Buprenorphine Extended-Release (Sublocade) (SUBLOCADE — Indivior UK Limited (distributed in Canada by Pharma Importing Inc.))

• Indicated for the management of moderate to severe opioid use disorder (OUD) in adult patients.
• Must be used as part of a complete treatment plan that includes counselling and psychosocial support — it is not authorized as a stand-alone therapy.
• Must only be administered subcutaneously by a healthcare professional.
• Not intended for opioid-naive patients; patients must already be physically dependent on opioids and adequately inducted on buprenorphine before the first SUBLOCADE injection.

• Animal reproductive and developmental toxicity studies showed a range of adverse effects on embryo-fetal, fetal, and pre-/post-natal development with SUBLOCADE, buprenorphine, and — most notably — the excipient NMP; fetal malformations and resorptions were reported at roughly 3 times the human maximum daily dose of NMP delivered by SUBLOCADE.
• Buprenorphine crosses the placental barrier and can be life-threatening to the fetus; animal data also suggest NMP may cross the placenta.
• Women of childbearing potential should use reliable, effective birth control and must tell their prescriber immediately if they become pregnant.
• Pregnant patients on SUBLOCADE must not discontinue it abruptly — abrupt discontinuation can cause pregnancy complications such as miscarriage or stillbirth; any discontinuation during pregnancy must be medically supervised as part of a comprehensive treatment plan.
• SUBLOCADE is not recommended during labour and delivery unless, in the physician's judgment, benefits outweigh risks; because opioids cross the placenta, use during labour and delivery can cause life-threatening respiratory depression in the newborn, a risk that is further increased if another opioid is also given.
• Prolonged use during pregnancy can cause neonatal opioid withdrawal syndrome (NOWS) in the newborn, which — unlike adult opioid withdrawal — can be life-threatening if not recognized and treated; this risk must be balanced against the risk of untreated opioid use disorder.

• Buprenorphine and its metabolite norbuprenorphine are excreted into human breast milk and infant urine; life-threatening respiratory depression can occur in a nursing infant exposed this way.
• It is not known whether NMP transfers into breast milk in humans; rat studies show that maternal NMP exposure during lactation can reduce offspring weight and survival.
• SUBLOCADE is not recommended while breastfeeding; if it is used, the developmental and health benefits of breastfeeding must be weighed against the mother's clinical need for treatment and any potential risk to the infant, and the infant should be monitored regularly by a healthcare professional for increased drowsiness or breathing difficulties.

• No patients aged 65 or older were enrolled in the controlled clinical trial of SUBLOCADE.
• In general, drug therapy in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, respiratory, and/or cardiac function, and of concomitant disease or other drug therapies, in this population.
• If SUBLOCADE is prescribed to a patient 65 years of age or older, they should be monitored for signs and symptoms of toxicity or overdose.

• No data are available in patients under 18 years of age; Health Canada has not authorized SUBLOCADE for pediatric use.
• SUBLOCADE can cause severe, possibly fatal, respiratory depression in a child who is accidentally exposed to it; children must be protected against any exposure to or access to the product, including used syringes and disposed material.

