
Refer to individual monographs for additional information.
Buprenorphine and its active metabolite, norbuprenorphine, are present in breast milk. It is not known if naloxone is present in breast milk; however, systemic absorption following oral administration is limited.
According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Refer to individual monographs for additional information.
Liver function tests (prior to initiation and periodically during therapy); pregnancy test (prior to initiation); hepatitis and HIV tests (prior to initiation), particularly for patients with opioid use disorder (SAMHSA 2021); respiratory and mental status (especially during initiation or dose escalation); CNS depression; blood pressure; symptoms of withdrawal; signs of dependence, abuse, or misuse; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013). Monitor for dental changes (eg, cavities, tooth erosion/decay, loss of fillings, tooth loss) with sublingual tablet use.
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
Also see individual agents.
Absorption: Absorption widely is variable among patients following sublingual and buccal use, but variability within each individual patient is low.
Bioavailability:
Buccal film: The exposure of one buprenorphine 4.2 mg/naloxone 0.7 mg buccal film is equivalent to one buprenorphine 8 mg/naloxone 2 mg sublingual tablet. The naloxone exposure from buccal film was 33% less than buprenorphine/naloxone sublingual tablets. The coadministration of liquids reduced the systemic exposure up to 59% for buprenorphine and up to 76% for naloxone, depending on the pH of the liquid.
Sublingual: Although pharmacokinetics were similar between the sublingual formulations, bioequivalence is variable.
Sublingual film: Potential for greater bioavailability with certain strengths of the sublingual film compared to the same strength of the sublingual tablet. In addition, the sizes and compositions among the sublingual film strengths are different which may result in different systemic exposures.
Sublingual tablet: Zubsolv has different bioavailability when compared to other buprenorphine/naloxone sublingual tablets. One Zubsolv buprenorphine 5.7 mg/naloxone 1.4 mg sublingual tablet provides equivalent buprenorphine exposure and 12% lower naloxone exposure compared to one buprenorphine 8 mg/naloxone 2 mg sublingual tablet.
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.
Protein binding: Buprenorphine: ~96%, primarily to alpha and beta globulin; Naloxone: ~45%, primarily to albumin.
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.
Film (Buprenorphine HCl-Naloxone HCl Sublingual)
2-0.5 mg (per each): $4.91 - $5.15
4-1 mg (per each): $8.79 - $9.23
8-2 mg (per each): $8.79 - $9.23
12-3 mg (per each): $17.58 - $18.46
Film (Suboxone Sublingual)
2-0.5 mg (per each): $6.01
4-1 mg (per each): $10.78
8-2 mg (per each): $10.78
12-3 mg (per each): $21.55
Sublingual (Buprenorphine HCl-Naloxone HCl Sublingual)
2-0.5 mg (per each): $4.51 - $5.83
8-2 mg (per each): $7.88 - $10.43
Sublingual (Zubsolv Sublingual)
0.7-0.18 mg (per each): $5.66
1.4-0.36 mg (per each): $5.66
2.9-0.71 mg (per each): $11.32
5.7-1.4 mg (per each): $11.32
8.6-2.1 mg (per each): $16.99
11.4-2.9 mg (per each): $22.65
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