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.

VALIUM (NDA-013263)

(DIAZEPAM)

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

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01/13/2023 (SUPPL-97)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Newly added information:

…

Neonatal Sedation and Withdrawal Syndrome

Use of Valium late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy). Monitor neonates exposed to Valium during pregnancy or labor for signs of sedation and monitor neonates exposed to Valium during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS

Newly added information:

…

Pregnancy

Advise pregnant females that use of Valium late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy). Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Valium during pregnancy (see Precautions, Pregnancy).

Nursing

Advise patients that breastfeeding is not recommended during treatment with Valium (see PRECAUTIONS: Nursing Mothers).

…

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Valium, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m2 basis). Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis.

The 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 risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to Valium during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Valium during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome).

Labor or Delivery

…

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

…

Nursing Mothers

Diazepam is present in breastmilk. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed infants, advise patient that breastfeeding is not recommended during treatment with Valium.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Before you take VALIUM, tell your healthcare provider about all of your medical conditions, including if you:

have or have had depression, mood problems, or suicidal thoughts or behavior
have lung disease or breathing problems
have liver or kidney problems
are pregnant or plan to become pregnant.
are breastfeeding or plan to breastfeed. VALIUM passes into your breast milk.

…

02/05/2021 (SUPPL-96)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions underlined)

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS;

ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND

WITHDRAWAL REACTIONS

• Concomitant use of benzodiazepines and opioids may result in profound

sedation, respiratory depression, coma, and death. Reserve concomitant

prescribing of these drugs in patients for whom alternative treatment

options are inadequate. Limit dosages and durations to the minimum

required. Follow patients for signs and symptoms of respiratory

depression and sedation (see WARNINGS and PRECAUTIONS).

• The use of benzodiazepines, including VALIUM, exposes users to risks of

abuse, misuse, and addiction, which can lead to overdose or death. Abuse

and misuse of benzodiazepines commonly involve concomitant use of other

medications, alcohol, and/or illicit substances, which is associated with an

increased frequency of serious adverse outcomes. Before prescribing

VALIUM and throughout treatment, assess each patient’s risk for abuse,

misuse, and addiction (see WARNINGS).

• The continued use of benzodiazepines, including VALIUM, may lead to

clinically significant physical dependence. The risks of dependence and

withdrawal increase with longer treatment duration and higher daily dose.

Abrupt discontinuation or rapid dosage reduction of VALIUM after

continued use may precipitate acute withdrawal reactions, which can be

life-threatening. To reduce the risk of withdrawal reactions, use a gradual

taper to discontinue VALIUM or reduce the dosage (see DOSAGE AND

ADMINISTRATION and WARNINGS).

5 Warnings and Precautions

Warnings

(Newly added information)

Abuse, Misuse, and Addiction

The use of benzodiazepines, including Valium, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse).

Before prescribing Valium and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Valium, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Valium along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Valium or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Valium).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions

The continued use of benzodiazepines, including Valium, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Valium after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence).

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence).

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

Information for Patients

(Newly added information)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Risks from Concomitant Use with Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Valium is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use with Opioids and PRECAUTIONS: Drug Interactions).

Abuse, Misuse, and Addiction

Inform patients that the use of Valium, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE).

Withdrawal Reactions

Inform patients that the continued use of Valium may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Valium may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of Valium may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE).

Medication Guide

(Extensive changes; please refer to label)

12/16/2016 (SUPPL-94)

Approved Drug Label (PDF)

Boxed Warning

(New section added)

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death

· Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

· Limit dosages and durations to the minimum required.

· Follow patients for signs and symptoms of respiratory depression and sedation.

5 Warnings and Precautions

WARNINGS

(additions underlined)

Concomitant use of benzodiazepiones, including Valium, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe Valium concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of Valium than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Valium, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Valium is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined.

7 Drug Interactions

(addition underlined)

Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid- related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

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

MEDICATION GUIDE

(Newly added, please refer to label)