2.1 Important Dosing and Administration Information

FOR ABDOMINAL SUBCUTANEOUS INJECTION ONLY. DO NOT ADMINISTER SUBLOCADE INTRAVENOUSLY, INTRAMUSCULARLY OR INTRADERMALLY [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.1, 5.6)] .

• Only healthcare providers should prepare and administer SUBLOCADE.
• Administer SUBLOCADE monthly with a minimum of 26 days between doses.
• Initiating treatment with SUBLOCADE as the first buprenorphine product has not been studied. Initiate SUBLOCADE treatment only following induction and dose-adjustment with a transmucosal buprenorphine-containing product [see Dosage and Administration ( 2.3)] .
• Administer each injection only using the syringe and safety needle included with the product [see Dosage and Administration ( 2.5)] .

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 SUBLOCADE. 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-opioid 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

Initiation of Treatment following Induction

Patients should first undergo induction and stabilization by initiating a buprenorphine-containing product, delivering the equivalent of 8-24 mg/day of transmucosal buprenorphine for a minimum of 7 days. Dosing and induction with buprenorphine-containing products should be based on instructions in their appropriate product label. One SUBOXONE ®(buprenorphine and naloxone) 8 mg/2 mg sublingual tablet provides equivalent buprenorphine exposure to one SUBUTEX ®(buprenorphine HCl) 8 mg sublingual tablet or one Bunavail ®(buprenorphine and naloxone) 4.2 mg/0.7 mg buccal film or one Zubsolv ®(buprenorphine and naloxone) 5.7 mg/1.4 mg sublingual tablet.

The recommended dose of SUBLOCADE following induction is 300 mg monthly for the first two months followed by a maintenance dose of 100 mg monthly.

The maintenance dose may be increased to 300 mg monthly for patients who tolerate the 100 mg dose, but do not demonstrate a satisfactory clinical response, as evidenced by self-reported illicit opioid use or urine drug screens positive for illicit opioid use.

A patient who misses a dose should receive the next dose as soon as possible, with the following dose given no less than 26 days later. Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect.

For patients in established treatment of 100 mg monthly, there may be instances when allowance for a two-month dosing interval may be appropriate (e.g., extended travel); in those instances, a single 300 mg dose may be given to cover a two-month period. Thereafter, the 100 mg monthly regimen would resume. Patients should be cautioned that the peak plasma level after injection of a 300 mg dose will be higher than their usual monthly dose and that they may experience sedation or other buprenorphine-related effects.

2.4 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 SUBLOCADE 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 (4-6 months), patients discontinuing SUBLOCADE may have detectable plasma and urine levels of buprenorphine for twelve months or longer [see Clinical Pharmacology ( 12.3)] .

2.5 Instructions for Use

IMPORTANT INFORMATION:

• For abdominal subcutaneous injection only. Do not inject intravenously, intramuscularly, or intradermally [see Warnings and Precautions ( 5.1, 5.6) ].
• To be prepared and administered by a healthcare provider only.
• Please read the instructions carefully before handling the product.
• As a universal precaution, always wear gloves.
• Remove SUBLOCADE from the refrigerator prior to administration. The product requires at least 15 minutes to reach room temperature. Do not open the foil pouch until the patient has arrived for his or her injection.
• Discard SUBLOCADE if left at room temperature for longer than 12 weeks.
• Do not attach the needle until time of administration.

STEP 1: GETTING READY

Remove the foil pouch and safety needle from the carton. Open the pouch and remove the syringe.

Discard the oxygen absorber pack. It is not needed.

Figure 1

STEP 2: CHECK THE LIQUID CLARITY

Check that the medication does not contain contaminants or particles. SUBLOCADE ranges from colorless to yellow to amber. Variations of color within this range do not affect the potency of the product.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Figure 2

STEP 3: ATTACH THE SAFETY NEEDLE

Remove the cap from the syringe and the safety needle supplied in the carton from its sterile package.

Gently twist the needle clockwise until it is tight and firmly attached.

Do not remove the plastic cover from the needle.

Figure 3

STEP 4: PREPARE THE ABDOMINAL INJECTION SITE

Choose an injection site on the abdomen between the transpyloric and transtubercular planes with adequate subcutaneous tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigment). It is recommended that the patient is in the supine position.

Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way.

Clean the injection site well with an alcohol swab.

To avoid irritation, rotate injection sites following a pattern similar to the illustration in Figure 4. Record the location of the injection to ensure that a different site is used at the time of the next injection.