• FOR SUBCUTANEOUS INJECTION ONLY. SUBLOCADE must NEVER be administered intravenously, intramuscularly, or intradermally — this is stated as a boxed Serious Warning in the monograph.
• Intravenous administration carries a serious risk of harm or death: SUBLOCADE forms a solid mass on contact with body fluids, and IV injection can cause occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli.
• Inadvertent intramuscular or intradermal injection increases the risk of serious injection-site reactions; post-marketing reports describe abscess, ulceration, and necrosis at the injection site, with some cases requiring surgical depot removal, debridement, antibiotic treatment, or discontinuation of SUBLOCADE.
• SUBLOCADE must never be handed to the patient — it is administered only by a healthcare professional and is never taken home or self-injected.
• SUBLOCADE is available only through a controlled distribution process in Canada: it may only be prescribed by healthcare professionals who have completed Indivior's SUBLOCADE Certification Program, accessible at sublocadecertification.ca or by calling the toll-free line 1-877-782-6966. This certification requirement is the Canada-specific risk-mitigation program described in the monograph; no separate US-style REMS program applies here.
• Approved injection sites, exactly as listed in the monograph: an injection site on the abdomen (specifically between the transpyloric and transtubercular planes), the back of the upper arm, the buttock, and the thigh — four body regions in total.
• Site rotation is required: if injecting into the same body region as the last injection, a different specific site within that region must be used to avoid irritation; sites should be rotated following a set pattern, and the location of each injection recorded so that a different site is used at the next appointment.
• The chosen site must have adequate subcutaneous tissue free of nodules, lesions, or excess pigmentation, and must not be irritated, reddened, bruised, infected, or scarred; the patient should be in the supine position for the injection.
• Induction is required before the first SUBLOCADE dose in patients not already receiving buprenorphine, using one of two methods: (1) Rapid Induction — an initial dose (e.g., 4 mg) of transmucosal (sublingual) buprenorphine, with the patient observed for 1 hour to confirm tolerability before the first SUBLOCADE injection; or (2) a 7-day induction and stabilization period on transmucosal buprenorphine delivering the equivalent of 8–24 mg/day for a minimum of 7 days. Patients already maintained on 8–24 mg/day transmucosal buprenorphine may transition directly to SUBLOCADE without a separate induction period.
• Dosing schedule: for both induction methods and for direct transition, the first two SUBLOCADE injections are 300 mg each; the second 300 mg dose may be given as early as 1 week and up to 1 month after the first, based on patient need. For patients already established on long-term maintenance therapy whose symptoms are controlled on 8–18 mg/day transmucosal buprenorphine, the second dose may instead be reduced to 100 mg, unless the patient experiences craving or withdrawal symptoms after the first 300 mg dose.
• Maintenance dosing: after the first two injections, the recommended maintenance dose is 100 mg once monthly. A monthly maintenance dose of 300 mg may be considered for patients who tolerate SUBLOCADE but do not achieve a satisfactory clinical response on 100 mg — though in clinical trials, 300 mg/month maintenance did not provide additional efficacy over 100 mg/month and was associated with a higher rate of adverse events and study discontinuation.
• Maintenance doses must be administered with at least 26 days between injections.
• Preparation: remove SUBLOCADE from the refrigerator before use — it requires at least 15 minutes to reach room temperature, and the foil pouch should not be opened until the patient has arrived for the injection. Once removed from the fridge, the product may be kept in its original packaging at room temperature for up to 28 days before administration; discard it if it has been at room temperature for longer than 28 days.
• Only the TERUMO SurGuard3® safety hypodermic needle supplied with the product (19 G, 5/8-inch / 16 mm) may be used — no substitute needle is permitted — and the needle is not attached to the syringe until immediately before administration.
• Because the solution is viscous, air bubbles rise slowly: hold the syringe upright to let bubbles rise, then expel air very slowly to avoid losing medication; pinch and lift the skin at the injection site to elevate the subcutaneous tissue off the underlying muscle (preventing accidental intramuscular injection), then use a slow, steady push to deliver the entire contents of the syringe.
• After withdrawing the needle, roughly 0.1 mL of SUBLOCADE remains in the needle and syringe dead space and should be disposed of appropriately; do not rub or massage the injection site afterward, and advise the patient to be mindful of tight clothing (belts, waistbands, sleeves) that could irritate the site over the following weeks, since a palpable lump may persist for several weeks as the depot slowly shrinks.
• Only a healthcare professional may prepare and administer SUBLOCADE; universal precautions (gloves) should be observed throughout.
• Missed maintenance dose: give the next dose as soon as possible, with the following dose then given at least 26 days later; unavoidable, occasional delays of up to 2 weeks are not expected to have a clinically significant impact on treatment effect.
• If a depot must be removed for medical reasons, it can be surgically excised under local anesthesia, but only within 14 days of the injection; the removed depot must be handled with adequate security, accountability, and proper disposal, and the patient monitored for withdrawal signs afterward.
• After discontinuation, once steady-state has been reached (4–6 months of treatment), patients may have detectable plasma and urine buprenorphine levels for 12 months or longer.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Signs of acute overdose include pinpoint pupils, blue or purple lips, sedation, slow heart rate, hypotension, toxic leukoencephalopathy, delayed post-hypoxic leukoencephalopathy, respiratory depression, and death; nausea and vomiting may also occur.
• Management: carefully monitor respiratory and cardiac status; when respiratory or cardiac function is depressed, prioritize re-establishing a patent airway and provide assisted or controlled ventilation, with oxygen, IV fluids, vasopressors, and other supportive measures as indicated.
• Naloxone may be of value in managing buprenorphine overdose, but higher-than-normal doses and repeated administration may be necessary because of buprenorphine's high receptor binding affinity.
• In a patient physically dependent on opioids, naloxone administration may precipitate an acute opioid withdrawal syndrome, with severity depending on the degree of dependence and the naloxone dose given; naloxone should be administered with caution when treating serious respiratory depression in a dependent patient.
• Naloxone dosing in neonates should be especially cautious, to avoid triggering acute neonatal opioid withdrawal syndrome (NOWS), which — unlike adult withdrawal — may be life-threatening in the neonate. For any suspected overdose, contact the regional poison control centre.

