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  • CLASSES

    Agents for Opioid Dependence
    Agents for Opioid Withdrawal

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Mixed opiate agonist-antagonist (buprenorphine) combined with naloxone (an opiate antagonist); naloxone is included as an abuse deterrent
    Used for induction treatment in patients dependent on heroin or other short-acting opioids who are in opioid withdrawal; also used for maintenance treatment of opioid dependence
    Prescribers must comply with the requirements of the Drug Addiction Treatment Act (DATA)

    COMMON BRAND NAMES

    BUNAVAIL, Suboxone, Zubsolv

    HOW SUPPLIED

    BUNAVAIL Transmucosal Film: 2.1-0.3mg, 4.2-0.7mg, 6.3-1mg
    BUNAVAIL/Buprenorphine Hydrochloride, Naloxone Hydrochloride/Buprenorphine, Naloxone Hydrochloride/Suboxone Buccal Film: 12-3mg, 2-0.5mg, 2.1-0.3mg, 4-1mg, 4.2-0.7mg, 6.3-1mg, 8-2mg
    Buprenorphine Hydrochloride, Naloxone Hydrochloride/Buprenorphine, Naloxone Hydrochloride/Suboxone Sublingual Film: 12-3mg, 2-0.5mg, 4-1mg, 8-2mg
    Buprenorphine Hydrochloride, Naloxone Hydrochloride/Buprenorphine, Naloxone Hydrochloride/Suboxone/Zubsolv Sublingual Tablet, SL: 0.7-0.18mg, 1.4-0.36mg, 11.4-2.9mg, 2-0.5mg, 2.9-0.71mg, 5.7-1.4mg, 8-2mg, 8.6-2.1mg

    DOSAGE & INDICATIONS

    For the treatment of opiate agonist dependence.
    for induction treatment in patients dependent on heroin or other short-acting opioid products who are in opioid withdrawal.
    Sublingual dosage (i.e., Suboxone sublingual film)
    Adults and Adolescents 16 years and older

    Although sublingual (SL) film may be administered buccally during maintenance therapy, exposure to naloxone is somewhat higher after buccal use than sublingual use. Therefore, ONLY the sublingual route should be used during induction to minimize exposure to naloxone and reduce the risk of precipitating withdrawal. DAY 1 DOSING: First induction dose buprenorphine; naloxone 2 mg/0.5 mg or 4 mg/1 mg SL film; may titrate in 2 or 4 mg increments of buprenorphine, at approximately 2-hour increments, under supervision, up to a total dose of buprenorphine/naloxone 8 mg/2 mg SL film. DAY 2 DOSING: A single daily dose of buprenorphine; naloxone up to 16 mg/4 mg SL film is recommended. DAY 3 DOSING AND BEYOND: Progressively adjust dose in increments or decrements of 2 mg/0.5 mg or 4 mg/1 mg to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms. Consider the frequency of visits when prescribing; multiple refills are not advised early in treatment or without appropriate patient follow-up visits. An adequate maintenance dose should be attained as quickly as possible; in some studies, prolonged induction over several days resulted in a high drop-out rate. OTHER CONSIDERATIONS: To avoid precipitating withdrawal, only initiate the first induction dose when objective signs of moderate withdrawal appear and not less than 6 hours after the patient last used an opioid. Not indicated for induction in patients dependent on methadone or long-acting opioids because these patients may be more susceptible to precipitated and prolonged withdrawal during induction than patients on short-acting agents. Prior to induction therapy, consider the type of opioid dependence (i.e., short- or long-acting opioids), the time since last opioid use, and the severity of opioid dependence.

    Sublingual dosage (i.e., Zubsolv sublingual tablet)
    Adults and Adolescents 16 years and older

    Prior to induction therapy, consider the type of opioid dependence (i.e., short- or long-acting opioids), the time since last opioid use, and the severity of opioid dependence. To avoid precipitating withdrawal, initiate the first induction dose only when objective signs of moderate withdrawal appear and not less than 6 hours after the patient last used a short-acting opioid. Not indicated for induction in patients dependent on long-acting opioids. Induction dosing is as follows: DAY 1 DOSING: Initial recommended induction dose is 1.4 mg/0.36 mg SL. During the remainder of Day 1, may administer 1 to 2 SL tablets of buprenorphine; naloxone 1.4 mg/0.36 mg SL at 1.5 to 2 hour intervals up to a total of 5.7 mg/1.4 mg. Some patients (e.g., those with recent exposure to buprenorphine) may tolerate up to 3 tablets (1.4 mg/0.36 mg per tablet) as a single, second SL dose. DAY 2 DOSING: A single daily dose of up to 11.4 mg/2.9 mg SL is recommended. Base dosage on clinical need to control acute withdrawal symptoms and administer under supervision. DAY 3 DOSING AND BEYOND: Maintenance target dose is 11.4 mg/2.9 mg SL as a single daily dose. See maintenance treatment section of product label for detailed dosing instructions. Initiate treatment with supervised administration, and progress to unsupervised administration. When determining prescription quantity for unsupervised administration, consider frequency of visits, patient's stability, and security of home. Buprenorphine with naloxone is preferred over buprenorphine alone for maintenance treatment, especially when drug administration will not be supervised.