Figure 4

STEP 5: REMOVE EXCESS AIR FROM SYRINGE

Hold the syringe upright for several seconds to allow air bubbles to rise. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution.

Remove needle cover and slowly depress the plunger to push out the excess air from the syringe.

• Small bubbles may remain in the medication. Large air gaps, however, can be minimized by pulling back on the plunger rod to pop air bubbles prior to expelling the air very slowly. Air should be expelled very carefully to avoid loss of medication.

If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage.

Figure 5

STEP 6: PINCH THE INJECTION SITE

Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle. Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection.

Figure 6

STEP 7: INJECT THE MEDICATION

SUBLOCADE is for subcutaneous injection only. Do not inject intravenously, intramuscularly, or intradermally [see Warnings and Precautions ( 5.1, 5.6)] .

Insert needle fully into the abdominal subcutaneous tissue. Actual angle of injection will depend on the amount of subcutaneous tissue.

Use a slow, steady push to inject the medication. Continue pushing until all of the medication is given.

Figure 7

STEP 8: WITHDRAW THE NEEDLE

Withdraw the needle at the same angle used for insertion and release the pinched skin.

Do not rub the injection area after the injection. There may be a small amount of blood or fluid at the injection site; wipe with a cotton ball or gauze before applying a gauze pad or bandage using minimal pressure.

Figure 8

STEP 9: LOCK THE NEEDLE GUARD AND DISCARD THE SYRINGE

Lock the needle guard into place by pushing it against a hard surface such as a table ( Figure 9).

Dispose of all syringe components in a secure sharps disposal container.

Figure 9

STEP 10: INSTRUCT THE PATIENT

Advise the patient that they may have a lump for several weeks that will decrease in size over time. Instruct the patient not to rub or massage the injection site and to be aware of the placement of any belts or clothing waistbands.

2.6 Limits on Distribution

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

2.7 Removal of the Depot

In the event the depot must be removed, it can be surgically excised under local anesthesia within 14 days of injection. Only the most recently-injected depot can be removed.

The removed depot should be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product and pharmaceutical biohazardous waste, and per applicable federal, state, and local regulations.

The residual plasma concentrations from previous injections will decrease gradually over subsequent months [see Clinical Pharmacology ( 12.3)] .

Patients who have the depot removed should be monitored for signs and symptoms of withdrawal and treated appropriately [see Warnings and Precautions ( 5.9)] .

5.1 Risk of Serious Harm or Death With Intravenous Administration

Intravenous injection presents significant risk of serious harm or death as SUBLOCADE forms a solid mass 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 [see Warnings and Precautions ( 5.6)] .

5.2 SUBLOCADE Risk Evaluation and Mitigation Strategy (REMS) Program

SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program 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 SUBLOCADE directly to a healthcare provider for administration by a healthcare provider.

Notable requirements of the SUBLOCADE REMS Program include the following:

• Healthcare Settings and Pharmacies that order and dispense SUBLOCADE must be certified in the SUBLOCADE REMS Program.
• Certified Healthcare Settings and Pharmacies must establish processes and procedures to verify SUBLOCADE 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 SUBLOCADE.

Further information is available at www.SublocadeREMS.com or call 1-866-258-3905.

5.3 Addiction, Abuse, and Misuse

SUBLOCADE 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 depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBLOCADE [see Warnings and Precautions ( 5.5), Drug Interactions ( 7), Patient Counseling Information ( 17)].

Use SUBLOCADE 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 SUBLOCADE is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for several months.

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, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.7)] .

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 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 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 patient's 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 Risk of Serious Injection Site Reactions

Injection site reactions are most commonly manifested by pain, erythema and pruritus. In some post-marketing case reports injection site reactions have involved abscess, ulceration, and necrosis. Some cases resulted in surgical depot removal, debridement, antibiotic administration, and SUBLOCADE discontinuation. The likelihood of serious injection site reactions may be increased with inadvertent intramuscular or intradermal administration. Carefully review injection technique [see Instructions for Use ( 2.5)] . Evaluate and treat serious injection site reactions as appropriate.

5.7 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 professionals 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 SUBLOCADE 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 should 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 of management of opioid addiction throughout pregnancy.

5.8 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 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.

5.9 Risk of Opioid Withdrawal With Abrupt Discontinuation of SUBLOCADE 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. The withdrawal syndrome is milder than that seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence ( 9.3)] .

