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 plan that includes counseling and psychosocial support. BRIXADI contains buprenorphine, a partial opioid agonist. 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.
( 1 ) BRIXADI should be used as part of a complete treatment plan that includes counseling and psychosocial support. ( 1 )
Contraindications
BRIXADI is contraindicated in patients with hypersensitivity (e.g., anaphylactic shock) to buprenorphine, or any other ingredients in the solution for injection [see Warnings and Precautions (5.10) ]. Hypersensitivity to buprenorphine or any other ingredients in BRIXADI. ( 4 )
Warnings and precautions
Addiction, Abuse, and Misuse: Buprenorphine can be abused in a manner similar to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. ( 5.3 ) Respiratory Depression: Life-threatening respiratory depression and death have occurred in association with buprenorphine. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BRIXADI.
( 5.4 , 5.5 ) Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.6 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.7 ) Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment with BRIXADI is discontinued, monitor patients for withdrawal and treat appropriately.
( 5.8 ) Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to and during treatment. ( 5.9 ) Latex Allergy: The packaging of this product contains natural rubber latex which may cause allergic reactions. ( 5.10 ) Risk of Withdrawal in Patients Dependent on Full Agonist Opioids: Administer a test dose of transmucosal buprenorphine and monitor for precipitated withdrawal before injecting BRIXADI. ( 5.11 ) Treatment of Emergent Acute Pain: Treat pain with a non-opioid analgesic whenever possible.
If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect. ( 5.12 )
5.1Risk of Serious Harm or Death with Intravenous Administration
Intravenous injection presents significant risk of serious harm or death as BRIXADI forms a liquid crystalline gel upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli, could result if administered intravenously [see Warnings and Precautions (5.2) , Drug Abuse and Dependence (9.2) ] . Do not administer intravenously, intramuscularly, or intradermally.
5.2BRIXADI Risk Evaluation and Mitigation Strategy (REMS)
BRIXADI is available only through a restricted program called the BRIXADI REMS because of the risk of serious harm or death that could result from intravenous self-administration. The goal of the REMS is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense BRIXADI directly to a healthcare provider for administration by a healthcare provider.
Notable requirements of the BRIXADI REMS include the following: Healthcare Settings and Pharmacies that order and dispense BRIXADI must be certified in the BRIXADI REMS. Certified Healthcare Settings and Pharmacies must establish processes and procedures to verify BRIXADI is provided directly to a healthcare provider for administration by a healthcare provider, and the drug is not dispensed to the patient. Certified Healthcare Settings and Pharmacies must not distribute, transfer, loan, or sell BRIXADI.
Further information is available at www.BRIXADIREMS.com or by calling 1-833-274-9234.
5.3Addiction, 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 use disorder and addictive behaviors [see Drug Abuse and Dependence (9.2) ] .
5.4Life-Threatening Respiratory and Central Nervous System (CNS) Depression
Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant drugs including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BRIXADI [see Drug Interactions (7) , Warnings and Precautions (5.5) , Patient Counseling Information (17) ] .
Use BRIXADI with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression) . 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 [see Patient Counseling Information (17) ] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion.
In patients who present with CSA, monitor patient during treatment and consider dose reduction using best practices for opioid taper. [see Clinical Supervision (2.5) ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent.
Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing or recommending an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with BRIXADI. Also consider prescribing or recommending such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.2) ].
Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the- counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.
Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of an opioid overdose reversal agent may be necessary due to the long duration of action of buprenorphine and its affinity for the mu receptor [see Overdosage (10) ]. Educate patients and caregivers on how to recognize respiratory depression and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose.
Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered.
5.5Managing Risks From Concomitant Use of Benzodiazepines or Other CNS Depressants
Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) increases the risk of adverse reactions including overdose, respiratory depression, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs.
Prohibiting or crea
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Interactions
Table 7: Clinically Significant Drug Interactions Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: 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 a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatment [see Warnings and Precautions (5.5) ] .
If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.4) ]. Examples: Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids.
Inhibitors of CYP3A4 Clinical Impact: The effects on buprenorphine exposure in patients treated with BRIXADI have not been studied, and the effects may be dependent on the route of administration. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity [see Clinical Pharmacology (12.3) ].
The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BRIXADI is achieved. Intervention: Patients Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inhibitors: Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate.
Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inhibitor : Monitor for signs and symptoms of over-medication. If signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, reduce the dose of BRIXADI. If available doses do not permit achievement of the desired dose, it may be necessary to discontinue treatment with BRIXADI and treat the patient with a formulation of buprenorphine that permits more precise dose adjustments.
Patients Stabilized on BRIXADI in the Setting of Concomitant Medication That is a CYP3A4 Inhibitor, and the Concomitant Medication is Discontinued : Monitor for withdrawal and consider a dosage adjustment of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level in the absence of the concomitant medication, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments.
