Source: FDA, National Drug Code (US) Revision Year: 2021
SUBLOCADE should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of the ATRIGEL delivery system [see Warnings and Precautions (5.11)].
Intravenous injection presents significant risk of serious harm or death as SUBLOCADE forms a solid mass upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, could result if administered intravenously [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.2)]. Do not administer intravenously, intramuscularly, or intradermally [see Warnings and Precautions (5.6)].
SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program because of the risk of serious harm or death that could result from intravenous self-administration. The goal of the REMS is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense SUBLOCADE directly to a healthcare provider for administration by a healthcare provider.
Notable requirements of the SUBLOCADE REMS Program include the following:
Further information is available at www.SublocadeREMS.com or call 1-866-258-3905.
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 all patients for progression of opioid use disorder and addictive behaviors [see Drug Abuse and Dependence (9.2)].
Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBLOCADE [see Warnings and Precautions (5.5), Drug Interactions (7), Patient Counseling Information (17)].
Use SUBLOCADE 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).
Due to its extended-release characteristics, if SUBLOCADE is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for several months.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.9)].
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.
Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBLOCADE. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.3)].
Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu-opioid receptor [see Overdosage (10)].
Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).
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 medical help, even if naloxone is administered [see Patient Counseling Information (17)].
Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose, respiratory depression, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.
As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.
Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.
Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use with buprenorphine. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.
For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.
If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.4)].
In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions (7)].
Injection site reactions are most commonly manifested by pain, erythema and pruritis. In some post-marketing case reports injection site reactions have involved 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 be increased with inadvertent intramuscular or intradermal administration. Carefully review injection technique [see Instructions for Use (2.7)]. Evaluate and treat serious injection site reactions as appropriate.
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations (8.1)].
Advise pregnant women receiving opioid addiction treatment with SUBLOCADE of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)]. This risk should be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance of management of opioid addiction throughout pregnancy.
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation. The withdrawal syndrome is milder than that seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence (9.3)].
Withdrawal signs and symptoms were not observed in the month following discontinuation of SUBLOCADE. Considering the long half-life, any withdrawal signs and symptoms that may occur would be expected to be delayed [see Clinical Pharmacology (12.2)]. Model simulations indicate that steady-state buprenorphine plasma concentrations decreased slowly over time following the last injection and remained at therapeutic levels for 2 to 5 months on average, depending on the dosage administered (100 or 300 mg, respectively).
Patients who elect to discontinue treatment with SUBLOCADE should be monitored for withdrawal signs and symptoms. Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing SUBLOCADE.
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through postmarketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases, however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. In one subject in the SUBLOCADE clinical program, surgical removal was followed by improvement in liver enzymes.
Liver function tests, prior to initiation of treatment, are recommended to establish a baseline. Monthly monitoring of liver function during treatment, particularly with 300 mg maintenance dose, is also recommended. An etiological evaluation is recommended when a hepatic adverse event is suspected.
Cases of hypersensitivity to buprenorphine-containing products have been reported both in clinical trials and in the postmarketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine is a contraindication to the use of SUBLOCADE [see Contraindications (4)].
Because of the partial opioid agonist properties of buprenorphine, 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.
While on SUBLOCADE, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving SUBLOCADE with a non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy should be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.
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 [see Patient Counseling Information (17)].
The above guidance should also be considered for any patient who has been treated with SUBLOCADE within the last 6 months.
There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. SUBLOCADE is not appropriate for use in opioid naïve patients.
In a pharmacokinetic study with transmucosal buprenorphine, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of SUBLOCADE has not been studied.
Because of the long-acting nature of the product, adjustments to dosages of SUBLOCADE are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly decreased, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with SUBLOCADE.
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 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Buprenorphine has been observed to prolong the QTc interval in some patients participating in clinical trials. Consider these observations in clinical decisions when prescribing buprenorphine to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Periodic electrocardiographic (ECG) monitoring is recommended in these patients. Avoid the 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 [see Clinical Pharmacology (12.2)].
SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery especially during the first few days following treatment and dose adjustment. Buprenorphine plasma levels accumulate during the first two months and are maintained with the 100 mg maintenance dose; further accumulation occurs with the 300 mg maintenance dose, which achieves steady-state after the fourth monthly injection. 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.
Buprenorphine may produce orthostatic hypotension in ambulatory patients.
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.
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.
Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.
The following adverse reactions are discussed in more detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of SUBLOCADE was evaluated in 848 opioid-dependent subjects (see Table 1). In these studies, there was a total of 557 subjects who received at least 6 monthly SC injections of SUBLOCADE and 138 subjects who received 12 monthly SC injections. Adverse events led to premature discontinuation in 4% of the group receiving SUBLOCADE compared with 2% in the placebo group (13-0001, NCT02357901).
In the Phase 3 open-label study (13-0003, NCT02510014), adverse events leading to drug dose reductions were reported in 7.3% of subjects receiving SUBLOCADE.
Table 1. Total Subjects Exposed to SUBLOCADE:
| Study 13-0001 (NCT02357901) Up to 6 Injections | Study 13-0003 (NCT02510014) | Total Subjects Exposed To SUBLOCADE | |||||
|---|---|---|---|---|---|---|---|
| Roll-Over Up to 6 Injections | De-Novo Up to 12 Injections | ||||||
| SUBLOCADE 300/100 mg | SUBLOCADE 300/300 mg | Placebo | From SUBLOCADE 300/100 mg To SUBLOCADE 300/Flex† | From SUBLOCADE 300/300 mg To SUBLOCADE 300/Flex† | From Placebo To SUBLOCADE 300/Flex† | SUBLOCADE 300/Flex | |
| N=203 | N=201 | N=100* | N=112‡ | N=113‡ | N= 32 | N=412 | N=848 |
* Not included in total subjects exposed to SUBLOCADE
† FLEX = 300 mg initial dose with an option to receive either 100 mg or 300 mg for subsequent dosing per clinician’s discretion
‡ = Not included in total unique subjects exposed to SUBLOCADE, already accounted for in Study 13-0001 section of table
Table 2 shows the non-injection site-related adverse reactions (ADRs) for the groups receiving SUBLOCADE 300/300 mg (6 doses of 300 mg SC injections) 300/100 mg (300 mg SC injections for the first two doses followed by 4 doses of 100 mg SC injections) and placebo (volume-matched ATRIGEL delivery system subcutaneous injections) reported following administration in the 6 month, double-blind, placebo-controlled study. The systemic safety profile for SUBLOCADE, given by a healthcare provider in clinical trials, was consistent with the known safety profile of transmucosal buprenorphine. Common adverse reactions associated with buprenorphine included constipation, nausea, vomiting, abnormal liver enzymes, headache, sedation and somnolence. Dose dependent hepatic effects observed in the Phase 3, double-blind study (13-0001, NCT02357901) included the incidence of ALT more than 3 times the upper limit of normal (>3 × ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300/300-mg, SUBLOCADE 300/100-mg, and placebo groups, respectively. The incidence of AST >3 × ULN was 11.4%, 7.9%, and 1.0%, respectively. Adverse drug reactions [by MedDRA Preferred Terms (PT)] reported in at least 2% of subjects receiving SUBLOCADE are grouped by System Organ Class (SOC).