Withdrawal signs and symptoms were not observed in the month following discontinuation of SUBLOCADE. Considering the long half-life, any withdrawal signs and symptoms that may occur would be expected to be delayed [see Clinical Pharmacology ( 12.2)] . Model simulations indicate that steady-state buprenorphine plasma concentrations decreased slowly over time following the last injection and remained at therapeutic levels for 2 to 5 months on average, depending on the dosage administered (100 or 300 mg, respectively).

Patients who elect to discontinue treatment with SUBLOCADE should be monitored for withdrawal signs and symptoms. Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing SUBLOCADE.

5.10 Risk of Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine 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 injecting drug use 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. In one subject in the SUBLOCADE clinical program, surgical removal was followed by improvement in liver enzymes.

Liver function tests, prior to initiation of treatment, are recommended to establish a baseline. Monthly monitoring of liver function during treatment, particularly with 300 mg maintenance dose, is also recommended. An etiological evaluation is recommended when a hepatic adverse event is suspected.

5.11 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 is a contraindication to the use of SUBLOCADE [see Contraindications ( 4)] .

5.12 Precipitation of Opioid Withdrawal in Patients Dependent on Full Agonist Opioids

Because of the partial opioid agonist properties of buprenorphine, buprenorphine may precipitate opioid withdrawal signs and symptoms in persons who are currently physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. Verify that patients have tolerated and are dose adjusted on transmucosal buprenorphine before subcutaneously injecting SUBLOCADE.

5.13 Risks Associated With Treatment of Emergent Acute Pain

While on SUBLOCADE, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving SUBLOCADE with a 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 physician, 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 SUBLOCADE [see Patient Counseling Information ( 17)] .

The above guidance should also be considered for any patient who has been treated with SUBLOCADE within the last 6 months.

5.14 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. SUBLOCADE is not appropriate for use in opioid naïve patients.

5.15 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 SUBLOCADE has not been studied.

Because of the long-acting nature of the product, adjustments to dosages of SUBLOCADE 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 SUBLOCADE.

Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3)] .

5.16 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 SUBLOCADE 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.

5.17 Impairment of Ability to Drive or Operate Machinery

SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery especially during the first few days following treatment and dose adjustment. Buprenorphine plasma levels accumulate during the first two months and are maintained with the 100 mg maintenance dose; further accumulation occurs with the 300 mg maintenance dose, which achieves steady-state after the fourth monthly injection. Caution patients about driving or operating hazardous machinery until they are reasonably certain that SUBLOCADE does not adversely affect their ability to engage in such activities.

5.18 Orthostatic Hypotension

Buprenorphine may produce orthostatic hypotension in ambulatory patients.

5.19 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. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

5.20 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.

5.21 Effects in Acute Abdominal Conditions

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

5.22 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 SUBLOCADE was evaluated in 848 opioid-dependent subjects (see Table 2). In these studies, there was a total of 557 subjects who received at least 6 monthly SC injections of SUBLOCADE and 138 subjects who received 12 monthly SC injections. Adverse events led to premature discontinuation in 4% of the group receiving SUBLOCADE compared with 2% in the placebo group (13-0001, NCT02357901).

In the Phase 3 open-label study (13-0003, NCT02510014), adverse events leading to drug dose reductions were reported in 7.3% of subjects receiving SUBLOCADE.

Table 3shows the non-injection site-related adverse reactions (ADRs) for the groups receiving SUBLOCADE 300/300 mg (6 doses of 300 mg SC injections) 300/100 mg (300 mg SC injections for the first two doses followed by 4 doses of 100 mg SC injections) and placebo (volume-matched ATRIGEL ®delivery system subcutaneous injections) reported following administration in the 6 month, double-blind, placebo-controlled study. The systemic safety profile for SUBLOCADE, given by a healthcare provider in clinical trials, was consistent with the known safety profile of transmucosal buprenorphine. Common adverse reactions associated with buprenorphine included constipation, nausea, vomiting, abnormal liver enzymes, headache, sedation and somnolence. Dose dependent hepatic effects observed in the Phase 3, double-blind study (13-0001, NCT02357901) included the incidence of ALT more than 3 times the upper limit of normal (> 3 × ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300/300-mg, SUBLOCADE 300/100-mg, and placebo groups, respectively. The incidence of AST > 3 × ULN was 11.4%, 7.9%, and 1.0%, respectively. Adverse drug reactions [by MedDRA Preferred Terms (PT)] reported in at least 2% of subjects receiving SUBLOCADE are grouped by System Organ Class (SOC).