Examples: azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), and protease inhibitors (e.g., ritonavir, indinavir, and saquinavir) CYP3A4 Inducers Clinical Impact: The effects of co-administered CYP3A4 inducers on buprenorphine exposure in patients treated with BRIXADI have not been studied. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity [see Clinical Pharmacology (12.3) ] .
CYP3A4 inducers may induce metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome. Intervention: Patients Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inducers: Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate.
Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inducer : Monitor for withdrawal. If the dose of BRIXADI is not adequate in the presence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, adjust the dose of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments.
Patients Stabilized on BRIXADI in the setting of Concomitant Medication that is a CYP3A4 Inducer, and the Concomitant Medication is Discontinued : Monitor for signs and symptoms of over-medication. If the dose provided by BRIXADI is excessive in the absence of the concomitant inducer, consider reducing the dose of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments [see Clinical Pharmacology (12.3) ] .
Examples: Rifampin, carbamazepine, phenytoin, phenobarbital Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A4 inducers, whereas delaviridine is a CYP3A4 inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delviradine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamics effects.
Intervention: It is recommended that patients who are on BRIXADI treatment have their dose monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen. Examples: Efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease Inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (e.g., nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetics and no significant pharmacodynamics effects.
Other PIs with CYP3A4 inhibitory activity (e.g., atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Intervention: If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with BRIXADI, the patient should be monitored for signs and symptoms of over-medication.
It may be necessary to discontinue treatment with BRIXADI and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments. Examples: Atazanavir, ritonavir Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention: None Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation, and during dose adjustment of the serotonergic drug. Discontinue BRIXADI if serotonin syndrome is suspected.
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Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
The data on use of buprenorphine, the active ingredient in BRIXADI 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 sublingual buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data ]. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses 21 times and equal to, respectively, the mean daily dose of 4.6 mg buprenorphine delivered by either 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly).
Pre- and post-natal development studies in rats demonstrated increased neonatal deaths at doses approximately equal to and above and dystocia at 11 times the mean daily dose of 4.6 mg buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 4 times and greater than the mean daily dose of 4.6 mg of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses 2 and 21 times the mean daily dose of 4.6 mg of buprenorphine, respectively.
In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
BRIXADI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Clinical Considerations Disease-associated maternal and embryo-fetal 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.
Dose Adjustment during Pregnancy and the Postpartum Period Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely, and the dose adjusted as necessary. Fetal/neonatal adverse reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with BRIXADI.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.6) ].
Labor or Delivery Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone or nalmefene, should be available for reversal of opioid induced respiratory depression in the neonate.
Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances.
Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.
In a multicenter, double-blind, randomized, controlled trial (Maternal Opioid Treatment: Human Experimental Research [MOTHER]) designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.
Among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs 10.4 mg), had shorter hospital stays (10.0 days vs 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs 9.9 days) compared to the methadone-exposed group.
There were no differences between groups in other primary outcomes (neonatal head circumference) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.
Animal Data The exposure margins below are based on the mean daily dose of 4.6 mg buprenorphine delivered by 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly) on body surface area comparisons, unless otherwise noted. No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (64 times and 127 times, respectively, on a mg/m 2 basis). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits.
Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (21 times on a mg/m 2 basis).
In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day (169 times on a mg/m 2 basis). Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day (64 times and 127 times, respectively, on a mg/m 2 basis). Buprenorphine was not teratogenic in rats and rabbits after subcutaneous (SC) doses of up to 5 mg/kg/day (9 and 5 times in rat, and 12 and 7 times in rabbit the highest daily exposure from 32 mg BRIXADI (weekly)
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Adverse reactions
The following adverse reactions are discussed in more detail in other sections of the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.3) ] Respiratory and CNS Depression [see Warnings and Precautions (5.4) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.6) ] Adrenal Insufficiency [see Warnings and Precautions (5.7) ] Opioid Withdrawal [see Warnings and Precautions (5.8 , 5.11) ] Hepatitis, Hepatic Events [see Warnings and Precautions (5.9) ] Hypersensitivity Reactions [see Warnings and Precautions (5.10) ] Orthostatic Hypotension [see Warnings and Precautions (5.17) ] Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.18) ] Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.19) ] 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Braeburn at 1-833-274-9234 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of BRIXADI was evaluated in 440 opioid-dependent patients across two, 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. In the first 12-week phase of the double-blind, double-dummy, active-controlled study, patients received BRIXADI (weekly) (16, 24, 32 mg) or matching placebo injections after a one-week titration. In the second 12-week phase of the study, patients remaining in the study received BRIXADI (monthly) (64, 96, 128, or 160 mg) or matching placebo injections.