Table 2. Adverse Reactions for Phase 3 Double-Blind Study: ≥2% of Subjects Receiving SUBLOCADE:
| System Organ Class Preferred Term | PLACEBO | SUBLOCADE 300/100 mg | SUBLOCADE 300/300 mg |
|---|---|---|---|
| Count (%) | Count (%) | Count (%) | |
| Total | N=100 | N=203 | N=201 |
| Gastrointestinal disorders | 12 (12%) | 51 (25.1%) | 45 (22.4%) |
| Constipation | 0 | 19 (9.4) | 16 (8) |
| Nausea | 5 (5) | 18 (8.9) | 16 (8) |
| Vomiting | 4 (4) | 19 (9.4) | 11 (5.5) |
| General disorders and administration site conditions | 17 (17%) | 40 (19.7%) | 49 (24.4%) |
| Fatigue | 3 (3) | 8 (3.9) | 12 (6) |
| Investigations* | 2 (2%) | 21 (10.3%) | 19 (9.5%) |
| Alanine aminotransferase increased (ALT) | 0 | 2 (1) | 10 (5) |
| Aspartate aminotransferase increased (AST) | 0 | 7 (3.4) | 9 (4.5) |
| Blood creatine phosphokinase increased (CPK) | 1 (1) | 11 (5.4) | 5 (2.5) |
| Gamma-glutamyl transferase increased (GGT) | 1 (1) | 6 (3) | 8 (4) |
| Nervous system disorders | 7 (7%) | 35 (17.2%) | 25 (12.4%) |
| Headache | 6 (6) | 19 (9.4) | 17 (8.5) |
| Sedation | 0 | 7 (3.4) | 3 (1.5) |
| Dizziness | 2 (2) | 5 (2.5) | 3 (1.5) |
| Somnolence | 0 | 10 (4.9) | 4 (2) |
* There were no cases of serious liver injury attributed to study drug.
Table 3 shows the injection site-related adverse events reported by ≥2 subjects in the Phase 3 studies. Most injection site adverse drug reactions (ADRs) were of mild to moderate severity, with one report of severe injection site pruritus. None of the injection site reactions were serious. One reaction, an injection site ulcer, led to study treatment discontinuation.
Table 3. Injection Site Adverse Drug Reactions Reported by ≥2 Subjects in the Phase 3 Studies:
| Preferred term, n (%) | 13-0001 (Ph3DB) | 13-0003 (Ph3OL) | All Phase 3* | |||||
|---|---|---|---|---|---|---|---|---|
| Roll–over | De-novo | |||||||
| SUBLOCADE 300/300 (N=201) | SUBLOCADE 300/100 (N=203) | Placebo (N=100) | SUBLOCADE 300 → SUBLOCADE 300/Flex (N=113) | SUBLOCADE 100 → SUBLOCADE 300/Flex (N=112) | Placebo → SUBLOCADE 300/Flex (N=32) | SUBLOCADE 300/Flex (N=412) | Total SUBLOCADE (N=848) | |
| Subjects with any injection site reactions | 38 (18.9%) | 28 (13.8%) | 9 (9.0%) | 6 (5.3%) | 13 (11.6%) | 2 (6.3%) | 61 (14.8%) | 140 (16.5%) |
| Injection site pain | 12 (6.0%) | 10 (4.9%) | 3 (3.0%) | 4 (3.5%) | 2 (1.8%) | 2 (6.3%) | 33 (8.0%) | 61 (7.2%) |
| Injection site pruritus | 19 (9.5%) | 13 (6.4%) | 4 (4.0%) | 2 (1.8%) | 6 (5.4%) | 1 (3.1%) | 17 (4.1%) | 56 (6.6%) |
| Injection site erythema | 6 (3.0%) | 9 (4.4%) | 0 | 1 (0.9%) | 4 (3.6%) | 0 | 21 (5.1%) | 40 (4.7%) |
| Injection site induration | 2 (1.0%) | 2 (1.0%) | 0 | 0 | 1 (0.9%) | 0 | 7 (1.7%) | 12 (1.4%) |
| Injection site bruising | 2 (1.0%) | 2 (1.0%) | 0 | 0 | 0 | 0 | 2 (0.5%) | 6 (0.7%) |
| Injection site swelling | 1 (0.5%) | 2 (1.0%) | 0 | 1 (0.9%) | 1 (0.9%) | 0 | 1 (0.2%) | 6 (0.7%) |
| Injection site discomfort | 1 (0.5%) | 1 (0.5%) | 0 | 0 | 0 | 0 | 3 (0.7%) | 5 (0.6%) |
| Injection site reaction | 1 (0.5%) | 0 | 0 | 0 | 3 (2.7%) | 0 | 1 (0.2%) | 5 (0.6%) |
| Injection site cellulitis | 0 | 1 (0.5%) | 0 | 0 | 0 | 0 | 2 (0.5%) | 3 (0.4%) |
| Injection site infection | 1 (0.5%) | 0 | 1 (1.0%) | 0 | 0 | 0 | 2 (0.5%) | 3 (0.4%) |
* Patients received SUBOXONE film for a run-in period before they switched to SUBLOCADE injection.