Table 4shows the injection site-related adverse events reported by ≥ 2 subjects in the Phase 3 studies. Most injection site adverse drug reactions (ADRs) were of mild to moderate severity, with one report of severe injection site pruritus. None of the injection site reactions were serious. One reaction, an injection site ulcer, led to study treatment discontinuation.

6.2 Postmarketing Experience

The most frequently reported systemic postmarketing adverse event observed with buprenorphine sublingual tablets was drug misuse or abuse. The most frequently reported systemic postmarketing adverse event with buprenorphine/naloxone sublingual tablets and film was peripheral edema.

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.

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 ingredients contained in SUBLOCADE.

Androgen deficiency:Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] .

Hypoglycemia:Cases of hypoglycemia have been reported in patients taking opioids. 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 SUBLOCADE have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of SUBLOCADE did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between 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 SUBLOCADE 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 SUBLOCADE 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 have been 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 SUBLOCADE are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly adjusted, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with SUBLOCADE.

Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. If signs and symptoms of toxicity or overdose occur within 2 weeks of SUBLOCADE administration, removal of the depot may be required [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.3)] .

8.7 Renal Impairment

Clinical studies of SUBLOCADE 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

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

9.2 Abuse

SUBLOCADE 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.

SUBLOCADE is distributed through a restricted distribution system, which is intended to prevent the direct distribution to a patient. SUBLOCADE 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 (approximately 0.1 mL) of SUBLOCADE will remain in the needle and syringe and should be properly disposed of [see How Supplied/Storage and Handling ( 16)] .

SUBLOCADE is injected as a liquid, and the subsequent precipitation of the poly (DL-lactide-co-glycolide) polymer creates a solid depot which contains buprenorphine. After initial formation of the depot, buprenorphine is released via diffusion from, and the biodegradation of, the depot. Clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. No accounts of subjects removing or attempting to remove the depot after administration of SUBLOCADE were reported in premarketing studies.

9.3 Dependence

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. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Warnings and Precautions ( 5.12)] .

Due to the long-acting nature of SUBLOCADE, 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 ( 5.7)] .

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. Clinical data are limited with regards to the possible surgical removal of the depot. Two cases of surgical removal were reported in premarketing clinical studies.

12.1 Mechanism of Action

SUBLOCADE Injection contains buprenorphine. Buprenorphine is a partial agonist at the mu- opioid receptor and an antagonist at the kappa-opioid receptor.

12.2 Pharmacodynamics

Pharmacodynamic Interaction with Fentanyl

An open-label, cross-over study was conducted in 8 opioid-tolerant subjects to assess the ability of intravenous buprenorphine to prevent respiratory depression associated with high doses of fentanyl administered in a clinical setting. Opioid-tolerant subjects were medically stable and taking oral morphine equivalents of ≥ 90 mg daily with no other CNS depressant use. Buprenorphine infusions at three dose levels and placebo infusions were administered, followed by up to four doses of fentanyl. The three intravenous buprenorphine dose levels were designated as low (0.25 mg/70kg bolus + 0.1 mg/70kg/hr), mid (0.5 mg/70kg bolus + 0.2 mg/70kg/hr), and high (1.25 mg/70kg bolus + 0.5 mg/70kg/hr). The low, mid, and high buprenorphine dose levels produced average plasma concentrations (from 2 hours to 6 hours after infusion onset) of 1.06 ng/mL, 2.26 ng/mL, and 6.04 ng/mL, respectively.

Escalating intravenous fentanyl boluses of 0.25, 0.35, 0.50 and 0.70 mg/70 kg (up to a maximum cumulative dose of 1.8 mg/70 kg) were administered over 90 seconds at + 2hr, + 3hr, + 4hr and + 5hr after the start of intravenous infusion of buprenorphine or placebo. Apnea events after each fentanyl bolus are shown in Figure 11. Four of the 8 subjects in the placebo infusion groups discontinued prior to the fourth fentanyl bolus because of apnea (2 after the second bolus and 2 after the third bolus); 3 of the remaining 4 subjects experienced apnea after the fourth fentanyl dose. All 8 subjects in the buprenorphine infusion groups completed the fentanyl boluses and 2 of the 8 experienced apnea.