    Buccal dosage (e.g., Bunavail buccal film)
    Adults and Adolescents 16 years and older

    DAY 1 DOSING: Initially, 2.1 mg/0.3 mg buccally. Administer the first dose only when objective and clear signs of moderate opioid withdrawal appear, and not less than 6 hours after the patient last used an opioid. Repeat at approximately 2 hours if needed, under supervision, to a total dose of 4.2 mg/0.7 mg based on the control of acute withdrawal symptoms. DAY 2 DOSING: Administer up to 8.4 mg/1.4 mg buccally single daily dose. OTHER CONSIDERATIONS: Prior to induction, consider the type of opioid dependence (i.e., long- or short-acting opioid products), the time since the last opioid use, and the degree of level of opioid dependence. Medication should be prescribed in consideration of the frequency of visits. Providing multiple refills is not advised early in treatment or without appropriate patient follow-up visits. Following induction, the patient may be transitioned to once daily buccal film administration. Buprenorphine; naloxone products have not been adequately evaluated for induction in patients on long-acting opioid products (e.g., methadone); buprenorphine monotherapy is recommended in patients taking long-acting opioids.

    For maintenance treatment in patients with opioid dependence.
    Sublingual or Buccal dosage (i.e., Suboxone sublingual film)
    Adults and Adolescents 16 years and older

    Following induction, a target maintenance dose of 16 mg/4 mg film once daily is suggested, given either SL or via buccal route. However, doses ranging from 4 to 24 mg/day of the buprenorphine component may be required. Titrate, in increments of 2 to 4 mg/day of buprenorphine, to a dose that holds the patient in treatment and suppresses opiate withdrawal symptoms. Higher dosages (12 to 16 mg/day of buprenorphine) have been associated with reduced opiate craving and fewer opiate-positive urine tests. Doses higher than 24 mg/day buccally or SL have not shown any added benefit. Buccal administration is not recommended during induction treatment since naloxone exposure is higher with the buccal route than the SL route; however, buprenorphine exposure is similar between the two routes. Therefore, during maintenance treatment, patients can switch between buccal and SL administration without significant risk of under or overdosing.

    Sublingual dosage (e.g., Suboxone or generic equivalent sublingual tablets)
    Adults and Adolescents 16 years and older

    Following induction, a target maintenance dose of 16 mg/4 mg SL once daily is suggested. However, doses ranging from 4 to 24 mg/day of the buprenorphine component may be required. Titrate, in increments of 2 to 4 mg/day of buprenorphine, to a dose that holds the patient in treatment and suppresses opiate withdrawal symptoms. Higher dosages (12 to 16 mg/day of buprenorphine) have been associated with reduced opiate craving and fewer opiate-positive urine tests. Doses higher than 24 mg SL once daily have not shown any added benefit. Initiate treatment with supervised administration, and progress to unsupervised administration. When determining prescription quantity for unsupervised administration, consider frequency of visits, patient's stability, and security of home. REDUCING DOSAGE AND STOPPING TREATMENT: Patients may remain on treatment indefinitely as long as the drug is beneficial. If discontinuing maintenance therapy, taper the dose to reduce the occurrence of withdrawal. Advise of the potential for relapse to illicit drug use. ALTERNATIVE MAINTENANCE DOSE REGIMEN†: Off-label regimens include 3 times per week dosing; the total weekly dose is divided and given in 3 doses over the week.

    Sublingual dosage (i.e., Zubsolv sublingual tablets)
    Adults and Adolescents 16 years and older

    Following induction to opioid dependence treatment, a target dose of 11.4 mg/2.9 mg SL once daily is recommended. Individualize, in increments or decrements of no more than 2.9 mg/0.71 mg, to a dose that holds the patient in treatment and suppresses opioid withdrawal. Usual maintenance range: 2.9 mg/0.71 mg to 17.1 mg/4.2 mg SL once daily. Doses higher than 17.1 mg/4.2 mg SL once daily have not shown any added benefit. Initiate treatment with supervised administration, and progress to unsupervised administration. When determining prescription quantity for unsupervised administration, consider frequency of visits, patient's stability, and security of home. REDUCING AND STOPPING TREATMENT: If discontinuing maintenance therapy, taper the dose to reduce the occurrence of withdrawal. Advise of the potential for relapse to illicit drug use. CONVERSION FROM BUPRENORPHINE INDUCTION DOSE TO MAINTENANCE DOSE OF BUPRENORPHINE; NALOXONE (ZUBSOLV): 8 mg buprenorphine SL per day: 5.7 mg/1.4 mg buprenorphine; naloxone SL per day; 12 mg buprenorphine SL per day: 8.6 mg/2.1 mg buprenorphine; naloxone SL per day; 16 mg buprenorphine SL per day: 11.4 mg/2.9 mg buprenorphine; naloxone SL per day. Dose adjustments may be necessary when switching between Zubsolv and other buprenorphine; naloxone products during maintenance therapy. EXAMPLE CORRESPONDING MAINTENANCE DOSES FOR SUBOXONE OR GENERIC EQUIVALENT COMPARED TO ZUBSOLV: 2 mg/0.5 mg Suboxone generic equivalent: 1.4 mg/0.36 mg Zubsolv; 4 mg/1 mg Suboxone generic equivalent: 2.9 mg/0.71 mg Zubsolv; 8 mg/2 mg Suboxone generic equivalent: 5.7 mg/1.4 mg Zubsolv; 12 mg/3 mg Suboxone generic equivalent: 8.6 mg/2.1 mg Zubsolv; 16 mg/4 mg Suboxone generic equivalent: 11.4 mg/2.9 mg Zubsolv.