In an interim analysis of the ongoing open-label long-term safety study (13-0003), safety was evaluated for up to 12 injections over the course of a year (see Table 1). Adverse events were reported for 432 of 669 subjects during the treatment period. The overall adverse event profile was similar to the double-blind trial described above.
The most frequently reported systemic postmarketing adverse event observed with buprenorphine sublingual tablets was drug misuse or abuse. The most frequently reported systemic postmarketing adverse event with buprenorphine/naloxone sublingual tablets and film was peripheral edema.
The following adverse reactions have been identified during post-approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SUBLOCADE.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].
Table 4 includes clinically significant drug interactions with SUBLOCADE.
Table 4. Clinically Significant Drug Interactions:
| Benzodiazepines and Other Central Nervous System (CNS) Depressants | |
|---|---|
| Clinical Impact: | Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. |
| Intervention: | Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions (5.4, 5.5)]. If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.4)]. |
| Examples: | Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids. |
| Inhibitors of CYP3A4 | |
| Clinical Impact: | The effects of co-administered CYP3A4 inhibitors on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied and the effects may be dependent on the route of administration; however, such interactions have been established in studies using transmucosal buprenorphine. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. The concomitant use of sublingual buprenorphine and CYP3A4 inhibitors (e.g., ketoconazole) can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects. |
| Intervention: | Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors [e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)] should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inhibitors, the patients should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, it may be necessary to remove the depot and treat the patient with a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inhibitor, and the concomitant medication is discontinued, the patient should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. |
| Examples: | Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) |
| CYP3A4 Inducers | |
| Clinical Impact: | The effects of co-administered CYP3A4 inducers on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. CYP3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome. |
| Intervention: | Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inducers, the patients should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inducer, and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if the dose provided by SUBLOCADE is excessive in the absence of the concomitant inducer, it may be necessary to remove the SUBLOCADE and treat the patient with a formulation of buprenorphine that permits dose adjustments [see Clinical Pharmacology (12.3)]. |
| Examples: | Rifampin, carbamazepine, phenytoin, phenobarbital |
| Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) | |
| Clinical Impact: | Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and sublingual buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. |
| Intervention: | Patients who are on chronic treatment with SUBLOCADE should be monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen. |
| Examples: | Efavirenz, nevirapine, etravirine, delavirdine |
| Antiretrovirals: Protease inhibitors (PIs) | |
| Clinical Impact: | Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on sublingual buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine after sublingual administration, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly. |
| Intervention: | If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with SUBLOCADE, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to remove the depot and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments. |
| Examples: | Atazanavir, ritonavir |
| Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) | |
| Clinical Impact: | Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. |
| Intervention: | None |
| Serotonergic Drugs | |
| Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
| Intervention: | If concomitant use is warranted, carefully monitor the patient for signs and symptoms of serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug. |
| Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
| Monoamine Oxidase Inhibitors (MAOIs) | |
| Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). |
| Intervention: | The use of SUBLOCADE is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
| Examples: | Phenelzine, tranylcypromine, linezolid |
| Muscle Relaxants | |
| Clinical Impact: | Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| Intervention: | Monitor patients receiving muscle relaxants and SUBLOCADE for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3), Warnings and Precautions (5.4, 5.5)]. |
| Diuretics | |
| Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
| Intervention: | Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
| Anticholinergic Drugs | |
| Clinical Impact: | The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
| Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when SUBLOCADE is used concomitantly with anticholinergic drugs. |
The data on use of buprenorphine, the active ingredient in SUBLOCADE, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see Human Data].
Observational studies have reported congenital malformations among buprenorphine‐exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see Human Data].