The 160 mg monthly dose is not an approved dose. Those randomized to receiving placebo injections were the active control groups and received sublingual buprenorphine/naloxone tablets at corresponding doses to BRIXADI. Patients receiving active BRIXADI injections also received placebo sublingual tablets. 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.
Adverse reactions commonly reported after BRIXADI administration (≥5%, regardless of dose and regimen) in the double-blind study, were injection site pain (9.9%), headache (7.5%), constipation (7.5%), nausea (7.0%), injection site erythema (6.6%), injection site pruritus (6.1%), Insomnia (5.6%), and urinary tract infection (5.2%). Table 5 shows the adverse reactions for BRIXADI compared with the active-control group (SL BPN/NX) in the double-blind study.
Table 5: Adverse Reactions in the Phase 3 Double-Blind Study: ≥ 2% of Patients Receiving BRIXADI (Excluding Injection Site Reactions). System Organ Class (SOC) BRIXADI Total = This group includes all subjects exposed to varying doses of both the BRIXADI (weekly) and BRIXADI (monthly) formulations. SL BPN/NX = SL BPN/NX denotes the active comparator: patients assigned to daily buprenorphine with sham (placebo) injections.
Patients randomized to this group could also receive a 'booster' injection of BRIXADI (weekly), 8mg, per protocol. All patients in Study 421 received a single test dose of 4mg SL BPN/NX before randomization into either arm. Preferred Term (PT) = report of adverse reactions that occurred in ≥ 2% of the patients randomized to BRIXADI in Study HS-11-421. Patients are represented once per PT (N=213) n(%) (N=215) n(%) Cardiac disorders 6 (2.8%) 9 (4.2%) Tachycardia 5 (2.3) 5 (2.3) Gastrointestinal disorders 43 (20.2%) 45 (20.9%) Constipation 16 (7.5) 16 (7.4) Diarrhea 6 (2.8) 7 (3.3) Nausea 15 (7.0) 17 (7.9) Vomiting 9 (4.2) 8 (3.7) Infections and infestations 42 (19.7%) 50 (23.3%) Urinary tract infection 11 (5.2) 10 (4.7) Upper respiratory tract infection 9 (4.2) 9 (4.2) Musculoskeletal and connective tissue disorders 20 (9.4%) 22 (10.2%) Arthralgia 7 (3.3) 3 (1.4) Nervous system disorders 27 (12.7%) 27 (12.6%) Headache 16 (7.5) 17 (7.9) Psychiatric disorders 20 (9.4%) 20 (9.3%) Anxiety 6 (2.8) 7 (3.3) Insomnia 12 (5.6) 6 (2.8) Injection site reactions in the double-blind study are presented in Table 6 below.
The majority of injection site-related adverse events were mild or moderate in severity. No injection site reactions were reported as severe intensity. Table 6: Injection site reactions in the Double-Blind Phase 3 Study: ≥ 2% of Patients Receiving BRIXADI Preferred Term (PT) = Injection site reactions (ISR) that occurred in ≥2% of patients receiving BRIXADI, in the controlled trial, HS-11-421. Patients are represented once per PT.
BRIXADI Total = This group includes patients exposed to varying doses of both the BRIXADI weekly and monthly formulations. (N=213) n(%) SL BPN/NX = SL BPN/NX denotes the active comparator: subjects assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a supplemental 'booster' injection of BRIXADI (weekly), 8mg, per protocol. (N=215) n(%) Administration site reactions = The ISRs that occurred in ≥2% of the patients randomized to BRIXADI were reported under the HGLT of Administration site reactions.
However, ISRs were also identified under the Bacterial infectious disorders HGLT (of which, there were three injection site related cellulitis reactions in the BRIXADI group and one in the SL BPN/NX group, respectively) but those numbers did not rise to level of reporting. Tabulation included all events coded as treatment emergent and injection site reactions, regardless of treatment emergent flags. 44 (20.7%) 49 (22.8%) Injection site pain 21 (9.9%) 17 (7.9%) Injection site erythema 14 (6.6%) 12 (5.6%) Injection site pruritus 13 (6.1%) 13 (6.0%) Injection site swelling 10 (4.7%) 7 (3.3%) Injection site reaction 9 (4.2%) 7 (3.3%)
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequently reported postmarketing adverse event observed with buprenorphine sublingual tablets, excluding drug exposure during pregnancy, was drug misuse or abuse.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with buprenorphine [see Contraindications (4) ]. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ] .
The following adverse reactions have been identified during post-approval use of an identical buprenorphine extended-release injection for subcutaneous use outside of the United States and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Injection site mass, abscess, ulceration, and necrosis : Cases of injection site abscess, ulceration and necrosis have been reported after treatment initiation. Some cases have required debridement and antibiotic treatment. The likeli
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Composition
Active ingredients
BUPRENORPHINE 64MG/0.18ML (356MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