    Buccal dosage (i.e., Bunavail buccal film)
    Adults and Adolescents 16 years and older

    From Day 3 onward, progressively adjust dose in increments or decrements of 2.1/0.3 mg buccally to a level that holds the patient in treatment and suppresses opioid withdrawal. Because of the differences in bioavailability, a different dose strength is used for this product compared to the other dose forms as follows: 8 mg/2 mg Suboxone generic SL tablet provides equivalent exposure to 4.2 mg/0.7 mg Bunavail buccal film. Following induction, the recommended target maintenance dose is 8.4 mg/1.4 mg buccally once daily. However, maintenance doses ranging from 2.1/0.3 to 12.6/2.1 mg/day buccally may be used depending on the individual patient. Suggested Max: 12.6/2.1 mg per day buccally. When determining prescription quantities for unsupervised prescribing, consider the patient's level of stability, the security of the home environment, and other factors likely to affect the patient's ability to manage supplies of take-home medication. STOPPING TREATMENT: If stopping treatment, taper the dose to reduce withdrawal. Also, warn patients of potential for relapse.

    Sublingual dosage (i.e., Cassipa sublingual film)
    Adults

    Buprenorphine 16 mg/naloxone 4 mg (i.e., Cassipa) is administered sublingually (SL) once daily. Cassipa should only be used after induction and stabilization of the patient and after the patient has been titrated to a dose of 16 mg/day of buprenorphine using another product. Patients switched between other buprenorphine; naloxone products, buprenorphine alone, and Cassipa should be started on the corresponding dosage of the previous administered product, taking into consideration that dosage adjustments may be necessary. Cassipa is only available in a single dose and cannot be adjusted; therefore, a change to other buprenorphine; naloxone products may be required. When determining prescription quantity for unsupervised administration, consider frequency of visits, patient's stability, and security of home. REDUCING AND STOPPING TREATMENT: If the decision is made to discontinue maintenance therapy, taper the dose to reduce the occurrence of withdrawal. Advise of the potential for relapse to illicit drug use.

    MAXIMUM DOSAGE

    Adults

    Suboxone oral dissolving film: 24 mg/6 mg per day sublingually or buccally.
    Suboxone sublingual tablets (or generic): 24 mg/6 mg per day sublingually.
    Zubsolv sublingual tablets: 17.1 mg/4.2 mg per day sublingually.
    Bunavail buccal film: 12.6 mg/2.1 mg per day buccally.
    Cassida sublingual film: 16 mg/4 mg per day sublingually.

    Geriatric

    Suboxone oral dissolving film: 24 mg/6 mg per day sublingually or buccally.
    Suboxone sublingual tablets (or generic): 24 mg/6 mg per day sublingually.
    Zubsolv sublingual tablets: 17.1 mg/4.2 mg per day sublingually.
    Bunavail buccal film: 12.6 mg/2.1 mg per day buccally.
    Cassida sublingual film: 16 mg/4 mg per day sublingually.

    Adolescents

    16 to 17 years:
    Suboxone oral dissolving film: 24 mg/6 mg per day sublingually or buccally.
    Suboxone sublingual tablets (or generic): 24 mg/6 mg per day sublingually.
    Zubsolv sublingual tablets: 17.1 mg/4.2 mg per day sublingually.
    Bunavail buccal film: 12.6 mg/2.1 mg per day buccally.
     
    Less than 16 years:
    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment: No dosage adjustments are necessary.
     
    Moderate hepatic impairment: Hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Induction treatment with these products is not recommended in patients with moderate hepatic impairment, as there is an increased risk of precipitated withdrawal at the beginning of treatment. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. Patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine's efficacy during maintenance treatment.
     
    Severe hepatic impairment: Use should be avoided.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are required.
     
