INDICATIONS AND USAGE

SUBLOCADE™ (buprenorphine extended-release) is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

MORE SAFETY INFORMATION

SELECTED PHARMACOKINETICS

SUBLOCADE is a once-monthly injection designed to deliver sustained buprenorphine plasma concentrations ≥2 ng/mL1,2

SUBLOCADE 300:100 mg achieved sustained buprenorphine plasma levels at steady state, which are associated with ≥70% mu-opioid receptor occupancy (μORO)1,2

Phase 3 Study Design
  • SUBLOCADE was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in treatment-seeking patients, who met the DSM-V criteria for moderate or severe opioid use disorder1
    • The safety of SUBLOCADE was evaluated in 848 opioid-dependent patients1
    • The primary endpoint was 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 241,3
  • Missing urine drug screen samples and/or self-reports were counted as positive for illicit opioids1
  • SUBLOCADE was administered once a month (28 ± 2 days) and the study design did not allow for supplemental buprenorphine1
  • Patients who met DSM-5 criteria for moderate or severe substance use disorder (cocaine or cannabis) and alcohol use disorder were excluded

Buprenorphine Plasma Levels of Individual Patients on SUBLOCADE 300:100 mg3

Plasma chart

  • The patient who received SUBLOCADE 300 mg showed 92% and 81% whole brain μORO on the 7th and 28th days post-injection, respectively3

Steady state (ss) was achieved at 4 to 6 months with SUBLOCADE1

Buprenorphine Mean Pharmacokinetic Parameters for SUBLOCADE1

Observed Plasma Concentrations chart

*Exposure after 1 injection of 300 mg SUBLOCADE following 24 mg transmucosal buprenorphine (TM BUP) stabilization.1

Steady-state exposure after 4 injections of 100 mg or 300 mg SUBLOCADE following 2 injections of 300 mg SUBLOCADE.1

  • After SUBLOCADE injection, an initial buprenorphine peak was observed and the median Tmax occurred at 24 hours after injection1
  • After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly to a plateau1

The observed plateau for maximal response was reached at buprenorphine plasma concentrations of approximately 2-3 ng/mL for illicit opioid use1

Exposure-response Relationship for Illicit Opioid Use1,3

Exposure chart

Exposure-response relationship for illicit opioid use was assessed using pooled data from the 300:100 mg and 300:300 mg arms.3

  • Exposure-response relationships were assessed for illicit opioid use based on urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use, using data obtained from 489 opioid‑dependent patients in the double-blind Phase 3 study1
  • In addition to study medication, all subjects received manual-guided psychosocial support at least once a week1

OPIOID BLOCKADE STUDY

SUBLOCADE blocked subjective opioid effects with sustained buprenorphine plasma concentrations1,2

Phase 2 Opioid Blockade Study Design
  • The primary objective of the study was to demonstrate that following the 300 mg subcutaneous (SC) injection of SUBLOCADE, the drug liking for 6 mg or 18 mg of a hydromorphone challenge was noninferior (ie, shown to be not substantially more likable) to the drug liking of a placebo challenge as measured by a 100-point visual analog scale (VAS)1,3
    • VAS is a 100-mm scale anchored by "none" moving to "extremely" modified to measure reports of "drug liking" and "high"3
  • Patients who met Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) criteria for moderate or severe OUD at screening, who were not seeking treatment, were inducted and stabilized on transmucosal buprenorphine to reach a final dose between 8 mg/day-24 mg/day3
  • Patients received 300 mg of SUBLOCADE on Day 1 (N=39) and Day 29 (N=30)3
  • A hydromorphone and placebo challenge was administered during transmucosal buprenorphine induction and then every week following each injection of SUBLOCADE and for 8 weeks after the second and last injection3

  • Patients were challenged with either hydromorphone or placebo on Days 5-7 of each week. The order of hydromorphone and placebo was randomized and patients received 1 challenge per day3
  • During the induction/stabilization phase with transmucosal buprenorphine (TM BUP), the hydromorphone challenges occurred 8 hours prior to TM BUP administration3
  • 2 monthly injections of SUBLOCADE were administered. Challenges took place for 3 months3

Select Baseline Characteristics in the Phase 2 Study

Select Baseline Characteristics3

Opioid Blockade Study Design1

Patients in the study were not seeking treatment (N=39 at the beginning of the study)1

Opioid Blockade Study Design
The key Phase 2 study was intended to test the hypothesis that monthly SUBLOCADE 300 mg would block the subjective effects of a mu-opioid receptor (μOR) agonist (hydromorphone)1,3

 

All 12 weeks of the treatment period demonstrated blockade for both 6 mg and 18 mg hydromorphone following the second SUBLOCADE injection1

Median drug-liking VAS scores begin trending toward 0 following the first injection of SUBLOCADE 300 mg1

  • Wide variation can be seen in isolated measurements from individual patients, shown in the figure below1

