2.1 Important Dosage and Administration Instructions

FOR SUBCUTANEOUS INJECTION ONLY. DO NOT ADMINISTER BRIXADI INTRAVENOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY [see Warnings and Precautions (5.1), Instructions for Use (2.6)].

• BRIXADI exists in two formulations.
• Doses of BRIXADI (weekly) cannot be combined to yield a monthly dose.
• Only healthcare providers should prepare and administer BRIXADI.
• Administer BRIXADI as a single injection. Do not divide.
• BRIXADI should be injected slowly, into the subcutaneous tissue of the buttock, thigh, abdomen, or upper arm.
  • In patients who are not currently receiving buprenorphine treatment, for BRIXADI (weekly), the upper arm site should only be used after steady-state has been achieved (4 consecutive doses) [see Instructions for Use (2.6)]. Injection in the arm site was associated with approximately 10% lower plasma levels than other sites.
• Injection sites should be alternated/rotated between injections for BRIXADI (weekly) [see Instructions for Use (2.6)].
• For all patients, the dose of BRIXADI must be individualized based on patient tolerability and/or efficacy.
• BRIXADI (weekly) should be administered in 7-day intervals.
• BRIXADI (monthly) should be administered in 28-day intervals.
• For patients not currently receiving buprenorphine treatment, begin with a test dose of 4 mg transmucosal buprenorphine to establish that buprenorphine is tolerated without precipitated withdrawal, and then transition to BRIXADI (weekly). Initiating treatment with BRIXADI as the first buprenorphine product has not been studied. Initiating treatment with BRIXADI (monthly) in new entrants to treatment has not been studied [see Dosage and Administration (2.3)].
• Patients who are currently being treated with other buprenorphine-containing products can start treatment with either BRIXADI (weekly) or BRIXADI (monthly) [see Dosage and Administration (2.3)].
• Administer each injection using only the syringe and safety needle included with the product [see Instructions for Use (2.6)]. Caution: The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals [see Warnings and Precautions (5.10)].

To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point, and the monthly dose may be administered up to 1 week before or after the monthly time point.

If a dose is missed, the next dose should be administered as soon as practically possible.

2.2 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. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions (5.4)].

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 receptor [see Overdosage (10)].

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) [see Patient Counseling Information (17)].

2.3 Recommended Dosing

2.4 Patient Selection

Patients appropriate for BRIXADI (weekly) are:

1. adults who have tolerated a single 4 mg dose of a transmucosal buprenorphine-containing product. The test dose of transmucosal buprenorphine-containing product should be administered based on instructions in the appropriate product label.
2. adults who are currently being treated with a transmucosal buprenorphine-containing product.

Patients appropriate for BRIXADI (monthly) are adults who are currently being treated with a transmucosal buprenorphine-containing product. BRIXADI (monthly) is not intended for patients who are not currently receiving buprenorphine treatment.

2.5 Clinical Supervision

Periodic assessment is necessary to determine effectiveness of the treatment plan and overall patient progress. When evaluating the patient, examine the injection site for signs of infection or evidence of tampering or attempts to remove the depot.

Due to the chronic nature of opioid use disorder, the need for continuing medication-assisted treatment should be re-evaluated periodically. There is no maximum recommended duration of maintenance treatment. For some patients, treatment may continue indefinitely. If considering stopping treatment, the clinical status of the patient should be considered.

If BRIXADI is discontinued, its extended-release characteristics should be considered, and the patient should be monitored for several months for signs and symptoms of withdrawal and treated appropriately. After steady-state has been achieved, which is 4 weeks for BRIXADI (weekly) and 4 months for BRIXADI (monthly), patients discontinuing BRIXADI may have detectable plasma levels of buprenorphine for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly). The correlation between plasma concentrations of buprenorphine and those detectable in urine is not known.

2.6 Instructions for Use

Prior to injecting BRIXADI, carefully read the instructions as well as the full prescribing information.

IMPORTANT INFORMATION:

• For subcutaneous injection only [see Warnings and Precautions (5.1)].
• To be prepared and administered by a healthcare provider only.
• Read the instructions carefully before handling the product.
• As a universal precaution, always wear gloves and inject BRIXADI under aseptic conditions.
• BRIXADI should be injected slowly, into the subcutaneous tissue of the buttock, thigh, abdomen, or upper arm.
• In patients who are not currently receiving buprenorphine treatment, for BRIXADI (weekly), the upper arm site should only be used after steady-state has been achieved (4 consecutive doses). Injection in the arm site was associated with approximately 10% lower plasma levels than other sites.
• Discard BRIXADI if the liquid contains visible particles or is cloudy. Discard BRIXADI after the expiration date shown on the carton or on the safety syringe label.