    Intermittent Hemodialysis
    No differences in buprenorphine pharmacokinetics were observed between 9 patients receiving dialysis and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone kinetics are unknown.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    Under the Drug Addiction Treatment Act (DATA), physicians with a current waiver to provide medication-assisted treatment (MAT) to a maximum of 100 opioid-dependent patients and who have maintained the waiver in accordance with applicable statutory requirements without interruption for at least 1 year may become eligible to provide MAT to a total of 275 opioid-dependent patients at any 1 time. The requirements of DATA must be met.[61057]
    Pharmacists who wish to verify whether a physician is qualified to prescribe buprenorphine; naloxone under the DATA may contact 1-866-BUP-CSAT.
    Storage: Store buprenorphine; naloxone in a location not accessible by others.
    Disposal: Remove from packaging and flush unused buprenorphine; naloxone down the toilet when it is no longer needed if a drug take-back option is not readily available.[41666] [55234] [57392]

    Oral Solid Formulations

    Sublingual tablet administration (Suboxone generic equivalent sublingual tablets):[28548] [36605]
    Place tablet under tongue to dissolve; allow the tablet to completely dissolve.
    Do not swallow or chew the tablets. Instruct patients to be consistent with tablet administration; swallowing the tablet will reduce the bioavailability of the drug.
    For doses requiring more than 2 tablets per dose, advise patients to either place all the tablets under the tongue at once or, if they cannot fit more than 2 tablets comfortably, place 2 tablets at a time under the tongue. With either option, patients should hold the tablets under the tongue until they completely dissolve.
     
    Sublingual tablet administration (Zubsolv sublingual tablets):[55234]
    Place tablet under tongue to dissolve; allow the tablet to completely dissolve.
    Do not cut, chew, or swallow the tablets as this will reduce the bioavailability of the drug.
    For doses requiring more than 1 tablet, advise the patient to place all tablets in different places under the tongue at the same time. 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.
    Advise patients not to eat or drink anything until the tablet is completely dissolved.
     
    Sublingual film administration (Suboxone sublingual film):[41666]
    Do not cut, chew, or swallow the sublingual film.
    The package should not be opened until the patient is ready to use the medication. The foil package should be opened by folding along the dotted lines and tearing down at slits or cutting with scissors along the arrow. After opening, the film should be used right away.
    Before taking the medication, drink water to moisten the inside of the mouth. This helps the film dissolve more easily.
    Place film under tongue; allow the film to completely dissolve.
    Do not move the film once placed as this will reduce the bioavailability of the drug.
    For doses requiring more than 1 film per dose, advise the patient to place the films on opposite sides of the mouth under the tongue; avoid letting the films touch.
    Proper administration technique should be demonstrated to the patient.
     
    Buccal administration of sublingual film (Suboxone sublingual film for buccal use):[41666]
    Do not cut, chew, or swallow the film.
    The foil package should not be opened until the patient is ready to use the medication. The foil package should be opened by folding along the dotted lines and tearing down at slits or cutting with scissors along the arrow. After opening, the film should be used right away.
    Before taking the medication, drink water to moisten the inside of the mouth. This helps the film dissolve more easily.
    Place one film on the inside of the right or left cheek and allow to dissolve completely.
    If an additional film is necessary to achieve the prescribed dose, place an additional film on the inside of the opposite cheek and allow to dissolve completely.
    If a third film is necessary to achieve the prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved.
    Do not move the film after placement since this will reduce the bioavailability of the drug.
    Proper administration technique should be demonstrated to the patient.
     
    Sublingual film administration (Cassipa sublingual film):[63545]
    Do not cut, chew, or swallow the sublingual film. Must be administered whole.
    The package should not be opened until the patient is ready to use the medication. After opening, the film should be used right away.
    Before taking the medication, rinse mouth with a small amount of room temperature water. High pH beverages should be avoided prior to dosing.
    Place one film under the tongue, close to the base on the left or right side; allow film to completely dissolve.
    Do not move the film after placement.
    Do not eat or drink anything until the film is completely dissolved.
    To ensure consistent bioavailability, follow the same manner of dosing with continued use of the product.
    Proper administration technique should be demonstrated to the patient.
     
    Buccal film administration (Bunavail buccal film):[57392]
    Do not open the foil package until you are ready to use the buprenorphine; naloxone buccal film. Open the foil package by folding along the dotted lines and tearing down at slits or cut with scissors in the direction of the arrows. After opening, use the film right away.
    Use the tongue to wet the inside of the cheek or rinse the mouth with water to moisten the area immediately before placement of the film.
    Hold the film with clean, dry fingers with the text (BN2, BN4, or BN6) facing up.
    Place the side of the 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.
    The film will stick to the inside of your cheek; leave the film in place until it completely dissolves.
    If multiple films need to be administered, immediately apply the next film according to the steps above. Note that when two films are required for one dose, one film should be placed on the inside of one cheek and the other film on the inside of the other cheek. For doses requiring 3 films, place it on the inside of the right or left cheek after the first 2 films have dissolved.
    Avoid touching or moving the film(s) with the tongue or finger(s).
    Avoid drinking or eating food until the film(s) dissolve.
    Do not chew or swallow the film, as this may result in lower peak concentrations and lower bioavailability.
    Use the entire film; do not cut or tear it.

