Help Transform Recovery^1‑3

Buprenorphine binds tighter to µ-opioid receptors than most other opioids^4,5

Buprenorphine exhibits a

higher binding affinity

A low dissociation constant (K_i) value corresponds to greater binding affinity, but it does not necessarily translate to greater receptor activity⁴
Binding affinity is an in vitro measurement and may not correlate with clinical potency⁵

at the μOR than most full μOR agonists^4,5

Buprenorphine Binds
Tightly to μORs⁴

Graph showing the binding affinity of several mu-opioid receptor agonists; Buprenorphine binds tightly to mu-opioid receptors

Ranges of K_i values reported in the literature were as much as 10- to 100,000‑fold different for some drugs. For example, K_i values reported for morphine ranged from 0.26 to 611 nM, and fentanyl ranged from 0.007 to 214 nM.⁵

*Morphine K_i reported in lieu of heroin because heroin is unstable in vitro.⁶

μOR=μ-opioid receptor; μORO=µ-opioid receptor occupancy; nM=nanomolar.

Based on independent studies≥70% µORO^† by buprenorphine was required for effective opioid blockade in most individuals^3,8

Image of illicit opioids and buprenorphine binding to mu-opioid receptors

When ≥70% of μORs are occupied by buprenorphine, the effects of other opioids are reduced, including negative reinforcing and rewarding effects (eg, euphoria ["high"] and drug-liking)^3,8‑10

Buprenorphine's binding action acts as a barrier^4,7

Binds more tightly to µORs than most other opioids (like fentanyl or heroin)^4,5,7
Due to its higher affinity and slower dissociation rate, buprenorphine can displace and block other opioids from latching onto the receptor^4,7‡

^‡Receptor affinity and dissociation rates are in vitro measurements. The relative binding affinities measured in vitro may not correlate with clinical potency.⁵

Illicit fentanyl and its analogs are highly potent synthetic opioids^11‑13

Highly lipophilic
Prolonged clearance from body

Higher μORO by buprenorphine may be needed for effective opioid blockade^3,14,15§

^§Opioid "blockade" is the degree to which MOUD attenuate exogenous opioid effects (eg, reinforcing, subjective, and physiological).¹⁵

^†Based on analyses of 2 studies published by Greenwald 2003 and 2007, which included 5 and 10 heroin-dependent subjects, respectively. Opioid blockade referred to the ability of buprenorphine to suppress opioid-rewarding effects.⁸

MOUD=medications for opioid use disorder.

INDICATION

SUBLOCADE® is for moderate to severe opioid use disorder in those who have initiated treatment with a single dose of transmucosal buprenorphine or are already being treated with buprenorphine as part of a complete treatment plan that includes counseling and psychosocial support.

IMPORTANT SAFETY INFORMATION

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.

CONTRAINDICATIONS: SUBLOCADE should not be administered to patients who are hypersensitive to buprenorphine or any component of the 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 Life-Threatening 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).

Opioids can cause sleep-related breathing disorders, e.g., central sleep apnea (CSA), sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. Consider decreasing the opioid using best practices for opioid taper if CSA occurs.

Strongly consider prescribing naloxone at the time SUBLOCADE is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency help, even if naloxone is administered.

Risk of Serious Injection Site Reactions: The most common injection site reactions are pain, erythema and pruritus with some involving 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 increase with inadvertent intramuscular or intradermal administration. Carefully review injection technique.

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 if administered before the effects have subsided, at least 6 hours for short-acting opioids and 24 hours for long-acting opioids. Verify that patients have tolerated transmucosal buprenorphine before administering the first injection of 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.

QTc Prolongation: QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. 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 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.

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 a pregnancy or side effects associated with taking SUBLOCADE or any safety related information, product complaint, request for medical information, or product query, please contact PatientSafetyNA@indivior.com or 1-877-782-6966.

See full Prescribing Information, including BOXED WARNING, and Medication Guide. For REMS information visit www.sublocadeREMS.com.

References: 1. SUBLOCADE [prescribing information]. North Chesterfield, VA: Indivior Inc. 2. The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update [published correction appears in J Addict Med. 2020 May/Jun; 14(3):267]. J Addict Med. 2020;14(Suppl 1):1‑81. doi:10.1097/ADM.0000000000000633 3. Laffont CM, Ngaimisi E, Gopalakrishnan M, et al. Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder. Front Pharmacol. 2022;13:105213. doi:10.3389/fphar.2022.105213 4. Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain Ther. 2020;9(1):41‑54. doi:10.1007/s40122‑019‑00143‑6 5. Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59(3):385‑390. doi:10.1016/j.yrtph.2010.12.007 6. Raleigh MD, Laudenbach M, Baruffaldi F, et al. Opioid dose- and route-dependent efficacy of oxycodone and heroin vaccines in rats. J Pharmacol Exp Ther. 2018;365(2):346‑353. doi:10.1124/jpet.117.247049 7. Substance Abuse and Mental Health Services Administration. Medications for Opioid Use Disorder: TIP Series 63. Rockville, MD: 2018. Publication PEP21‑02‑01‑002. Updated 2021. Accessed June 12, 2024. 8. Nasser AF, Heidbreder C, Gomeni R, Fudala PJ, Zheng B, Greenwald MK. A population pharmacokinetic and pharmacodynamic modelling approach to support the clinical development of RBP‑6000, a new, subcutaneously injectable, long‑acting, sustained‑release formulation of buprenorphine, for the treatment of opioid dependence. Clin Pharmacokinet. 2014;53(9):813‑824. doi:10.1007/s40262‑014‑0155‑0 9. Greenwald MK, Johanson CE, Moody DE, et al. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003;28(11):2000‑2009. doi:10.1038/sj.npp.1300251 10. Greenwald MK, Johanson CE, Bueller J, et al. Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry. 2007;61(1):101‑110. doi:10.1016/j.biopsych.2006.04.043 11. Providers Clinical Support System. Practice-based guidelines: buprenorphine in the age of fentanyl. https://pcssnow.org/wp‑content/uploads/2023/05/PCSS-Fentanyl-Guidance-FINAL-1.pdf. Published May 2023. Accessed April 17, 2024. 12. Huhn AS, Hobelmann JG, Oyler GA, Strain EC. Protracted renal clearance of fentanyl in persons with opioid use disorder. Drug Alcohol Depend. 2020;214:108147. doi:10.1016/j.drugalcdep.2020.108147 13. Sutcliffe IC, Corey RA, Alhosan N, et al. Interaction with the lipid membrane influences fentanyl pharmacology. Adv Drug Alcohol Res. 2022;10:280. doi:10.3389/odar.2022.102260 14. Grande LA, Cundiff O, Greenwald MK, et al. Evidence on buprenorphine dose limits: A review. J Addict Med. 2023;17(6):509‑516. doi:10.1097/ADM.0000000000001188 15. 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;141:1‑11. doi:10.1016/j.drugalcdep.2014.07.035

P-BAG-US-01599 Feb 2025