In published animal reproduction studies with NMP, an excipient in SUBLOCADE, preimplantation losses, delayed ossification, reduced fetal weight, developmental delays and reduced cognitive function were reported at doses equivalent to the doses of NMP via SUBLOCADE. Decreased pup survival at 2 times the dose of NMP and malformation and postimplantation losses were reported at 3 times the dose of NMP via SUBLOCADE. In animal reproduction studies with SUBLOCADE, SUBLOCADE administered subcutaneously to pregnant rats and rabbits during the period of organogenesis at a buprenorphine dose equivalent to 38 and 15 times, respectively, the maximum recommended human dose (MRHD) of 300 mg caused embryolethality, which appeared to be attributable primarily to the SUBLOCADE vehicle. In addition, reduced fetal body weights, increased visceral malformations and skeletal malformations were observed in rats and rabbits at a buprenorphine dose equivalent to 38 and 15 times, respectively, the MRHD. These effects were also observed with the SUBLOCADE vehicle alone, but the skeletal and visceral malformations in rat appear at least partially attributable to buprenorphine [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
SUBLOCADE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.
Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with SUBLOCADE.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.7)].
Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Pregnancy in an opioid dependent woman poses challenges to treating physicians and potential hazards for the fetus including control of illicit drug, nicotine and alcohol use, infections, premature birth, abortion, low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress, meconium aspiration, narcotic withdrawal, postnatal growth deficiency, microcephaly, (neuro-) developmental disorders and increased neonatal mortality.
A multicenter, double-blind, double-dummy, flexible-dose study in 175 pregnant women [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] was conducted to study outcomes in neonates born to mothers using methadone or buprenorphine, including the number of neonates requiring treatment for NOWS, the Peak NOWS score, the total amount of morphine needed to treat NOWS, the length of hospital stay for neonates, and neonatal head circumference. The authors found that 18% of pregnant women in the methadone group and 33% in the buprenorphine group discontinued treatment over the course of the pregnancy. They reported no significant difference in the incidence of NOWS, but in the prenatally buprenorphine-exposed condition, the duration of treatment for NOWS was shorter, duration of hospital stays were shorter and the amount of morphine required was significantly less; however, methodological concerns limit the conclusions that may be made.
Preimplantation losses, delayed ossification and reduced fetal body weights were reported in published studies following treatment of pregnant rats during organogenesis with NMP, an excipient in SUBLOCADE, via inhalation at approximately equivalent doses of NMP delivered by SUBLOCADE. Fetal malformations and resorptions have also been reported following oral administration of 3 times the MDD of NMP delivered by SUBLOCADE at the MDD based on a body surface area comparison.
Post-implantation loss and increased cardiovascular and skull malformations were demonstrated in pregnant rabbits administered oral NMP, an excipient in SUBLOCADE, at doses 3.2 times the human MDD of NMP via SUBLOCADE in the absence of maternal toxicity. No adverse effects were reported at an oral dose equivalent to the MDD via SUBLOCADE based on a body surface area comparison.
Decreased pup survival was noted following oral treatment of pregnant rats prior to and during gestation and lactation with NMP, an excipient in SUBLOCADE at doses 1.8 times the MDD. Developmental delays and impaired cognitive function were reported in pups born to pregnant rats treated with NMP via inhalation during gestation at doses equivalent to the MDD of NMP via SUBLOCADE based on a body surface area comparison.
In an embryofetal development study in rats, SUBLOCADE administered subcutaneously to pregnant animals before mating and again on GD 7 during the period of organogenesis resulted in increased post-implantation loss, which correlated with higher mean number of resorptions and decreased number of viable fetuses per litter, and decreased mean fetal body weights at 900 mg/kg (approximately 38 times the maximum recommended human dose [MRHD] of 300 mg of SUBLOCADE on an AUC basis); however, similar effects were observed with an equivalent level of ATRIGEL delivery system alone, indicating they may be attributable to the vehicle. Dose-related increases in incidences of skeletal malformations of the head and visceral malformations were observed with SUBLOCADE with significant changes at 900 mg/kg (approximately 38 times the MRHD on an AUC basis). Although similar effects were observed with equivalent levels of ATRIGEL delivery system, the incidence of skeletal malformations, primarily skull malformations, was higher in the SUBLOCADE groups suggesting that buprenorphine contributed to the increased incidence. Based on these results, the NOAEL for developmental toxicity was 300 mg/kg (approximately 15 times the MRHD on an AUC basis).
