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.

CONTRAVE (NDA-200063)

(BUPROPION HYDROCHLORIDE; NALTREXONE HYDROCHLORIDE)

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

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11/05/2025 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Suicidal Behavior and Ideation

Additions and/or revisions underlined:

…

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin re-uptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older. CONTRAVE is not approved for use in pediatric patients.

…

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of CONTRAVE, naltrexone, or bupropion. 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.

…

Acute generalized exanthematous pustulosis (AGEP)
Aseptic meningitis

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is CONTRAVE?

CONTRAVE is a prescription medicine which contains 2 medicines (naltrexone and bupropion) that may help adults with obesity, or some adults with overweight who also have weight-related medical problems, to lose excess body weight and keep the weight off.

CONTRAVE should be used with a reduced calorie-diet and increased physical activity.

It is not known if CONTRAVE changes your risk of heart problems or stroke or of death due to heart problems or stroke.

It is not known if CONTRAVE is safe and effective in children under 18 years of age.

CONTRAVE contains naltrexone and bupropion and should not be used with other products that contain naltrexone or bupropion. Bupropion is the same ingredient in some other medicines used to treat depression and to help people quit smoking. CONTRAVE is not approved to treat depression or other mental illnesses, or to help people quit smoking (smoking cessation)

…

05/07/2024 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and or revisions underlined:

…

Drug reaction with eosinophilia and systemic symptoms (DRESS)

11/30/2023 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of CONTRAVE. 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.

Loss of consciousness, malaise
Brugada pattern/syndrome

08/04/2020 (SUPPL-15)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; extensive revision-please refer to labeling)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Risk Summary

Data from published literature report the presence of bupropion and its metabolites in human milk. Limited data from postmarketing reports with bupropion use during lactation have not identified a clear association of adverse effects on a breastfed infant (see Data). Naltrexone and its major metabolite, 6?-naltrexol, are present in human milk. There are no data on bupropion, naltrexone, or their metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CONTRAVE and any potential adverse effects on the breastfed infant from CONTRAVE or from the mother’s underlying condition.

Data

In a lactation study of ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight- adjusted dose. Postmarketing reports have described seizures in breastfed infants. The relationship of bupropion exposure and these seizures is unclear.

8.7 Hepatic Impairment

(Additions and/or revisions underlined)

n a pharmacokinetic study conducted for CONTRAVE in subjects with hepatic impairment (mild, moderate, and severe), exposure to naltrexone, bupropion, and their metabolites were increased. Therefore, the maximum recommended daily maintenance dose of CONTRAVE is two tablets (one tablet each morning and evening) in patients with moderate hepatic impairment. CONTRAVE is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Pregnancy

Advise pregnant patients and all patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if Contrave should be discontinued [see Use in Specific Populations (8.1)].

Patients with type 2 diabetes mellitus on antidiabetic therapy should be advised to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s).

06/13/2018 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Increases in Serum Creatinine

In the one-year controlled trials of CONTRAVE, larger mean increases in serum creatinine from baseline to trial endpoint were observed in the CONTRAVE group compared with the placebo group (0.07 mg/dL and 0.01 mg/dL, respectively) as well as from baseline to the maximum value during follow-up (0.15 mg/dL and 0.07 mg/dL, respectively). Increases in serum creatinine that exceeded the upper limit of normal and were also greater than or equal to 50% higher than baseline occurred in 0.6% of subjects receiving CONTRAVE compared to 0.1% receiving placebo. The observed increase in serum creatinine may be the result of OCT2 inhibition.

8 Use in Specific Populations

8.3 Renal Impairment

(Additions and/or revisions are underlined)

In a pharmacokinetic study conducted for CONTRAVE in subjects with renal impairment (mild, moderate and severe), exposure to naltrexone metabolite, 6-beta naltrexol, and bupropion metabolites, threohydrobupropion and erythrohydrobupropion, was increased. Therefore, the maximum recommended daily maintenance dose for CONTRAVE is two tablets (one tablet each morning and evening) in patients with moderate or severe renal impairment. No dose adjustment is required in patients with mild renal impairment. CONTRAVE is not recommended for use in patients with end-stage renal disease.

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

MEDICATION GUIDE CONTRAVE® (CON-trayv) (naltrexone HCl and bupropion HCl) extended-release tablets

(Additions and/or revisions are underlined)

Do not drink a lot of alcohol while taking CONTRAVE. If you drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your chance of having a seizure.

05/04/2017 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

(addition underlined)

…

• Use of other bupropion-containing products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN)

…

5 Warnings and Precautions

5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

(additions underlined)

CONTRAVE is not approved for smoking cessation treatment, but serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Warnings and Precautions (5.1)]. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression,

Inrarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking CONTRAVE and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of opioid dependence. No causal relationship has been demonstrated.

6 Adverse Reactions

6.2 Postmarketing Experience

(subsection added)

Additional adverse reactions have been identified during post approval use of CONTRAVE. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Loss of consciousness, malaise

7 Drug Interactions

(addition underlined)

Digoxin

Coadministration of CONTRAVE with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with CONTRAVE and digoxin

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

17 PATIENT COUNSELING INFORMATION

(additions underlined)

…

Patients should be advised that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking bupropion. patients to discontinue CONTRAVE and contact a healthcare professional if they experience such symptoms.

…