Clinical Safety Profile
The safety of BRIXADI was evaluated in 440 opioid-dependent patients across 2 phase 3 clinical studies: one double-blind, active-control (N=213) and one open-label (N=227). In these studies, a total of 305 patients were exposed to BRIXADI for at least 24 weeks, and 132 patients were exposed for at least 48 weeks.1
Adverse reactions led to premature discontinuation in 10 (4.7%) patients in the group receiving BRIXADI compared to 5 (2.3%) patients in the sublingual buprenorphine/naloxone group during the double-blind study.1
Adverse Reactions Occurring in ≥2% of Patients Receiving BRIXADI in the Phase 3 Double-Blind Study1
SL BPN/NX, sublingual buprenorphine/naloxone.
Injection Site Reactions Occurring in ≥2% of Patients Receiving BRIXADI in the Phase 3 Double-Blind Study1
*Events included are those that occurred in ≥2% of patients randomized to BRIXADI in Study HS-11-421. Patients are represented once per preferred term.1
†This group includes all subjects exposed to varying doses of both BRIXADI Weekly and BRIXADI Monthly.1
‡SL BPN/NX denotes the active comparator: patients assigned to daily BPN with sham (placebo) injections. Patients randomized to this group could also receive a “booster” injection of BRIXADI Weekly, 8 mg, per protocol.1
§The injection site reactions (ISRs) that occurred in ≥2% of the patients randomized to BRIXADI were reported under the High-Level Group Term (HLGT) of Administration Site Reactions. However, ISRs were also identified under the Bacterial Infectious Disorders HGLT (3 injection site–related cellulitis reactions in the BRIXADI group and 1 in the SL BPN/NX group), but those numbers did not rise to the level of reporting. Tabulation included all events coded as treatment emergent and ISRs, regardless of treatment-emergent flags.1
All patients in Study HS-11-421 received a single test dose of 4 mg SL BPN/NX before randomization into either arm.1
Excluding injection site reactions, the safety profile of BRIXADI was generally comparable to that of sublingual buprenorphine/naloxone.2
No injection site reactions were reported as being severe in intensity.1
Over 48 weeks of treatment in a long-term safety study, BRIXADI had a safety profile consistent with the phase 3 double-blind study.1,3
BRIXADI is available through a restricted distribution via the BRIXADI REMS Program1
Only healthcare professionals should prepare and administer BRIXADI. BRIXADI should never be dispensed directly to a patient because of the serious harm or death that could result from intravenous administration.
Visit the BRIXADI REMS website
IMPORTANT SAFETY INFORMATION AND INDICATIONS
WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; BRIXADI RISK EVALUATION AND MITIGATION STRATEGY
- Serious harm or death could result if administered intravenously. BRIXADI forms a liquid crystalline gel upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli, if administered intravenously.
- Because of the risk of serious harm or death that could result from intravenous self-administration, BRIXADI is only available through a restricted program called the BRIXADI REMS. Healthcare settings and pharmacies that order and dispense BRIXADI must be certified in this program and comply with the REMS requirements.
BRIXADI (buprenorphine) extended-release injection (weekly, 50 mg/mL buprenorphine) and BRIXADI (monthly, 356 mg/mL buprenorphine) are different formulations. Doses of BRIXADI (weekly) cannot be combined to yield an equivalent monthly dose.
BRIXADI is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock) to buprenorphine or any other ingredients in the solution for injection.
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse: BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor all patients for progression of opioid dependence and addictive behaviors.
Respiratory and CNS Depression: Buprenorphine has been associated with life-threatening respiratory depression and death. Use BRIXADI with caution in patients with compromised respiratory function. Due to its extended-release characteristics, if BRIXADI is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with BRIXADI. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone, and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Concomitant Use of Benzodiazepines or other CNS Depressants: Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increase the risk of adverse reactions including respiratory depression, overdose and death. 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 risk associated with concomitant use. Inform patients and caregivers that potentially fatal additive effects may occur if BRIXADI is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.