    STORAGE

    BUNAVAIL:
    - Protect from freezing
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Suboxone:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Zubsolv:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Buprenorphine; naloxone is contraindicated in patients with a history of buprenorphine hypersensitivity or naloxone hypersensitivity as serious adverse reactions, including anaphylactic shock, have been reported.[28548] [36605] [41666] [55234] [57392] [61916] [63545]

    Requires an experienced clinician

    Prescription use of buprenorphine; naloxone for opioid dependence requires an experienced clinician in the area of substance abuse treatment and is limited to healthcare providers who meet certain qualifying requirements, have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence, and who have been assigned a unique identification number that must be included on every prescription. Outpatient maintenance and outpatient detoxification treatment may be provided only by Opioid Treatment Programs (OTPs) certified by the U.S. Federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA). In the U.S., outpatient maintenance therapy should be administered in accordance with the treatment standards in the Code of Federal Regulations (CFR), Title 42, Section 8.12, including limitations on unsupervised administration, dispensing by authorized pharmacies, and certification of treatment programs. Under the Drug Addiction Treatment Act (DATA), physicians with a current waiver to provide medication-assisted treatment (MAT) to a maximum of 100 opioid-dependent patients and who have maintained the waiver in accordance with applicable statutory requirements without interruption for at least 1 year may become eligible to provide MAT to a total of 275 opioid-dependent patients at any one time if the requirements of DATA are met.[28548] [36605] [41666] [55234] [57392] [61057] [61916] [63545]

    Opioid-naive patients, pain

    There have been reported deaths of opioid-naive patients who received a 2 mg dose of buprenorphine, smaller than the lowest strength of buprenorphine; naloxone, for analgesia. Buprenorphine; naloxone is not appropriate as a pain analgesic.[28548] [36605] [41666] [55234] [57392] [63545]

    Alcoholism, depression, ethanol ingestion, ethanol intoxication, opioid overdose, opioid use disorder, substance abuse

    Buprenorphine is a partial opioid agonist that can be abused in a manner similar to other opioids, legal or illicit. Patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient's level of stability is essential. Do not prescribe multiple refills early in treatment or without appropriate patient follow-up visits.[28548] [36605] [41666] [55234] [57392] [60270] [63545] Discuss the availability of naloxone with all patients and strongly consider prescribing it in patients treated for opioid use disorder (OUD) because of the potential for relapse. Consider prescribing naloxone in patients using other CNS depressants or if the patient has household members or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu opioid receptor. [65733] Consumption of ethanol will result in additive CNS depressant effects. Advise patients to avoid ethanol ingestion and ethanol intoxication, including the ingestion of alcohol contained in prescription or non-prescription medications, during therapy.[28548] [36605] [41666] [55234] [57392] [60270] [63545]

    Accidental exposure, potential for overdose or poisoning

    Like all opioid agonists, buprenorphine is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Buprenorphine; naloxone should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure may cause respiratory failure and a fatal overdose. Destroy any unused medication appropriately.[28548] [36605] [41666] [55234] [57392] [63545]

    Asthma, chronic obstructive pulmonary disease (COPD), coma, cor pulmonale, emphysema, hypoxemia, intravenous administration, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea

    Buprenorphine has been associated with life-threatening respiratory depression and death. Many postmarketing reports regarding coma and death involved misuse by self-injection (e.g., intravenous administration) or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine; naloxone. Use buprenorphine with caution in patients with chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, emphysema, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, or preexisting respiratory depression. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with advanced age, debilitation, or sleep apnea are at an increased risk for the development of respiratory depression associated with buprenorphine. Use with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in patients with CSA. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Management of respiratory depression should include observation, necessary supportive measures, and opioid antagonist use when indicated.[28548] [36605] [41666] [55234] [57392] [63545]

    Coadministration with other CNS depressants

    Avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective dosages and minimum treatment durations needed. Monitor patients closely for signs or symptoms of respiratory depression and sedation.[61143] Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. However, do not categorically deny medication-assisted treatment (MAT) of opioid use disorder to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone. As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol. Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate. Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient's buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use. Also, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines.[28548] [36605] [41666] [55234] [57392] [62374] [63545]

    Acute abdomen

    As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdomen.

    Biliary tract disease, pancreatitis

    Buprenorphine has been shown to increase intracholedochal pressure. As with other opioid agonists, buprenorphine may cause spasm of the sphincter of Oddi. Biliary effects due to opioid agonists have resulted in increased serum amylase concentrations. Use buprenorphine; naloxone with caution in patients with dysfunction of the biliary tract. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.[28548] [36605] [41666] [55234] [57392] [60270] [63545]

    Geriatric

    Caution is advised for use of buprenorphine; naloxone in geriatric patients, since they may be more sensitive to the respiratory and CNS depressant effects of the drug. Clinical studies of buprenorphine; naloxone products have not included sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger adults in opioid dependency treatment. In general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, respiratory, or cardiac function, and concomitant disease or other drug therapy.[28548] [36605] [41666] [55234] [57392] [63545]

    Abrupt discontinuation

    Abrupt discontinuation of prolonged buprenorphine; naloxone therapy can result in opioid withdrawal symptoms. When discontinuing buprenorphine; naloxone, gradually taper the dosage. Buprenorphine is a partial agonist at the mu-opioid receptor, and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset.[28548] [36605] [41666] [55234] [57392] [63545]

    CNS depression, head trauma, increased intracranial pressure, intracranial mass, psychosis

