A SYSTEMIC SAFETY PROFILE CONSISTENT WITH THE KNOWN SAFETY PROFILE OF TM BUPRENORPHINE1
- The safety of SUBLOCADE® was evaluated in 848 opioid-dependent patients; 557 patients received at least 6 monthly SC injections, and 138 patients received 12 monthly SC injections1*
Adverse Drug Reactions (≥2% of Patients) in the Phase 3, Double-Blind Study1
|System Organ Class Preferred Term||SUBLOCADE 300/100 mg n=203 (%)||SUBLOCADE 300/300 mg n=201 (%)||Placebo n=100 (%)|
|Gastrointestinal disorders||51 (25.1)||45 (22.4)||12 (12)|
|Constipation||19 (9.4)||16 (8)||0|
|Nausea||18 (8.9)||16 (8)||5 (5)|
|Vomiting||19 (9.4)||11 (5.5)||4 (4)|
|General disorders and administration site conditions||40 (19.7)||49 (24.4)||17 (17)|
|Fatigue||8 (3.9)||12 (6)||3 (3)|
|Investigations||21 (10.3)||19 (9.5)||2 (2)|
|Alanine aminotransferase (ALT) increased||2 (1)||10 (5)||0|
|Aspartate aminotransferase (AST) increased||7 (3.4)||9 (4.5)||0|
|Blood creatine phosphokinase (CPK) increased||11 (5.4)||5 (2.5)||1 (1)|
|Gamma-glutamyl transferase (GGT) increased||6 (3)||8 (4)||1 (1)|
|Nervous system disorders||35 (17.2)||25 (12.4)||7 (7)|
|Headache||19 (9.4)||17 (8.5)||6 (6)|
|Sedation||7 (3.4)||3 (1.5)||0|
|Dizziness||5 (2.5)||3 (1.5)||2 (2)|
|Somnolence||10 (4.9)||4 (2)||0|
Dose-dependent hepatic effects observed in the Phase 3, double-blind study included the incidence of ALT more than 3 times the upper limit of normal (>3 x ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300/300mg, SUBLOCADE 300/100mg, and placebo groups, respectively. The incidence of AST >3 x ULN was 11.4%, 7.9%, and 1.0%, respectively1
- Across the development program (n=1044), 1 subject was withdrawn due to a serious adverse event (abnormal liver function test)2
- TEAEs that led to discontinuation of SUBLOCADE were reported in a similar percentage of patients in the SUBLOCADE 300/300 mg and SUBLOCADE 300/100 mg groups compared with the placebo group (5.0% and 3.4% vs 2.0%, respectively)2
SUBLOCADE was evaluated in patients with moderate and severe OUD, with varying substance use at screening, including both injecting and non-injecting users.1
No serious injection site reactions were reported for SUBLOCADE1
Injection Site Adverse Drug Reactions Reported by ≥2% of Patients in the Phase 3 Studies1
|Preferred Term||SUBLOCADE 300/100 mg n=203 (%)||SUBLOCADE 300/300 mg n=201 (%)||Placebo n=100 (%)|
|Patients with any injection site reactions||28 (13.8)||38 (18.9)||9 (9.0)|
|Injection site pain||10 (4.9)||12 (6.0)||3 (3.0)|
|Injection site pruritus (itch)||13 (6.4)||19 (9.5)||4 (4.0)|
|Injection site erythema (irritation)||9 (4.4)||6 (3.0)||0|
- In some postmarketing case reports, serious injection site reactions have been reported. The likelihood may increase with inadvertent intramuscular or intradermal administration.1
- One reaction, an injection site ulcer, led to study treatment discontinuation1
Long-term experience with SUBLOCADE1
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
- Adverse events were reported in 432 of 669 patients during the treatment period1
The overall adverse event profile in the open-label, long-term safety study was similar to that of the double-blind trial.1
- *SUBLOCADE was administered by a healthcare provider in clinical trials.1
SUBLOCADE® (buprenorphine extended-release) injection, for subcutaneous use (CIII) is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a 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.
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.
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 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 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.
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.
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.
- 1. SUBLOCADE [prescribing information]. North Chesterfield, VA: Indivior Inc.; 2021.
- 2. Data on file. Indivior Inc. North Chesterfield, VA. 2020.