Neonatal Opioid Withdrawal Syndrome, Pregnancy, and Lactation: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare providers should observe newborns for signs of NOWS and manage accordingly. Advise pregnant women receiving opioid addiction treatment with BRIXADI of the risk of neonatal opioid withdrawal syndrome. Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties.
Adrenal Insufficiency: If adrenal insufficiency is diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
Risk of Opioid Withdrawal with Abrupt Discontinuation: Patients who elect to discontinue BRIXADI treatment should be monitored for withdrawal signs and symptoms with consideration given to the product’s extended-release characteristics.
Risk of Hepatitis, Hepatic Events, and Use in Patients with Impaired Hepatic Function: Liver function tests should be performed on all patients prior to initiation, during treatment, and if a hepatic event is suspected. Because buprenorphine levels cannot be rapidly decreased, patients with pre‐existing moderate to severe hepatic impairment are not candidates for treatment with BRIXADI. Patients who develop moderate to severe hepatic impairment while being treated with BRIXADI should be monitored for signs and symptoms of toxicity or overdose of buprenorphine and may require a dose adjustment.
Hypersensitivity Reactions: Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported in patients receiving buprenorphine-containing products. The most common signs and symptoms include rashes, hives, and pruritus. The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals.
Precipitation of Opioid Withdrawal in Patients Dependent on Full Opioid Agonists: BRIXADI injection may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. In patients who are new entrants to treatment, to avoid precipitating an opioid withdrawal syndrome, administer a 4 mg test dose of transmucosal buprenorphine when objective signs of mild to moderate withdrawal appear and monitor for precipitated withdrawal before injecting BRIXADI.
Risks Associated with Treatment of Emergent Acute Pain: While on BRIXADI, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving BRIXADI with non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a healthcare provider, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is being treated with BRIXADI.
Use in Opioid Naïve Patients: There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. BRIXADI is not appropriate for use in opioid naïve patients.
Patients at Risk for Arrhythmia: Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.
Impairment of Ability to Drive and Operate Machinery: BRIXADI may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Caution patients about driving or operating hazardous machinery until they are reasonably certain that BRIXADI does not adversely affect their ability to engage in such activities.
Orthostatic Hypotension: Buprenorphine may produce orthostatic hypotension in ambulatory patients.
Elevation of Cerebrospinal Fluid Pressure: Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased.
Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Effects in Acute Abdominal Conditions: Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Unintentional Pediatric Exposure: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.
ADVERSE REACTIONS
Adverse reactions commonly associated with BRIXADI administration (in ≥5% of patients) were injection site pain, headache, constipation, nausea, injection site erythema, injection site pruritus, insomnia, and urinary tract infection.
To report SUSPECTED ADVERSE REACTIONS, contact Braeburn at 1-833-274-9234 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.
INDICATIONS AND USAGE
BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine.
BRIXADI should be used as part of a complete treatment program that includes counseling and psychosocial support.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; BRIXADI RISK EVALUATION AND MITIGATION STRATEGY
- Serious harm or death could result if administered intravenously. BRIXADI forms a liquid crystalline gel upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli, if administered intravenously.
- Because of the risk of serious harm or death that could result from intravenous self-administration, BRIXADI is only available through a restricted program called the BRIXADI REMS. Healthcare settings and pharmacies that order and dispense BRIXADI must be certified in this program and comply with the REMS requirements.
BRIXADI (buprenorphine) extended-release injection (weekly, 50 mg/mL buprenorphine) and BRIXADI (monthly, 356 mg/mL buprenorphine) are different formulations. Doses of BRIXADI (weekly) cannot be combined to yield an equivalent monthly dose.
BRIXADI is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock) to buprenorphine or any other ingredients in the solution for injection.
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse: BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor all patients for progression of opioid dependence and addictive behaviors.