    Use buprenorphine with caution in patients with CNS depression, toxic psychosis, head trauma, intracranial mass, or increased intracranial pressure. Monitor for signs of drowsiness and depressed respirations, particularly when initiating buprenorphine; naloxone. Opioids may aggravate such conditions and alter neurologic parameters (e.g., level of consciousness, pupillary responses). Buprenorphine-induced hypoventilation can produce cerebral hypoxia, carbon dioxide retention, and raise CSF pressure.[28548] [36605] [41666] [55234] [57392] [63545]

    Driving or operating machinery

    Buprenorphine may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery, especially during treatment induction and dose adjustment. Advise patients not to drive or operate dangerous machinery unless they are tolerant to the effects of buprenorphine; naloxone and know how they will react to the medication.[28548] [36605] [41666] [55234] [57392] [61916] [63545]

    Adrenal insufficiency, hypothyroidism, myxedema

    Use buprenorphine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid-stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency.[28548] [36605] [41666] [55234] [57392] [60660] [63545] In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine.[56900] Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.[60660]

    Orthostatic hypotension

    Use buprenorphine; naloxone with caution in patients with orthostatic hypotension. Like other opioids, buprenorphine may produce orthostatic hypotension in ambulatory patients.

    Hepatic disease, hepatitis

    Avoid buprenorphine; naloxone in patients with severe hepatic disease. Buprenorphine; naloxone therapy may not be appropriate for patients with moderate hepatic impairment. Hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher concentrations of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment and may interfere with buprenorphine efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine; naloxone is not recommended for initiation of treatment in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine; naloxone may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product treated without naloxone. However, carefully monitor patients and consider the possibility of naloxone interfering with buprenorphine efficacy. Also, cases of cytolytic hepatitis and hepatitis with jaundice have been reported during clinical trials and postmarketing use of buprenorphine; naloxone. In many cases, preexisting elevations in liver function tests (LFTs), concurrent hepatitis B or C infections, concurrent use of hepatotoxic drugs, or ongoing injecting drug use may have played a causative or contributing role. Baseline assessment of LFTs and periodic evaluation throughout treatment are recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine; naloxone may need to be carefully discontinued and strict monitoring initiated to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use.[28548] [36605] [41666] [55234] [57392] [63545]

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    Data on buprenorphine use in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations. Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure. The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Monitor withdrawal signs and symptoms closely and adjust the dose as necessary. Further, prolonged maternal use of opioids, such as buprenorphine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. In the Maternal Opioid Treatment: Human Experimental Research (MOTHER) trial, neonatal opioid withdrawal effects were evaluated in buprenorphine or methadone-treated pregnant women. Among women who remained on treatment until delivery, there was no difference in the number of neonates requiring NOWS treatment or in the peak severity of NOWS between patients in either group. However, buprenorphine-treated mothers required less morphine, had shorter hospital stays, and a shorter duration of treatment for NOWS. There were no differences between groups in neonatal head circumference, weight and length at birth, preterm birth, gestational age at delivery, Apgar scores, or rates of maternal or neonatal adverse events. Because of the higher discontinuation rate in the buprenorphine group (33% vs. 18%), the findings are difficult to interpret. Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor or obstetric delivery.[28548] [36605] [41666] [55234] [57392] [63545]

    Breast-feeding

    Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for buprenorphine; naloxone and potential adverse effects on the infant from buprenorphine; naloxone or the underlying maternal condition. Advise breast-feeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties. Buprenorphine and its metabolite norbuprenorphine are present in low concentrations in human milk and infant urine. Available data have not shown adverse reactions in breast-fed infants. There are no data with buprenorphine; naloxone in breast-feeding; however, oral absorption of naloxone is limited. Data were consistent from 2 studies (n = 13) of breast-feeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 mg/day to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose. In a study of 6 lactating women who were taking a median sublingual dose of buprenorphine of 0.29 mg/kg/day at 5 to 8 days post-delivery, breast milk contained median infants dose of buprenorphine and norbuprenorphine equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose. In a separate study of 7 breast-feeding women, the median sublingual dose of buprenorphine was 7 mg/day an average of 1.12 months post-delivery. At 4 weeks of age, 4 of the 7 infants (57%) in this study were exclusively breast-fed. Assuming a milk consumption of 150 mL/kg/day, an exclusively breast-fed infant would have received mean relative infant doses of buprenorphine and norbuprenorphine that were 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.[28548] [36605] [41666] [55234] [57392] [61917] [63545]

    Infertility, reproductive risk

    Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk to males or females. Monitor patients receiving buprenorphine; naloxone for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.    