300mg chart

  • The study was not designed, nor intended, to draw any head-to-head comparisons between transmucosal buprenorphine and SUBLOCADE 3
  • Patients were challenged with both doses of hydromorphone and placebo at baseline, during the week they were stabilized on TM BUP, and during each of the 12 weeks of study for 3 consecutive days (each week on days 5-7) in a randomized fashion3
    • VAS measurements of drug-liking were assessed before and after these challenges
  • Complete blockade continued throughout the 8 weeks of observation that followed the second SUBLOCADE injection1

Key to figure:

  • The red and blue squares represent the median Emax drug-liking scores, placebo-corrected (VAS drug liking for that week’s 0 mg dose subtracted) during the hydromorphone challenge of 6 mg and 18 mg, respectively1
  • In some cases, 95% confidence intervals (CIs) 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 patients at that location1
  • Beneath that treatment week indicator is the number of patients (N) who provided those VAS measurements for all 3 challenges with placebo, 6 mg hydromorphone, and 18 mg hydromorphone1

PHASE 3 TRIAL

Efficacy and safety of SUBLOCADE were evaluated in a randomized, double‑blind, placebo‑controlled, multicenter trial1

Study Design1,3

Study design chart

§IDC=individualized drug counseling (manual-guided psychosocial support at least once a week).

Induction and Stabilization
  • Following screening, there was a 3-day induction period during which patients received 2 mg to 24 mg of TM BUP, which was then followed by a stabilization period lasting from 4 to 11 days, during which patients received 8 mg to 24 mg of TM BUP1,3

Primary Endpoint

  • 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 to 241,3

Study Design Details
  • Missing urine drug screen samples and/or self-reports were counted as positive for illicit opioids1
  • SUBLOCADE was administered once a month (28 ± 2 days)1
  • The study design did not allow for supplemental buprenorphine1

Select baseline characteristics in the Phase 3 Study1

Subject demographics table
Additional Patient Characteristics
  • All patients met DSM-5 criteria for moderate to severe OUD1
  • Patients who met DSM-5 criteria for moderate or severe substance use disorder (SUD) (cocaine or cannabis) and alcohol use disorder were excluded3

Primary Endpoint

Significantly more illicit opioid-free weeks with SUBLOCADE and individualized drug counselling (manual-guided psychosocial support at least once a week) (IDC) vs placebo and IDC1II

Primary endpoint

Percentage of Patients Who Achieved Illicit Opioid-free Weeks1

Endpoint chart

Based on CDF, the proportion of patients achieving illicit opioid-free weeks was significantly higher in both SUBLOCADE arms compared to placebo (P < 0.0001)1,3

 

IIIllicit opioid-free weeks was defined as a negative report after a urine drug screening combined with a negative self-report of illicit opioid use from Week 5 to 24.1


A significantly higher percentage of patients achieved a greater percentage of opioid-free weeks with SUBLOCADE and IDC vs placebo and IDC1

CDF of Percentage of Opioid-free Weeks1

  • 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% [300:100 mg], 29.1% [300:300 mg], 2% [placebo])1
  • For various percentages of opioid-free weeks, the table shows 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 positive1

Safety

SUBLOCADE safety was evaluated in 848 opioid-dependent patients1

The systemic safety profile for SUBLOCADE was consistent with the known safety profile of transmucosal buprenorphine (TM BUP)

  • Common adverse reactions associated with buprenorphine included constipation, nausea, vomiting, abnormal liver enzymes, headache, sedation, and somnolence1
  • 557 patients received at least 6 monthly subcutaneous injections and 138 patients received 12 monthly subcutaneous injections1

Adverse Drug Reactions (≥2% of Patients) in the Phase 3 Double-blind Study1

Safety chart
  • Treatment-emergent adverse events (TEAEs) reported in the 300:300 mg, 300:100 mg, and placebo groups were 66.7%, 76.4%, and 56.0%, respectively3
  • TEAEs that led to discontinuation of SUBLOCADE were reported in a similar percentage of patients in the 300:300 mg and the 300:100 mg groups compared with the placebo group (5.0% and 3.4% vs 2.0%, respectively)3
  • Dose-dependent hepatic effects observed in the Phase 3, double-blind study included the incidence of alanine aminotransferase (ALT) more than 3 times the upper limit of normal (>3 x ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300:300 mg, 300:100 mg, and placebo groups, respectively. The incidence of aspartate aminotransferase (AST) >3 x ULN was 11.4%, 7.9%, and 1.0%, respectively1

SUBLOCADE was given by a healthcare provider in clinical trials.1


Injection site reactions reported for SUBLOCADE1

Injection Site Adverse Drug Reactions Reported by ≥2% of Patients in the Phase 3 Double-blind Study1

  • Most injection site-related adverse events were of mild to moderate severity, with the exception of 1 report of severe injection site pruritus1
    • Injection site adverse drug reactions in ≥2% of patients in the Phase 3 trial, including roll-over study, were induration, bruising, swelling, discomfort, reaction, cellulitis, and infection1
  • There were no serious injection site reactions. One reaction, an injection site ulcer, led to study treatment discontinuation1

Longer-term experience for SUBLOCADE

  • In an interim analysis of the ongoing open-label long-term safety study, safety was evaluated for up to 12 injections over the course of a year1
  • The overall adverse event profile in the long-term safety study was similar to the double-blind trial1
  • Adverse events were reported for 432 of 669 patients during the treatment period1