Respiratory and CNS Depression: Buprenorphine has been associated with life-threatening respiratory depression and death. Use BRIXADI with caution in patients with compromised respiratory function. Due to its extended-release characteristics, if BRIXADI is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with BRIXADI. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone, and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Concomitant Use of Benzodiazepines or other CNS Depressants: Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increase the risk of adverse reactions including respiratory depression, overdose and death. 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 risk associated with concomitant use. Inform patients and caregivers that potentially fatal additive effects may occur if BRIXADI is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider.
Neonatal Opioid Withdrawal Syndrome, Pregnancy, and Lactation: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare providers should observe newborns for signs of NOWS and manage accordingly. Advise pregnant women receiving opioid addiction treatment with BRIXADI of the risk of neonatal opioid withdrawal syndrome. Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties.
Adrenal Insufficiency: If adrenal insufficiency is diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
Risk of Opioid Withdrawal with Abrupt Discontinuation: Patients who elect to discontinue BRIXADI treatment should be monitored for withdrawal signs and symptoms with consideration given to the product’s extended-release characteristics.
Risk of Hepatitis, Hepatic Events, and Use in Patients with Impaired Hepatic Function: Liver function tests should be performed on all patients prior to initiation, during treatment, and if a hepatic event is suspected. Because buprenorphine levels cannot be rapidly decreased, patients with pre‐existing moderate to severe hepatic impairment are not candidates for treatment with BRIXADI. Patients who develop moderate to severe hepatic impairment while being treated with BRIXADI should be monitored for signs and symptoms of toxicity or overdose of buprenorphine and may require a dose adjustment.
Hypersensitivity Reactions: Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported in patients receiving buprenorphine-containing products. The most common signs and symptoms include rashes, hives, and pruritus. The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals.
Precipitation of Opioid Withdrawal in Patients Dependent on Full Opioid Agonists: BRIXADI injection may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. In patients who are new entrants to treatment, to avoid precipitating an opioid withdrawal syndrome, administer a 4 mg test dose of transmucosal buprenorphine when objective signs of mild to moderate withdrawal appear and monitor for precipitated withdrawal before injecting BRIXADI.
Risks Associated with Treatment of Emergent Acute Pain: While on BRIXADI, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving BRIXADI with non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a healthcare provider, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is being treated with BRIXADI.
Use in Opioid Naïve Patients: There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. BRIXADI is not appropriate for use in opioid naïve patients.
Patients at Risk for Arrhythmia: Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.
Impairment of Ability to Drive and Operate Machinery: BRIXADI may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Caution patients about driving or operating hazardous machinery until they are reasonably certain that BRIXADI does not adversely affect their ability to engage in such activities.
Orthostatic Hypotension: Buprenorphine may produce orthostatic hypotension in ambulatory patients.
Elevation of Cerebrospinal Fluid Pressure: Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased.
Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Effects in Acute Abdominal Conditions: Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Unintentional Pediatric Exposure: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.
ADVERSE REACTIONS
Adverse reactions commonly associated with BRIXADI administration (in ≥5% of patients) were injection site pain, headache, constipation, nausea, injection site erythema, injection site pruritus, insomnia, and urinary tract infection.
To report SUSPECTED ADVERSE REACTIONS, contact Braeburn at 1-833-274-9234 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.
INDICATIONS AND USAGE
BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine.
BRIXADI should be used as part of a complete treatment program that includes counseling and psychosocial support.
References: 1. BRIXADI. Prescribing information. Braeburn Inc; 2023. 2. Lofwall MR, Walsh SL, Nunes EV, et al. Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern Med. 2018;178(6):764-773. 3. Frost M, Bailey GL, Lintzeris N, et al. Long-term safety of a weekly and monthly subcutaneous buprenorphine depot (CAM2038) in the treatment of adult out-patients with opioid use disorder. Addiction. 2019;114(8):1416-1426.