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    coma / Early / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    neonatal respiratory depression / Rapid / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    withdrawal / Early / 25.2-25.2
    depression / Delayed / 9.0-13.0
    constipation / Delayed / 1.0-12.1
    psychological dependence / Delayed / 1.0-10.0
    peripheral vasodilation / Rapid / 9.3-9.3
    erythema / Early / 1.0-5.0
    blurred vision / Early / 0-1.0
    palpitations / Early / 0-1.0
    physiological dependence / Delayed / 5.0
    hyperbilirubinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    hypoxia / Early / Incidence not known
    infertility / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known

    Mild

    headache / Early / 36.4-36.4
    nausea / Early / 15.0-15.0
    insomnia / Early / 1.0-14.0
    hyperhidrosis / Delayed / 1.0-14.0
    anxiety / Delayed / 11.0-14.0
    abdominal pain / Early / 11.2-11.2
    vomiting / Early / 7.5-7.5
    chills / Rapid / 1.0-7.5
    drowsiness / Early / 1.0-7.0
    lacrimation / Early / 3.0-7.0
    asthenia / Delayed / 6.5-6.5
    dyspepsia / Early / 2.0-6.0
    dizziness / Early / 2.0-6.0
    cough / Delayed / 2.0-6.0
    fever / Early / 1.0-6.0
    infection / Delayed / 5.6-5.6
    rhinorrhea / Early / 1.0-5.0
    fatigue / Early / 1.0-5.0
    pharyngitis / Delayed / 3.0-5.0
    rhinitis / Early / 4.7-4.7
    diarrhea / Early / 3.7-3.7
    back pain / Delayed / 3.7-3.7
    lethargy / Early / 5.0
    miosis / Early / 5.0
    hypoesthesia / Delayed / 1.0
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    psychomotor impairment / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as dihydrocodeine. Dihydrocodeine is found in several combination cough products. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression if buprenorphine is used with dihydrocodeine. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of doxylamine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Diphenhydramine: (Moderate) If concurrent use of diphenhydramine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Hydrocodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Oxycodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as oxycodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Acetaminophen; Pentazocine: (Major) Avoid concomitant use of pentazocine with buprenorphine. Coadministration may reduce the analgesic effect of either drug and/or precipitate withdrawal symptoms. (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Acetaminophen; Propoxyphene: (Major) Buprenorphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists due to the fact that buprenorphine is a partial mu-receptor agonist that has greater receptor affinity than many full agonists. Buprenorphine may also be used concurrently with some opioid agonists, and additive CNS depressive effects are possible. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. Any effect of buprenorphine may last for several days, since buprenorphine dissociates from the mu-receptor very slowly. Due to the mu-receptor high affinity binding, buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. The additive or antagonistic effects are dependent upon the dose of pure opiate agonist used; antagonistic effects are more common at low to moderate doses of the pure opioid agonist.
    Acetaminophen; Tramadol: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as tramadol. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Additionally, concurrent use of opiates with other drugs that modulate serotonergic function, such as tramadol, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. There is also a potential for increased risk of seizures if tramadol is given with other opiates.
    Aclidinium; Formoterol: (Moderate) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Acrivastine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Albuterol: (Minor) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, fluticasone; vilanterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Alfentanil: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as alfentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Alfuzosin: (Major) Buprenorphine should be used cautiously and with close monitoring with should be used cautiously and with alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Alosetron: (Moderate) Concurrent use of buprenorphine and antidiarrheals can lead to severe constipation and possibly additive CNS depression.
    Alprazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amiloride: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Amiodarone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Antiarrhythmics with an established risk for QT prolongation and TdP include disopyramide, flecainide, propafenone, quinidine (including dextromethorphan; quinidine), procainamide, amiodarone, ibutilide, and sotalol. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as amiodarone may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with buprenorphine. Amisulpride causes dose- and concentration- dependent QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Amitriptyline: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tricyclic antidepressants (TCAs) and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation. (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tricyclic antidepressants (TCAs) and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Amoxapine: (Major) Concomitant use of buprenorphine with amoxapine may cause excessive sedation and somnolence. Limit the use of buprenorphine and amoxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Amphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Amphetamine; Dextroamphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Amphetamines: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Amprenavir: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of strong CYP3A4 inhibitors such as anti-retroviral protease inhibitors (e.g., amprenavir, fosamprenavir, indinavir, nelfinavir) may result in increased systemic exposure to buprenorphine, with the potential for excessive buprenorphine-related side effects; however, studies have shown that nelfinavir has little effect on buprenorphine pharmacokinetics and no significant pharmacodynamic effects. In general, if a protease inhibitor and buprenorphine are used concurrently, monitor accordingly for sedation and respiratory depression and adjust the buprenorphine dosage if needed. Consider conservative buprenorphine therapy in patients already on a CYP3A4 inhibitor. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Anagrelide: (Major) Buprenorphine should be used cautiously and with close monitoring with anagrelide. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of buprenorphine and anagrelide for cardiovascular effects and evaluate as necessary.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apalutamide: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with apalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If apalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Apomorphine: (Major) Use apomorphine and buprenorphine together with caution due to the risk of additive QT prolongation and CNS depression. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). The FDA-approved labeling for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval, such as apomorphine. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if buprenorphine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in buprenorphine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Buprenorphine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of buprenorphine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e.arformoterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Aripiprazole: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of aripiprazole and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of aripiprazole and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation, such as buprenorphine. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concomitant drug use is unavoidable, frequently monitor electrocardiograms.
    Artemether; Lumefantrine: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If coadministration is necessary, consider ECG monitoring.