HOW SUBLOCADE WORKS

Clinical development and study results for SUBLOCADE

  • Addictive effects of opioids are mediated by the μORs, making them a target of interest in treating OUD4
  • SUBLOCADE is a once-monthly injection for moderate to severe OUD. Watch the video to learn more1
REFERENCES: 1. SUBLOCADE [prescribing information]. North Chesterfield, VA: Indivior Inc.; 2018. 2. Nasser AF, Greenwald MK, Vince B, et al. Sustained-release buprenorphine (RBP-6000) blocks the effects of opioid challenge with hydromorphone in subjects with opioid use disorder. J Clin Psychopharmacol. 2016;36:18-26. 3. Data on file. Indivior Inc. North Chesterfield, VA. 2018. 4. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration.
IMPORTANT SAFETY INFORMATION AND BOXED WARNING
INDICATIONS AND USAGE

WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION;
SUBLOCADE RISK EVALUATION AND MITIGATION STRATEGY

  • Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously
  • Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

Prescription use of this product is limited under the Drug Addiction Treatment Act.

CONTRAINDICATIONS: SUBLOCADE should not be administered to patients who are hypersensitive to buprenorphine or any component of the ATRIGEL® delivery system.

WARNINGS AND PRECAUTIONS

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 patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors.

Risk of Respiratory Depression and Concomitant Use of Benzodiazepines or Other CNS Depressants with Buprenorphine: Buprenorphine has been associated with life‐threatening respiratory depression, overdose, and death, particularly when misused by self-injection or with concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines, other CNS depressants, opioid analgesics, and alcohol while under treatment with SUBLOCADE. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider.

Use 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).

Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. Newborns should be observed for signs of NOWS and managed accordingly. Advise pregnant women receiving opioid addiction treatment with SUBLOCADE of the risk of neonatal opioid withdrawal syndrome.

Adrenal Insufficiency: Adrenal insufficiency has been reported with opioid use. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid.

Discontinuation of SUBLOCADE Treatment: Due to the long-acting nature of SUBLOCADE, if treatment is discontinued, monitor patients for several months for withdrawal and treat appropriately.

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.

Risk of Hepatitis, Hepatic Events: Because cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine, monitor liver function tests prior to treatment and monthly during treatment.

Hypersensitivity Reactions: Hypersensitivity to buprenorphine-containing products have been reported most commonly as rashes, hives, and pruritus. Some cases of bronchospasm, angioneurotic edema, and anaphylactic shock have also been reported.

Precipitation of Opioid Withdrawal in Patients Dependent on Full Agonist Opioids: 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.

Risks Associated With Treatment of Emergent Acute Pain: When patients need acute pain management, or may require anesthesia, treat patients receiving SUBLOCADE currently or within the last 6 months with a non-opioid analgesic whenever possible. If opioid therapy is required, patients may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function, as higher doses may be required for analgesic effect and therefore, a higher potential for toxicity exists with opioid administration.

Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with SUBLOCADE.

Use in Opioid Naïve Patients: Because death has been reported for opioid naïve individuals who received buprenorphine sublingual tablet, SUBLOCADE is not appropriate for use in opioid naïve patients.

Use in Patients With Impaired Hepatic Function: Because buprenorphine levels cannot be rapidly decreased, SUBLOCADE is not recommended for patients with pre-existing moderate to severe hepatic impairment. 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.

Use in Patients at Risk for Arrhythmia: Buprenorphine has been observed to prolong the QTc interval in some patients participating in clinical trials. Avoid use of buprenorphine in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval.

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. 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.

Orthostatic Hypotension: Buprenorphine may produce orthostatic hypotension.

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.

Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Effects in Acute Abdominal Conditions: Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

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

ADVERSE REACTIONS: Adverse reactions commonly associated with SUBLOCADE (≥5% of subjects) during clinical trials were constipation, headache, nausea, vomiting, increased hepatic enzymes, fatigue, and injection site pain and pruritus. This is not a complete list of potential adverse events. Please see the full Prescribing Information for a complete list.

DRUG INTERACTIONS

CYP3A4 Inhibitors and Inducers: Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over- or under-dosing.

Serotonergic Drugs: If concomitant use with serotonergic drugs is warranted, monitor for serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug.

Consult the full Prescribing Information for SUBLOCADE for more information on potentially significant drug interactions.

USE IN SPECIFIC POPULATIONS

Pregnancy: Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

Lactation: Buprenorphine passes into the mother's milk. Advise breastfeeding women to monitor the infant for increased drowsiness and breathing difficulties.

Fertility: Chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Geriatric Patients: Monitor geriatric patients receiving SUBLOCADE for sedation or respiratory depression.

To report pregnancy or side effects associated with taking SUBLOCADE, please call 1-877-782-6966.

INDICATIONS AND USAGE

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

For more information about SUBLOCADE, see the full Prescribing Information including BOXED WARNING, and Medication Guide. For REMS information visit www.sublocadeREMS.com.