2.7 Limits on Distribution

BRIXADI is subject to a risk evaluation and mitigation strategy (REMS) program that includes, among other elements, a restricted distribution program. The purpose of the restricted distribution program is to ensure that BRIXADI is only administered by a healthcare provider [see Warnings and Precautions (5.2)].

2.8 Removal of BRIXADI

BRIXADI forms a biodegradable liquid crystalline gel upon injection that is not always palpable and may not be conducive to surgical removal. Therefore, removal is not recommended.

5.1 Risk 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.

5.2 BRIXADI 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.

5.3 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 use disorder and addictive behaviors [see Drug Abuse and Dependence (9.2)].

5.4 Risk of Life-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 (2.6)].

5.5 Managing Risks From Concomitant Use of Benzodiazepines or Other CNS Depressants with Buprenorphine

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including respiratory depression, overdose, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied 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 with buprenorphine. 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 patients' buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.4)].

In addition, 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 [see Drug Interactions (7)].

5.6 Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, 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 [see Use in Specific Populations (8.1)].

Advise pregnant women receiving opioid addiction treatment with BRIXADI of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)]. This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.7 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.8 Risk of Opioid Withdrawal with Abrupt Discontinuation of BRIXADI Treatment

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 milder than that seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence (9.2, 9.3)].

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 [See Clinical Pharmacology (12.3)].

Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing BRIXADI.

5.9 Risk of Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine for the treatment of opioid use disorder, both in clinical trials and through postmarketing adverse event reports.

The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases.

Liver function tests are recommended prior to initiation of treatment to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Monitor patients with declining hepatic function for side effects resulting from increased exposure to buprenorphine.

5.10 Hypersensitivity Reactions

Cases of hypersensitivity to buprenorphine containing products have been reported both in clinical trials and in the postmarketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or other components is a contraindication to the use of BRIXADI [see Contraindications (4)].

5.11 Precipitation of Opioid Withdrawal Signs and Symptoms

Because of the partial agonist properties of buprenorphine, 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, administer a test dose of transmucosal buprenorphine and monitor for precipitated withdrawal and treat appropriately [see Dosage and Administration (2.3)].

5.12 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. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy should be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

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 physically dependent on an opioid and that the patient is being treated with BRIXADI [see Patient Counseling Information (17)].

Please refer to Section 2.5 for further details on duration of exposure following discontinuation for both weekly and monthly BRIXADI formulations. [see Clinical Supervision (2.5)].

5.13 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.

5.14 Use in Patients With Impaired Hepatic Function

In a pharmacokinetic study with transmucosal buprenorphine, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of BRIXADI, has not been studied.

Because of the long-acting nature of the product, adjustments to dosages of BRIXADI are not rapidly reflected in plasma buprenorphine levels. 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 several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine and patients may require a dose adjustment [see Use in Specific Populations (8.6)].

5.15 QTc Prolongation

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.

Consider these observations in clinical decisions when prescribing BRIXADI to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia. [see Clinical Pharmacology (12.2)].

5.16 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, especially for the first few days following treatment and dose adjustment. Buprenorphine plasma levels accumulate during the BRIXADI (weekly) or BRIXADI (monthly) injections, which achieves steady-state at the fourth weekly or monthly injection. 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. [see Clinical Pharmacology (12.3)].

5.17 Orthostatic Hypotension

Buprenorphine may produce orthostatic hypotension in ambulatory patients.

5.18 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 where cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

5.19 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.

5.20 Effects in Acute Abdominal Conditions

Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

5.21 Unintentional Pediatric Exposure

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

6.1 Clinical 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.

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.

6.2 Postmarketing 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 likelihood of serious injection site reactions may be increased with inadvertent intramuscular or intradermal administration.

Insufficient dosing: Cases of drug withdrawal reactions consistent with insufficient drug dosing have been reported, often occurring at or after two weeks of treatment initiation and resolving upon dose increase.

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opiods. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of BRIXADI have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of BRIXADI did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently to the drug than younger patients. Other reported clinical experience with buprenorphine has not identified differences in responses between the geriatric and younger patients.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe BRIXADI should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

8.6 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of BRIXADI has not been studied.