• Most commonly reported treatment-related adverse reactions in the pivotal clinical trial (≥5% of subjects): constipation, nausea, vomiting, headache, fatigue, increased hepatic enzymes, and injection-site pain and pruritus (itching).
• Other injection-site reactions reported in ≥1% of subjects: erythema (redness), induration/nodule, bruising, and swelling/oedema.
• Other adverse reactions reported in ≥1% of subjects: somnolence, sedation, dizziness, lethargy, generalized pruritus, rash, and upper abdominal pain.
• Overall, 16% of SUBLOCADE-treated patients in the pivotal trial reported some form of injection-site reaction, compared with 9% on placebo; most reactions were mild to moderate in severity.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Precipitated opioid withdrawal can occur if buprenorphine (whether the transmucosal induction dose or SUBLOCADE itself) is given before clear, objective signs of opioid withdrawal are present, because buprenorphine's high receptor affinity can displace full agonists from the mu-opioid receptor.
• Serious, life-threatening, or fatal respiratory depression, particularly in combination with benzodiazepines, alcohol, or other CNS depressants, or immediately following injection and after a dose increase.
• QTc interval prolongation, which can progress to torsade de pointes, a life-threatening polymorphic ventricular arrhythmia; risk factors named in the monograph include female sex, age ≥65, baseline QTc prolongation, structural or ischemic heart disease, arrhythmia history, electrolyte disturbances, bradycardia, and concomitant QTc-prolonging drugs.
• Serious injection-site reactions have been reported post-marketing — abscess, ulceration, and necrosis — particularly associated with inadvertent intramuscular or intradermal injection; some cases required surgical depot removal, debridement, antibiotic administration, or discontinuation of SUBLOCADE.
• Hepatotoxicity: cytolytic hepatitis and hepatitis with jaundice have been reported, ranging from asymptomatic transaminase elevation to (rarely) hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy; in the pivotal trial, ALT and AST rose to ≥3× the upper limit of normal in about 4.5% (300/100 mg arm) to 7.9% (300/300 mg arm) of SUBLOCADE-treated patients versus 3% on placebo, and 1.5% of the 300/300 mg group discontinued due to hepatic injury.
• Adrenal insufficiency has been reported with opioid use, more often after more than one month of therapy, presenting with non-specific symptoms such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
• Serotonin syndrome — a rare but potentially life-threatening reaction — can occur with concomitant serotonergic drugs (certain antidepressants, triptans, tramadol, St. John's Wort, among others).
• Serious hypersensitivity reactions, including bronchospasm, angioneurotic oedema, and anaphylactic shock, have been reported with buprenorphine-containing products.
• Because SUBLOCADE is a long-acting depot with a terminal plasma half-life of 43–60 days, opioid withdrawal on discontinuation may be delayed rather than immediate — no withdrawal signs were observed in the month following discontinuation in trials — but therapeutic buprenorphine levels are expected to persist for approximately 2 to 5 months (for the 100 mg and 300 mg maintenance doses, respectively), and detectable plasma/urine levels can persist for 12 months or longer.
• Neonatal opioid withdrawal syndrome (NOWS) can occur in infants of mothers treated with SUBLOCADE during pregnancy and, unlike adult withdrawal, may be life-threatening if not recognized and treated.
• Diversion, abuse, or attempted tampering with or removal of the injection-site depot is a recognized risk because it contains buprenorphine, a Schedule I controlled substance; in vitro testing suggests it would be difficult to prepare an insufflatable or inhalable powder from SUBLOCADE or an excised depot, but buprenorphine can still be extracted from it at levels that could potentially be abused, so ongoing clinical monitoring of the injection site for signs of tampering is required throughout treatment.
• Opioids, including SUBLOCADE, can cause or worsen sleep-related breathing disorders such as sleep apnea (including central sleep apnea) and hypoxia in a dose-dependent way; new or worsening central sleep apnea may require discontinuation.

