Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SUBLOCADE (NDA-209819)

(BUPRENORPHINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/22/2025 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Additions and/or revisions underlined:

…

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with SUBLOCADE. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.2)].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of an opioid overdose reversal agent may be necessary due to the long duration of action of buprenorphine and its affinity for the mu-opioid receptor [see Overdosage (10)].

Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered.

5.5 Managing Risks From Concomitant Use of Benzodiazepines or Other CNS Depressants with Buprenorphine

Additions and/or revisions underlined:

Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) 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.

…

If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on 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)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.

7 Drug Interactions

Changes to Table 5: Clinically Significant Drug Interactions; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Labor or Delivery

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 overdose reversal agent, such as naloxone or nalmefene, should be available for reversal of opioid induced respiratory depression in the neonate.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about SUBLOCADE?

…

Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse opioid overdose. If naloxone or nalmefene is given, you must call 911 or get emergency medical help right away to treat overdose or accidental use of an opioid.

…

Do not take SUBLOCADE with certain medicines. Taking SUBLOCADE with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

…

What are the possible side effects of SUBLOCADE? SUBLOCADE can cause serious side effects, including:

Trouble breathing. Taking SUBLOCADE with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause breathing problems that can lead to coma and death.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide). SUBLOCADE Risk Evaluation and Mitigation Strategy (REMS)

Advise patients that because of the risk of serious harm or death due to intravenous self-administration, SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program.

Healthcare settings and pharmacies are certified and only dispense SUBLOCADE directly to a healthcare provider for administration by healthcare providers [see Warnings and Precautions (5.2)].

Life Threatening Respiratory DepressionEducate 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 Warnings and Precautions 5.4)].

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to an opioid overdose reversal agent. Also discuss the importance of having access to an opioid overdose reversal agent if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter (some products), or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

There are important differences among the opioid overdose reversal agents. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered. Repeat administration may be necessary, particularly for overdose involving buprenorphine [see Dosage and Administration (2.2), Warnings and Precautions (5.4), Overdosage (10)].

Advise patients and caregivers:

how to treat with an opioid overdose reversal agent in the event of an opioid overdose
to tell family and friends about their opioid overdose reversal agent, and to keep it in a place where family and friends can easily access it in an emergency
to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do

Interaction With Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if SUBLOCADE is used with benzodiazepines or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4, 5.5), Drug Interactions (7)].

…

02/21/2025 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Precipitation of Opioid Withdrawal in Patients Dependent on Full Agonist Opioids

Additions and revisions underlined:

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 if administered before the effects of the full opioid agonist have subsided, at least 6 hours for short-acting opioids (e.g., heroin, morphine) and 24 hours for long-acting opioids (e.g., methadone).

Verify that patients have tolerated transmucosal buprenorphine before administering the first injection of SUBLOCADE.

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Rapid Induction study

The proportion of patients who experienced an adverse event associated with opioid withdrawal was 31.4% in patients who received SUBLOCADE injection after an initial dose of transmucosal buprenorphine (rapid induction) and 25.1% in those who first received transmucosal buprenorphine for at least 7 days (standard induction). Three fentanyl positive patients in the rapid induction arm had serious adverse events associated with opioid withdrawal, and none in the standard induction arm.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

You may have detectable levels of SUBLOCADE in your body for several months after stopping treatment with

. . .

SUBLOCADE is a prescription medicine used to treat adults with moderate to severe addiction (dependence) to opioid

drugs (prescription or illegal) who:

have started treatment with a single dose of a buprenorphine medicine in the form of a sublingual tablet or buccal

film (transmucosal) or

are already being treated with buprenorphine.

SUBLOCADE is part of a complete treatment plan that should include counseling and psychosocial support.

. . .

Talk with your healthcare provider before starting any new medicines

during or after stopping treatment with SUBLOCADE.

. . .

If you are not currently receiving buprenorphine treatment, your healthcare provider will give you a test dose of

buprenorphine first to see if you are able to tolerate it, before switching to SUBLOCADE.

. . .

Try not to let any restrictive clothing such as belts, waistbands, or sleeves rub against the injection site.

. . .

SUBLOCADE can cause serious side effects, including:

Trouble breathing. Taking SUBLOCADE with other opioid medicines, benzodiazepines, alcohol, or other central

nervous system depressants can cause breathing problems that can lead to coma and death.

Sleepiness, dizziness, and problems with coordination.
Physical dependence or abuse.

. . .

Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, light-headedness, feeling faint or

loss of consciousness.

12/15/2023 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information:

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

08/23/2022 (SUPPL-10)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

…

Animal Data

…

In a pre- and postnatal development study in rats, SUBLOCADE was administered subcutaneously to pregnant animals once during implantation (on GD 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 15 times the MRHD on an AUC basis).

06/17/2022 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.16 QTc Prolongation

Section title revised

Additions and revisions underlined:

Thorough QT studies with buprenorphine products have demonstrated QT prolongation < or equal to 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, 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 in clinical decisions 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.

06/17/2021 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Risk of Serious Injection Site Reactions

Additions and/or revisions underlined:

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 …

03/04/2021 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risk of Serious Harm or Death with Intravenous Administration

Additions and/or revisions underlined:

… 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)].

5.4 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Additions and/or revisions underlined:

… 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)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

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)].

5.5 Managing Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants With Buprenorphine

Additions and/or revisions underlined:

… 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, 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)].

Newly added subsection:

5.6 Risk of Serious Injection Site Reactions

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

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)].

Muscle Relaxants

Under Intervention, the following language is added:

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)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What is the most important information I should know about SUBLOCADE?

Additions and/or revisions underlined:

SUBLOCADE contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs. Call your healthcare provider right away or get emergency help if you:

Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose. If naloxone is given, you must call 911 or get emergency medical help right away to treat overdose or accidental use of an opioid.

Additions and/or revisions underlined:

Do not take certain medicines during treatment with SUBLOCADE. Taking other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) while on SUBLOCADE can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBLOCADE.
You may have detectable levels of SUBLOCADE in your body for a long period after stopping treatment with SUBLOCADE.

What are the possible side effects of SUBLOCADE?

SUBLOCADE can cause serious side effects, including:

Additions and/or revisions underlined:

Trouble breathing. Taking other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants during treatment with SUBLOCADE can cause breathing problems that can lead to coma and death.
Sleepiness, dizziness, and problems with coordination.
Opioid withdrawal.
SUBLOCADE may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects of SUBLOCADE.

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Inform patients and caregivers of the 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 the signs and symptoms of an opioid overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving buprenorphine, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.4), Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

How to treat with naloxone in the event of an opioid overdose
To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.4 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Newly added information to the end of this subsection:

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.

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions

Serotonergic Drugs

Additions and/or revisions underlined:

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect 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).