The effect of hepatic impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated in a pharmacokinetic study. While no clinically significant changes were observed in subjects with mild hepatic impairment, the plasma levels have been shown to be higher and half-life values have been shown to be longer for buprenorphine in subjects with moderate and severe hepatic impairment.

Because of the long-acting nature of the product, adjustments to dosages of BRIXADI are not rapidly reflected in plasma buprenorphine levels. Therefore, 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 caused by increased levels of buprenorphine [see Warnings and Precautions (5.14), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Clinical studies of BRIXADI did not include subjects with renal impairment. No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

9.1 Controlled Substance

BRIXADI contains buprenorphine, a Schedule III substance under the Controlled Substances Act.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused similar to other opioids. Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines [see Warnings and Precautions (5.5)].

BRIXADI is distributed through a restricted distribution program, which is intended to prevent the direct distribution to a patient. BRIXADI should only be dispensed directly to a healthcare provider for administration by a healthcare provider. It is supplied in prefilled syringes and is intended for administration only by subcutaneous injection by a healthcare provider. The entire contents of the prefilled syringe should be administered. After administration, a small amount of BRIXADI may remain in the needle and syringe should be properly disposed of [see How Supplied/Storage and Handling (16)].

Upon injection, BRIXADI spontaneously transforms from a low viscous solution to a liquid crystalline gel that encapsulates buprenorphine and releases it at a steady rate as the depot biodegrades [see Warnings and Precautions (5.1)].

Clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. No attempts to remove BRIXADI have been reported in clinical trials.

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate 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. Monitor patients during discontinuation of BRIXADI for symptoms of withdrawal [see Warnings and Precautions (5.8)].

Due to the long-acting nature of BRIXADI, withdrawal signs and symptoms may not be evident immediately following the discontinuation of treatment.

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.6)].

Clinical Presentation

The manifestations of acute buprenorphine overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death.

Treatment of Overdose

In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re‐establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be considered as indicated. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.

Clinicians should consider the potential role and contribution of buprenorphine, other opioids, and other CNS depressant drugs in a patient's clinical presentation.

12.1 Mechanism of Action

BRIXADI contains buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Opioid Blockade Study, NCT02611752

The opioid blockade study assessed the blockade of subjective opioid effects, PK, and safety of BRIXADI weekly in 47 patients with moderate or severe opioid use disorder. Forty-six patients completed the study. Subjects were randomized to receive two injections of BRIXADI (weekly) once weekly for 2 weeks either at a 24 mg or 32 mg dose level.

After stabilization on immediate-release morphine, all patients completed a 3-day qualification/baseline hydromorphone (HM) challenge session, which included intramuscular administration of 3 doses of HM (0 mg [placebo], 6 mg and 18 mg) once daily for 3 consecutive days. Patients were not exposed to buprenorphine during the baseline/qualification phase.

Following the qualification phase, eligible patients were randomly assigned to receive 2 doses of either 24 mg (22 patients) or 32 mg (24 patients) BRIXADI (weekly) with each dose administered one week apart. Two HM challenge sessions (Days 1-3 and 4-6 for the first session and Days 8-10 and 11-13 for the second session, respectively) were conducted after each dose of BRIXADI (weekly).

The primary endpoint was the peak effect (Emax) on a 100-mm bipolar (i.e., 50=neutral response) "Drug Liking" Visual Analog Scale (VAS). The pre-defined upper bound of the 95% CI for complete blockade of drug liking was an 11 mm difference between VAS Emax scores obtained for HM doses compared with placebo.

During the qualification/baseline phase, mean Emax scores for placebo were neutral while intramuscular hydromorphone 6 and 18 mg produced dose-related increases in the scores. Beginning with the first injection of BRIXADI (weekly) 24 mg or 32 mg weekly, no active intramuscular hydromorphone dose resulted in a mean drug liking VAS Emax score of 11 mm or greater when compared to placebo, which demonstrated complete blockade that was sustained throughout the first and second dosing intervals (see Figure 15). Individual subject scores are shown in Figure 16.

Figure 15: Mean Difference in Placebo-Corrected Peak Drug Liking

Figure 16: Mean Difference in Placebo-Corrected Peak Drug Liking with Individual Scores

14.2 Phase 3 Double-Blind Study, NCT02651584

The efficacy and safety of BRIXADI for the treatment of opioid use disorder was evaluated in a Phase 3, 24-Week, randomized, double-blind, double-dummy, active controlled, multicenter study in patients who met the DSM-5 criteria for moderate or severe opioid use disorder and who were actively seeking but not currently receiving buprenorphine treatment. Patients were randomized to receive either BRIXADI injections with placebo sublingual tablets or sublingual buprenorphine/naloxone (SL BPN/NX) tablets with placebo injections. All patients received individual drug counseling for the duration of the study.