• Use with caution in patients taking benzodiazepines or other CNS depressants (including alcohol): reserve concomitant use for patients with no adequate alternative, consider dose reduction of the CNS depressant, and follow patients closely for respiratory depression and sedation.
• Use with caution in moderate hepatic impairment; severe hepatic impairment is contraindicated. Because buprenorphine levels cannot be rapidly lowered once a depot has formed, patients with pre-existing or newly developed moderate hepatic impairment should be monitored for several months for signs of toxicity or overdose, and patients who develop severe hepatic impairment during treatment should be discontinued.
• Baseline liver function tests and hepatitis B/C status should be obtained before starting SUBLOCADE, with periodic monitoring during treatment, since patients who are hepatitis-positive, on other hepatotoxic drugs, or have existing liver dysfunction are at greater risk of liver injury.
• Use with caution in debilitated patients and in those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease), CNS depression or coma, toxic psychoses, prostatic hypertrophy or urethral stricture, acute alcoholism, delirium tremens, or kyphoscoliosis.
• Use with caution in patients with compromised respiratory function (e.g., decreased respiratory reserve, hypoxia, hypercapnia) and in those with biliary tract dysfunction, since buprenorphine can increase intracholedochal pressure.
• Use with caution in renal impairment; the effect of severe renal impairment was not specifically studied with SUBLOCADE.
• SUBLOCADE should not be administered to opioid-naive patients — deaths have been reported in opioid-naive individuals who received even a single 2 mg sublingual buprenorphine tablet.
• Buprenorphine may impair the mental or physical ability to drive or operate machinery, especially in the first few days following an injection or a dose adjustment.
• Peri-operative/acute pain management: treat patients on SUBLOCADE with a non-opioid analgesic whenever possible; if opioid therapy is required, use a high-affinity full opioid analgesic under close monitoring for respiratory effects by personnel trained in anesthesia, since SUBLOCADE can blunt the analgesic effect of other opioids and higher-than-usual doses may be needed. This precaution also applies to any patient treated with SUBLOCADE within the preceding 6 months.

• Hypersensitivity to buprenorphine or to any ingredient in the formulation, including any component of the delivery system (NMP or PLGH).
• Severe respiratory insufficiency (e.g., acute or severe bronchial asthma, chronic obstructive airway disease, status asthmaticus, acute respiratory depression, or cor pulmonale).
• Severe hepatic impairment.
• Acute alcoholism or delirium tremens.
• Known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any disease/condition affecting bowel transit (e.g., ileus of any type).
• Suspected surgical abdomen (e.g., acute appendicitis or pancreatitis), or severe CNS depression, increased cerebrospinal or intracranial pressure, or head injury.
• Concomitant use of, or use within 14 days of, monoamine oxidase (MAO) inhibitor therapy.
• Convulsive or seizure disorders.
• Congenital Long QT Syndrome or baseline QT interval prolongation.
• Uncorrected hypokalemia, hypomagnesemia, or hypocalcemia.