Figure 11 Occurrence of Apnea Events After Fentanyl Doses in a Pharmacodynamic Interaction Study

There were 2 opioid-tolerant subjects in the low intravenous buprenorphine (BUP) group (Arm A), 3 in the mid BUP group (Arm B), and 3 in the high BUP group (Arm C). The numbers in parentheses represent the geometric mean of buprenorphine plasma concentrations in each group from 2 hours to 6 hours after infusion onset. The escalating fentanyl doses 1 to 4 were 0.25, 0.35, 0.50 and 0.70 mg/70 kg body weight. The same subject in the low BUP group had apnea after the third and fourth fentanyl boluses.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Study 13-0002, NCT02044094

The opioid blockade study evaluated the blockade of subjective opioid effects, PK and safety of subcutaneous injections of SUBLOCADE in 39 subjects with OUD (not treatment-seeking).

The peak (E max) effect of “Drug Liking” Visual Analog Scale (VAS) measurement after challenge with IM injections of 6 mg and 18 mg hydromorphone (HM) was not inferior (i.e., shown to be not substantially more likeable) compared to the E maxof “Drug Liking” VAS measured after challenge with placebo (at weeks 1 through 4 following the first injection of 300 mg SUBLOCADE). The noninferiority (NI) margin, the largest difference allowed for the 6 or 18 mg HM VAS to exceed the placebo VAS (the maximum VAS recorded following IM injection of 0 mg HM) before being considered significant, was set at 20. Based on comparison to the historical response to opioid agonists in unblocked subjects, a difference of less than 20 points (on a unipolar scale) between the mean maximum response to hydromorphone and the mean maximum placebo response for the same challenge was considered to indicate near-complete blockade.

All 12 weeks of the treatment period demonstrated blockade for both 6 mg and 18 mg following SUBLOCADE injections. However, wide variation can be seen in isolated measurements from individual subjects, shown in the figure below. For comparison, stabilization doses of SL buprenorphine in Week 0 failed to provide full blockade to 18 mg of HM. Complete blockade continued throughout the 8 weeks of observation that followed the 2 ndSUBLOCADE injection.

Figure 12 Median (95% Confidence Interval) of Placebo-Corrected Drug-Liking Scores by Hydromorphone Dose and by Week

• Key to Figure: The grey shaded area indicates the period where subjects were stabilized with 8 to 24 mg/day sublingual (SL) buprenorphine; the two vertical arrows represent treatment injections of SUBLOCADE, with 300 mg of buprenorphine.
• The light grey and dark grey squares represent the median E maxdrug-liking scores, placebo-corrected (VAS drug liking for that week's 0 mg dose subtracted) during the hydromorphone challenge of 6 and 18 mg, respectively. This median Placebo-Corrected E maxis shown by treatment week, together with its 95% confidence interval (CI; vertical line).  In some cases, 95% CI are not visible as the median was equal to the confidence limit. The horizontal line at 20 mm delineates the non-inferiority margin for opioid blockade. Next to median estimates, individual data are summarized by circles, the area of which is proportional to the number of subjects at that location.
• The X axis shows how many weeks following injection #1 that each weeks' Placebo-Corrected Drug-Liking Score was measured. Beneath that treatment week indicator, is the number of subjects (N) who provided those VAS measurements for all three challenges with placebo, 6 and 18 mg hydromorphone.

14.2 Study 13-0001, NCT02357901

The efficacy of SUBLOCADE for the treatment of opioid use disorder was evaluated in a Phase 3, 24- week, randomized, double-blind, placebo-controlled, multicenter trial in treatment-seeking patients who met the DSM-5 criteria for moderate or severe opioid use disorder. Patients were randomized to one of following dosing regimens: 6 once-monthly 300 mg doses, 2 once-monthly 300 mg doses followed by 4 once-monthly 100 mg doses, or 6 once-monthly subcutaneous injections of placebo. All doses were administered by a physician or suitably qualified designee and were separated by 28 ± 2 days. In addition to study medication, all subjects received manual-guided psychosocial support at least once a week (Individual Drug Counseling = IDC).

Prior to the first dose, treatment was initiated with SUBOXONE ®(buprenorphine/naloxone) sublingual film (SUBOXONE SL Film); doses were adjusted from 8/2 mg to 24/6 mg per day over a period of 7-14 days. Patients were randomized to SUBLOCADE injection or placebo after cravings and withdrawal symptoms were clinically controlled. After randomization, supplemental dosing with SUBOXONE SL Film was not permitted during the study.