On the first day of treatment patients received an open-label 4 mg test dose of sublingual buprenorphine. Patients who tolerated the test dose (two patients did not tolerate the test dose) were randomized and given a 16 mg injection of BRIXADI (weekly) or matched placebo. During the next 6 days patients were allowed up to two further 8 mg injections as needed. Patients received an injection of 16, 24, or 32 mg on Day 8 matched to the dose they received in the previous seven days. Patients received injections weekly (every 7 days +/- 2-day window) for twelve weeks total and then transitioned to an equivalent dose of BRIXADI (monthly) (every 28 days, +/- 7-day window) for the remaining twelve weeks. Dose adjustments were permitted for the duration of the study. Supplemental 8 mg BRIXADI (weekly) injections were allowed during the second phase of the study and were also used in the active-controlled group. Overall, supplemental 8 mg injections were given to 14 patients (6.6%) in the BRIXADI arm and 17 patients (7.9%) in the SL BPN/NX arm. Table 8 shows the doses of BRIXADI (weekly) administered following the initial titration period and at the final visit before transition to BRIXADI (monthly) was allowed. Table 9 shows the first and final BRIXADI (monthly) dose administered to each patient.

For the first twelve weeks patients completed weekly visits. For the final twelve weeks patients were transitioned to monthly visits. Patients were also required to complete three additional randomly scheduled visits during the final twelve weeks. Efficacy was evaluated using urine drug screens combined with self-reported use of illicit opioid use. Missing urine drug screen samples and/or self-reports were counted as positive for illicit opioids.

A total of 428 patients were randomized equally (215 patients in the SL BPN/NX group and 213 in the BRIXADI group). Of the randomized patients, 69.0% (147/213) of the patients in BRIXADI treatment group and 72.6% (156/215) of the patients in the SL BPN/NX treatment group completed the 24-week period. Patient demographics and baseline characteristics are provided in Table 10.

Table 11 below illustrates the proportion of patients who were considered to be responders. A patient was a responder if they met all of the following criteria:

• Negative opioid assessment (urinalysis and self-report) during week 12 (evaluated during week 13 visit).
• No more than one positive opioid assessment in the three illicit opioid use assessments performed during week 9 to 11 (evaluated during visits at weeks 10 to 12).
• Negative opioid assessment during the final month of the study.
• No more than one positive opioid assessment at the three scheduled monthly visits and three random site visits.

This responder definition was designed to identify patients who were successfully treated with both BRIXADI (weekly) (administered in the first 12 weeks of treatment) and BRIXADI (monthly) (administered in the second 12 weeks of treatment). Therefore, patients were required to have negative opioid assessments at the end of each treatment phase. Each phase also included an allowable grace period (an initial period of time when positive opioid assessments were not taken into account) and the definition also allowed for sporadic positive assessments. Based on the results of this trial, the efficacy of BRIXADI was demonstrated. Table 11 shows the response rate for each treatment arm along with the associated 95% confidence interval for their difference.

The cumulative distribution function (CDF) of the percentage of negative opioid assessments (urine samples negative for illicit opioid use combined with self-reports negative for illicit opioid use) from Week 4 through Week 24 are shown in Figure 17 and Table 12. The figure and table are cumulative, so that a patient whose percentage of opioid-free assessments is, for example 50%, is also included at every level of negative opioid assessments below 50%. Missing values and values after premature discontinuation were considered positive. Based on the CDF of the percentage of negative opioid assessments, superiority was demonstrated with BRIXADI with statistical significance compared with SL BPN/NX. However, on the right-hand side of the curves where patients were reporting mostly negative opioid assessments (80% or greater) there was little to no difference between BRIXADI and SL BPN/NX.

Figure 17: Patients Achieving Varying Percentages of Negative Opioid Assessments (urine and self-report) in weeks 4 through 24

Store BRIXADI at room temperature at 20°C to 25°C (68°F to 77° F); with excursions permitted at 15°C to 30° C (59°F to 86°F) [see USP Controlled Room Temperature].

BRIXADI is a Schedule III drug product. Handle with adequate security and accountability. After administration, syringes should be properly disposed, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

Safe Use

Before initiating treatment with BRIXADI, explain the points listed below to patients and caregivers.