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

THE ADDICTION CYCLE

Patients struggle with the cycle of addiction1

The cycle of addiction consists of 3 repeating stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation1,2

Addiction cycle details
  • These stages are associated with symptoms that drive addiction: rewarding or pleasurable effects, avoidance of substance withdrawal, and substance-seeking behavior, respectively1
  • The cycle becomes more severe as a person continues illicit opioid use, and as it produces changes in brain function, it can reduce a person’s ability to control their use1
  • Changes affect specific regions of the brain (basal ganglia, prefrontal cortex, and extended amygdala) and have a crucial impact on motivation and behavior1,2
  • Rewarding effects positively reinforce illicit opioid use and increase the likelihood of repeated use1

Brain Disease Model of Addiction1,2

Click the tabs to activate

The brain disease model of addiction

 

The brain disease model of addiction and its associated stages and symptoms are adapted from Volkow et al 2016 and the 2016 Surgeon General's Report on Alcohol, Drugs, and Health.

Rewarding

Binge/Intoxication

Involves enhancement of drug-induced activation of the brain's reward system (basal ganglia) and generates pleasurable feelings (subjective effects).1-3

Addictive drugs stimulate reward regions in the brain by sharp increases in the release of dopamine, which elicits a reward signal that triggers associative learning (conditioning) at the receptor level.2

Upon repeated exposure to the same reward, dopaminergic neurons initiate an anticipatory response (conditioned stimuli) instead of responding only to the reward.2

 

The brain disease model of addiction and its associated stages and symptoms are adapted from Volkow et al 2016 and the 2016 Surgeon General's Report on Alcohol, Drugs, and Health.

Negative affect

Withdrawal/Negative Affect

Negative affect activates brain regions involved in emotions that result in negative mood and enhanced sensitivity to stress.2

The dopamine-enhancing effects of most drugs are also associated with adaptations in the circuitry of the extended amygdala in the basal forebrain that leads to increased reactivity to stress and negative emotions ("antireward" system).2

In individuals with addiction, the "antireward" system of the brain becomes overactive. This effect can induce a highly dysphoric phase that is associated with subsiding of a drug's effects, drug withdrawal, and the reduced reactivity of dopamine cells in the brain's reward circuitry.2

Consequently, individuals take drugs to obtain transient relief from dysphoria rather than for pleasure.2

 

The brain disease model of addiction and its associated stages and symptoms are adapted from Volkow et al 2016 and the 2016 Surgeon General's Report on Alcohol, Drugs, and Health.

Craving

Preoccupation/Anticipation

Decreased signaling of the prefrontal cortex is associated with the inability to balance the strong desire for the drug with the will to abstain, which triggers relapse and reinitiates the cycle of addiction.1,2

In this stage, down-regulation of dopamine signaling dulls the reward circuits' sensitivity to pleasure, which also occurs in this area of the brain. This has a serious impact, impairing executive process, including the capacities for self-regulation, and decision-making.2

Changes in the prefrontal cortex create an imbalance involved in reward and emotional responses. These changes have a crucial effect on the development of compulsive behavior. This is why, despite knowing potentially catastrophic consequences, people are unable to reduce drug-taking behavior.2

 

The brain disease model of addiction and its associated stages and symptoms are adapted from Volkow et al 2016 and the 2016 Surgeon General's Report on Alcohol, Drugs, and Health.

Learn About the Brain Disease Model of Addiction

Addictive effects of opioids are mediated by mu-opioid receptors (μORs) in the brain4

  • μORs are found throughout the central and peripheral nervous systems5

Medications that target the brain's μORs have been shown to be clinically useful for the treatment of opioid addiction6

 

Connection Between Buprenorphine and Opioid Receptors

BUPRENORPHINE PHARMACOLOGY

Association between mu-opioid receptor occupancy (μORO) and opioid use disorder (OUD) treatment

Observations in published scientific data have shown that increases in buprenorphine plasma concentrations and μORO correlate to a reduction of OUD symptoms8-10*

Studies chart

≥2 ng/mL

plasma concentration has been shown in studies to be relevant in addressing symptoms of OUD7‑9,11,12

*5 and 10 heroin-dependent patients were included in the trials published by Greenwald 2003 and 2007, respectively.9,10

 

These data led to a formulation targeted to achieve buprenorphine plasma concentrations of ≥2 ng/mL or ≥70% μORO7

Blockade & Drug Liking
  • Drug liking has been described as the subjective drug effects during a full agonist-induced challenge with terms that reflect abuse potential (eg, "liking," "good effect")8

  • Blockade has been defined as the absence of reactivity to the physiological-related subjective drug effects or a response to the reinforcing effects of an opioid agonist, when statistically compared to placebo8

REFERENCES: 1. US Department of Health and Human Services (HHS), Office of the Surgeon General. Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC: HHS, November 2016. 2. Volkow ND, Koob GF, McLellan AT. Neurobiologic advances from the brain disease model of addiction. N Engl J Med. 2016;374:363-371. 3. SUBLOCADE [prescribing information]. North Chesterfield, VA: Indivior Inc.; 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. 5. Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012;6:11-16. 6. Veilleux JC, Colvin PJ, Anderson J, York C, Heinz AJ. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2010;30:155-166. 7. Data on file. Indivior Inc. North Chesterfield, VA. 2018. 8. Greenwald MK, Comer SD, Fiellin DA. Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. Drug Alcohol Depend. 2014;144:1-11. 9. Greenwald MK, Johanson C-E, Bueller J, et al. Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry. 2007;61:101-110. 10. Greenwald MK, Johanson C-E, Moody DE, et al. Effects of buprenorphine maintenance dose μ-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003;28:2000-2009. 11. 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. 12. Laffont CM, Gomeni R, Heidbreder C, Jones JP, Nasser AF. Population pharmacokinetic modeling after repeated administrations of RBP-6000, a new, subcutaneously injectable, long-acting, sustained-release formulation of buprenorphine, for the treatment of opioid use disorder. J Clin Pharmacol. 2016;56:806-815.
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.