Efficacy was evaluated over Weeks 5 through 24 based on weekly urine drug screens combined with self-reported use of illicit opioid use. A “grace period” was applied for Weeks 1 through 4 to allow patients to stabilize in treatment. During this period, opioid use, if it occurred, was not considered in the analysis. Missing urine drug screen samples and/or self-reports during Weeks 5-24 were counted as positive for illicit opioids.

A total of 504 patients were randomized 4:4:1:1 [203 subjects in the 300 mg/100 mg group, 201 patients in the 300 mg/300 mg group and 100 patients in the placebo group (2 groups of volume-matched placebo)]. Patient demographics and baseline characteristics are provided in Table 8.

Based on the cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use collected from Week 5 through Week 24 ( Table 9), regardless of dose, SUBLOCADE was superior to the placebo group with statistical significance. The proportion of patients achieving treatment success (defined as patients with ≥ 80% opioid-free weeks) was statistically significantly higher in both groups receiving SUBLOCADE compared to the placebo group (28.4% [300 mg/100 mg], 29.1% [300 mg/300mg], 2% [placebo]).

For various percentages of opioid-free weeks, Table 9shows the fraction of patients achieving that criterion. The table is cumulative, so that a patient whose percent of opioid-free weeks is, for example, 50%, is also included at every level of opioid-free week percentage below 50%. Missing values and values after premature discontinuation were considered positive.

Figure 13 Subjects Achieving Varying Percentages of Opioid-Free Weeks

Storage and Handling

Store refrigerated at 2°C to 8°C (35.6°F to 46.4°F).

Once outside the refrigerator this product may be stored in its original packaging at room temperature, 15°C to 30°C (59°F to 86°F), for up to 12 weeks prior to administration. Discard SUBLOCADE if left at room temperature for longer than 12 weeks.

SUBLOCADE 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.

Rx Only.

SUBLOCADE Risk Evaluation and Mitigation Strategy (REMS)

Advise patients that because of the risk of serious harm or death due to intravenous self-administration, SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies are certified and only dispense SUBLOCADE directly to a healthcare provider for administration by healthcare providers [see Warnings and Precautions ( 5.2)] .

Life Threatening Respiratory Depression

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 Warnings and Precautions 5.4)] .

Interaction With Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if SUBLOCADE is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4, 5.5), Drug Interactions ( 7)].

Serotonin Syndrome

Inform patients that SUBLOCADE could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Drug Interactions ( 7)].

Adrenal Insufficiency

Inform patients that SUBLOCADE could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.8)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with buprenorphine. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions ( 5.11)].

Driving or Operating Heavy Machinery

Caution patients that SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous machinery. Instruct patients not to drive or operate hazardous machinery until they are reasonably certain that SUBLOCADE does not adversely affect their ability to engage in such activities [see Warnings and Precautions ( 5.17)] .

Dependence and Withdrawal

Inform patients that SUBLOCADE can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued [see Warnings and Precautions ( 5.9, 5.12)].

Orthostatic Hypotension

Inform patients that, like other opioids, SUBLOCADE may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions ( 5.18)].

Long Duration of Action

Inform patients that they may have detectable levels of buprenorphine for a prolonged period of time after treatment with SUBLOCADE. Considerations of drug-drug interactions, buprenorphine effects, and analgesia may continue to be relevant for several months after the last injection [see Clinical Pharmacology ( 12.3)] .

Drug Interactions

Instruct patients to inform their healthcare providers of any other prescription medications, over the-counter medications, or herbal preparations that are prescribed or currently being used [see Drug Interactions ( 7)].

Pregnancy

Lactation

Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties [see Use in Specific Populations ( 8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3), Clinical Pharmacology ( 12.2)].

Emergency Analgesia

Patients should be advised to instruct their family members to, in the event of emergency, 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 SUBLOCADE [see Warnings and Precautions ( 5.13)] .

Clinical Monitoring

Tell your patients to seek emergency attention if they have signs or symptoms of respiratory or CNS depression or overdose [see Warnings and Precautions ( 5.4, 5.5)] .

Tell your patients not to tamper with or try to remove their depot [see Dosage and Administration ( 2.7)].

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SUBLOCADE ®and SUBOXONE ® are registered trademarks of Indivior UK Limited.

Manufactured for Indivior Inc., North Chesterfield VA, 23235