In an embryofetal development study in rabbits, administration of a single subcutaneous injection of SUBLOCADE to pregnant animals on Gestation Day 7 during the period of organogenesis resulted an increased litter incidence of skeletal malformations at 155 mg/kg (approximately 7 times the MRHD on an AUC basis), which appear to be buprenorphine-related adverse effects. There was also an increased litter incidence of external malformations, visceral, and skeletal malformations and variations at 390 mg/kg SUBLOCADE (approximately 15 times the MRHD on an AUC basis); however, similar effects were observed with an equivalent level of the ATRIGEL delivery system, indicating they may be attributable to the vehicle. In addition, increased post-implantation loss, which correlated with increased mean number of resorptions and decreased mean number of viable fetuses, and decreased fetal body weights were observed at 390 mg/kg (approximately 15 times the MRHD on an AUC basis); however, similar findings were also observed with an equivalent level of the ATRIGEL delivery system alone. Based on these results, the NOAEL for developmental toxicity for SUBLOCADE was 78 mg/kg (approximately 3 times the MRHD on an AUC basis).
In a pre- and postnatal development study in rats, SUBLOCADE was administered subcutaneously to pregnant animals once during implantation (on Gestation Day 7) and once during weaning (on Lactation Day 7). There were no adverse effects on offspring survival, sexual maturation, behavioral assessment, or reproductive performance at up to 300 mg/kg (approximately 10 times the MRHD on an mg/m² basis).
Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine. Available data have not shown adverse reactions in breastfed infants. Caution should be exercised when SUBLOCADE is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SUBLOCADE and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.
Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.
In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).
Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].
Male: Male fertility may be reduced based on animal data demonstrating adverse effects of SUBLOCADE on sperm parameters [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of SUBLOCADE have not been established in pediatric patients.
Clinical studies of SUBLOCADE did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between geriatric and younger patients.
Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe SUBLOCADE should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.
Clinical studies of SUBLOCADE did not include subjects with renal impairment. No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.
The effect of hepatic impairment on the pharmacokinetics of SUBLOCADE has not been studied.
The effect of hepatic impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated in a pharmacokinetic study. While no clinically significant changes have been observed in subjects with mild hepatic impairment, the plasma levels have been shown to be higher and half-life values have been shown to be longer for buprenorphine in subjects with moderate and severe hepatic impairment.
Because of the long-acting nature of the product, adjustments to dosages of SUBLOCADE are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly adjusted, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with SUBLOCADE.
Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. If signs and symptoms of toxicity or overdose occur within 2 weeks of SUBLOCADE administration, removal of the depot may be required [see Dosage and Administration (2.9), Warnings and Precautions (5.10), Clinical Pharmacology (12.3)].
SUBLOCADE contains buprenorphine, a Schedule III substance under the Controlled Substances Act.
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to healthcare providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.
SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused similar to other opioids. Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.
SUBLOCADE is distributed through a restricted distribution system, which is intended to prevent the direct distribution to a patient. SUBLOCADE should only be dispensed directly to a healthcare provider for administration by a healthcare provider. It is supplied in prefilled syringes and is intended for administration only by subcutaneous injection by a healthcare provider. The entire contents of the prefilled syringe should be administered. After administration, a small amount (approximately 0.1 mL) of SUBLOCADE will remain in the needle and syringe and should be properly disposed of [see How Supplied/Storage and Handling (16)].
SUBLOCADE is injected as a liquid, and the subsequent precipitation of the poly (DL-lactide-co-glycolide) polymer creates a solid depot which contains buprenorphine. After initial formation of the depot, buprenorphine is released via diffusion from, and the biodegradation of, the depot. Clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. No accounts of subjects removing or attempting to remove the depot after administration of SUBLOCADE were reported in premarketing studies.
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Warnings and Precautions (5.12)].
Due to the long-acting nature of SUBLOCADE, withdrawal signs and symptoms may not be evident immediately following the discontinuation of treatment.
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.7)].
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