    Asenapine: (Major) Buprenorphine should be avoided in combination with asenapine. Asenapine has been associated with QT prolongation. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). The manufacturer of asenapine recommends avoiding coadministration with with other agents also known to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as dihydrocodeine. Dihydrocodeine is found in several combination cough products. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression if buprenorphine is used with dihydrocodeine. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) If concurrent use of orphenadrine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Aspirin, ASA; Carisoprodol: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Aspirin, ASA; Oxycodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as oxycodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Atazanavir: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir.
    Atazanavir; Cobicistat: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. cobicistat is a strong CYP3A4 inhibitor. (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
    Atomoxetine: (Major) Buprenorphine should be used cautiously and with close monitoring with atomoxetine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as atomoxetine. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
    Atropine; Difenoxin: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate. (Moderate) Buprenorphine is an opioid analgesic. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of buprenorphine and antidiarrheals, such as atropine; diphenoxylate, can lead to severe constipation and possibly additive CNS depression.
    Atropine; Diphenoxylate: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate. (Moderate) Buprenorphine is an opioid analgesic. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of buprenorphine and antidiarrheals, such as atropine; diphenoxylate, can lead to severe constipation and possibly additive CNS depression.
    Azithromycin: (Major) Avoid coadministration of azithromycin with buprenorphine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
    Baclofen: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants, like baclofen. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Barbiturates: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bedaquiline: (Major) Buprenorphine should be used cautiously and with close monitoring with bedaquiline. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Bedaquiline has also been reported to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
    Belladonna; Opium: (Moderate) Buprenorphine may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists due to the fact that buprenorphine is a partial mu receptor agonist that has greater receptor affinity than many full agonists. Additive CNS, respiratory, and hypotensive effects are possible with this combination.
    Belumosudil: (Moderate) Concomitant use of buprenorphine and belumosudil can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when belumosudil is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping belumosudil, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If belumosudil is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and belumosudil is a CYP3A inhibitor.
    Belzutifan: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with belzutifan is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If belzutifan is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and belzutifan is a CYP3A inducer.
    Benzhydrocodone; Acetaminophen: (Major) Avoid the concomitant use of buprenorphine and opiate agonists, such as benzhydrocodone, when buprenorphine is used for analgesia. Buprenorphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of buprenorphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as benzhydrocodone. Exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
    Benzphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Berotralstat: (Moderate) Concomitant use of buprenorphine and berotralstat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when berotralstat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping berotralstat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If berotralstat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and berotralstat is a CYP3A4 inhibitor.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Boceprevir: (Moderate) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as boceprevir. During co-administration, use the lowest buprenorphine starting dose and slowly titrate to desired effect. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is advisable. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including buprenorphine.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including buprenorphine or buprenorphine; naloxone.
    Brompheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Phenylephrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Budesonide; Formoterol: (Moderate) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Bumetanide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when a loop diuretic is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Buprenorphine: (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Bupropion: (Moderate) If concomitant use of buprenorphine and bupropion is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving mixed opiate agonists/antagonists. Naltrexone will antagonize the therapeutic benefits of mixed opiate agonists/antagonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects (respiratory insufficiency or arrest or circulatory collapse) with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur. (Moderate) If concomitant use of buprenorphine and bupropion is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Buspirone: (Moderate) If concurrent use of buspirone and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Butorphanol: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Major) Naloxone reverses the analgesic and adverse effects of opiate agonists and mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, and pentazocine). Reversal of respiratory depression by partial agonists or mixed agonist/antagonists may be incomplete or require higher doses of naloxone. For example, large doses of naloxone are required to antagonize buprenorphine. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. Respirations should be mechanically assisted as clinically indicated. Patients with severe pain or patients who are physically dependent on opiate analgesics can experience severe pain or withdrawal symptoms, respectively. Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Clinicians should be prepared to manage possible reactions after naloxone administration.
    Cabotegravir; Rilpivirine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as rilpivirine, Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may further increase the risk of QT prolongation and TdP.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of buprenorphine with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of buprenorphine with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Cannabidiol: (Moderate) Concomitant use of mixed opioid agonists/antagonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of mixed opioid agonists/antagonists with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opioid agonist/antagonist is initiated in a patient taking cannabidiol, reduce initial dosage and titrate to clinical response. If cannabidiol is initiated in a patient taking a mixed opioid agonist/antagonist, use a lower initial dose of cannabidiol and titrate to clinical response. Educate patients about the risks and symptoms of excessive CNS depression.
    Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. If concomitant use of buprenorphine and metaxalone is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Carbamazepine: (Moderate) Inducers of CYP3A4 such as carbamazepine, may induce the hepatic metabolism of buprenorphine or opiate agonists, which may lead to opiate withdrawal or inadequate pain control.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of diphenhydramine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbidopa; Levodopa; Entacapone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
    Carbinoxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Phenylephrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Carbinoxamine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including buprenorphine or buprenorphine; naloxone.
    Carisoprodol: (Moderate) Concomitant use of buprenorphine with other CNS depress