• Benzodiazepines: a serious interaction — post-marketing reports describe coma and death with combined use, often related to misuse or self-injection; monitor patients closely and warn them never to self-administer benzodiazepines beyond their healthcare professional's direction.
• Other CNS depressants (other opioids, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, gabapentin, pregabalin, baclofen, centrally-acting antiemetics, and alcohol): additive risk of hypotension, respiratory depression, profound sedation, coma, and death; reserve concomitant use for patients with no adequate alternative and limit dose/duration.
• Monoamine oxidase inhibitors (MAOIs): contraindicated concomitantly and within 14 days of stopping an MAOI, due to risk of serotonin syndrome or opioid toxicity (including respiratory depression and coma).
• QTc interval-prolonging drugs should be avoided in combination, including Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide), Class IC antiarrhythmics (e.g., flecainide, propafenone), Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone), certain antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, ziprasidone, risperidone), certain antidepressants (e.g., fluoxetine, citalopram, tricyclic/tetracyclic agents), methadone, macrolide antibiotics (e.g., erythromycin, clarithromycin, azithromycin), certain quinolone antibiotics, azole antifungals, ondansetron, and several other classes named in the monograph — combined use raises the risk of torsade de pointes.
• Drugs that disrupt electrolyte levels (loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high-dose corticosteroids; proton pump inhibitors) should be avoided in combination, since electrolyte disturbances compound QTc-prolongation risk.
• Naltrexone (an opioid antagonist) can precipitate sudden, prolonged, and intense opioid withdrawal in a patient currently on SUBLOCADE, or block the intended therapeutic effect of SUBLOCADE in a patient currently on naltrexone.
• CYP3A4 inhibitors (e.g., macrolide antibiotics such as erythromycin, azole antifungals such as ketoconazole, protease inhibitors such as ritonavir): established to increase buprenorphine exposure with sublingual buprenorphine via reduced first-pass metabolism; this specific interaction has not been directly studied for subcutaneous SUBLOCADE (which bypasses first-pass metabolism), but monitor patients for respiratory depression and sedation as a precaution.
• CYP3A4 inducers (rifampin, carbamazepine, phenytoin, phenobarbital) may increase buprenorphine clearance, risking reduced plasma concentrations, lack of efficacy, or an abstinence (withdrawal) syndrome; monitor patients starting or stopping these drugs for withdrawal signs.
• Serotonergic drugs (SSRIs, SNRIs, tricyclic antidepressants, triptans, 5-HT3 receptor antagonists, mirtazapine, trazodone, tramadol, lithium, St. John's Wort, and tapentadol) carry a risk of serotonin syndrome; monitor closely, particularly during treatment initiation or dose adjustment of the serotonergic drug.
• Diuretics: opioids can reduce diuretic efficacy by inducing antidiuretic hormone release; monitor for diminished diuretic effect and blood pressure changes.
• Anticholinergic drugs: concomitant use may increase the risk of urinary retention and/or severe constipation, which can progress to paralytic ileus.
• Antiretrovirals — non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz, nevirapine, etravirine, and delavirdine: significant pharmacokinetic interactions with buprenorphine have been shown via CYP3A4 effects, though without significant pharmacodynamic consequences in studies to date; exercise caution and use therapeutic monitoring.

• The monograph explicitly states that interactions with food have not been studied for SUBLOCADE.
• The Canadian patient medication information nonetheless lists grapefruit juice among substances that "may also interact" with SUBLOCADE, consistent with its known effect on other CYP3A4-metabolized drugs; patients should mention regular grapefruit juice consumption to their healthcare professional.
• Alcohol is addressed by the monograph as a drug (not food) interaction (see Drug interactions), but remains one of the most clinically important substances to avoid: co-ingestion can cause dangerously additive sedation, respiratory depression, and death, and should be avoided throughout treatment.

• SUBLOCADE is not a patient-timed, self-administered medication — because it is given by a healthcare professional as a scheduled monthly injection, there is no daily "time of day" for the patient to take it.
• The two starting doses (300 mg each) are separated by 1 week to 1 month, based on patient need; each subsequent maintenance dose must then be given at least 26 days after the previous one.
• The monograph specifies no requirement to give the injection with or without food or at a particular time of day, and it explicitly states that food interactions have not been studied.

• Store refrigerated at 2–8°C (35.6–46.4°F) prior to use.
• Once removed from the refrigerator, SUBLOCADE may be kept in its original packaging at room temperature (15–30°C / 59–86°F) for up to 28 days before administration; discard it if it has been at room temperature for longer than 28 days.
• The foil pouch should not be opened until the patient has arrived for the injection, and the product needs at least 15 minutes outside the refrigerator to reach room temperature before it is injected.
• After use, all syringe/needle components must be disposed of in a secure sharps disposal container per facility procedure, with adequate security and accountability maintained throughout handling and storage, reflecting its status as a controlled substance.

• SUBLOCADE is a once-monthly injection for opioid use disorder given only by a trained, certified healthcare professional — it is never handed to you to take home or inject yourself.
• It must only ever be injected just under the skin (subcutaneously); tell your healthcare team right away if anything about the injection technique seems off, since being injected the wrong way (into a vein or muscle) could cause serious harm.
• Before your first SUBLOCADE injection, you must complete an induction period on sublingual (under-the-tongue) buprenorphine and show clear signs of tolerating it and being in withdrawal from other opioids.
• Expect a small lump (the depot) under the skin at the injection site for several weeks after each dose — this is expected and will gradually shrink; do not rub or massage it, and watch for tight clothing that could irritate the area.
• Never combine SUBLOCADE with alcohol, benzodiazepines, or other sedating medications without your prescriber's explicit direction — this combination can cause fatal breathing problems.
• Because SUBLOCADE releases buprenorphine slowly over weeks to months, its effects — including any withdrawal symptoms if treatment is stopped — can be delayed rather than immediate; always work with your healthcare professional before stopping or changing treatment, and keep every monthly appointment since maintenance doses must stay at least 26 days apart.