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.

LIBRAX (NDA-012750)

(CHLORDIAZEPOXIDE HYDROCHLORIDE; CLIDINIUM BROMIDE)

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

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01/13/2023 (SUPPL-68)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS:

…

Neonatal Sedation and Withdrawal Syndrome

Newly added subsection:

Use of benzodiazepines 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 Librax, which contains a benzodiazepine (chlordiazepoxide hydrochloride), during pregnancy and labor for signs of sedation and monitor neonates exposed to Librax during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS:

Information for Patients

…

Pregnancy

Newly added subsection:

Advise pregnant females that use of Librax 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.

Nursing

Newly added subsection:

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed (see

PRECAUTIONS, Nursing Mothers).

…

Pregnancy

Newly added section:

Additions and/or revisions underlined:

Risk Summary

Chlordiazepoxide Hydrochloride

Neonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: 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).

Clidinium Bromide

Over decades of use, there is an absence of published data on orally administered clidinium bromide in pregnant women, including an absence of any reports of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

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 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 Librax, which contains a benzodiazepine (chlordiazepoxide hydrochloride), during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Librax during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome).

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

Oral daily doses of 2.5 mg/kg chlordiazepoxide hydrochloride with 1.25 mg/kg clidinium bromide or 25 mg/kg chlordiazepoxide hydrochloride with 12.5 mg/kg clidinium bromide (0.6 and 6.1 times, respectively, the maximum recommended clinical dose for both drugs, based on body surface area) were administered to rats in a reproduction study through two successive matings. In the first mating, no significant differences were noted between the control or the treated groups, with the exception of a slight decrease in the number of animals surviving during lactation among those receiving the highest dosage. In the second mating, similar results were obtained except for a slight decrease in the number of pregnant females and in the percentage of offspring surviving until weaning. No congenital anomalies were observed in both matings in either the control or treated groups.

Nursing Mothers

Newly added section:

Chlordiazepoxide Hydrochloride

There are no data on the presence of chlordiazepoxide in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, there are reports of sedation, poor feeding and poor weight gain in infants exposed to other benzodiazepines through breast milk.

Reproduction studies in rats fed chlordiazepoxide hydrochloride, 10, 20 and 80 mg/kg daily (2.4, 4.8 and

19.4 times respectively, the maximum recommended clinical dose of 40 mg/day, based on body surface area), and bred through one or two matings showed no adverse effects on lactation of the dams.

Clidinium Bromide

There are no data on the presence of clidinium in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergic drugs, clidinium may cause suppression of lactation.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Librax and any potential adverse effects on the breastfed infant from Librax. Infants exposed to Librax through breast milk should be monitored for sedation, poor feeding and poor weight gain.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

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

…

are pregnant or plan to become pregnant. Librax may harm your unborn baby.
- Taking Librax late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).
- Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Librax.

are breastfeeding or plan to breastfeed. Librax may pass through your breast milk and may cause sedation, poor feeding or poor weight gain in your baby. Talk to your healthcare provider about the best way to feed your baby if you take Librax. Librax may decrease the amount of breast milk your body makes.

02/05/2021 (SUPPL-67)

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 and

PRECAUTIONS, Drug Interactions).

• The use of benzodiazepines, including chlodiazepoxide hydrochloride, a component of

Librax, 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 Librax and throughout

treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS).

• The continued use of benzodiazepines, including Librax, 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 Librax 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 Librax or reduce the dosage (see WARNINGS and DOSAGE AND

ADMINISTRATION).

5 Warnings and Precautions

Precautions

(Additions and/or revisions underlined)

CNS Adverse Reactions

In geriatric or debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia, oversedation or confusion (not more than 2 Librax capsules per day initially, to be increased gradually as needed and tolerated).

Warnings

(Newly added information)

Abuse, Misuse, and Addiction

The use of benzodiazepines, including chlordiazepoxide hydrochloride, a component of Librax, 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).

Before prescribing Librax and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Librax, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Librax 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 Librax or reduce the dosage (a patient-specific plan should be used to taper the dosage) (see DOSAGE AND ADMINISTRATION).

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 Librax, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Librax 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).

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).

7 Drug Interactions

(Additions and/or revisions underlined)

Opioids

The concomitant use of benzodiazepines, including chlordiazepoxide hydrochloride, a component of Librax, 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 Librax and opioids, and follow patients closely for respiratory depression and sedation.

Oral Anticoagulants

Although clinical studies have not established a cause and effect relationship, physicians should be aware that variable effects on blood coagulation have been reported very rarely in patients receiving oral anticoagulants and chlordiazepoxide hydrochloride, a component of Librax.

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

Information for Patients

(Additions and/or revisions underlined)

Abuse, Misuse, and Addiction

Inform patients that the use of Librax, 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).

Withdrawal Reactions

Inform patients that the continued use of Librax may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Librax 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 Librax may require a slow taper (see WARNINGS and DRUG ABUSE AND DEPENDENCE).

Concomitant Use With Opioids and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Librax is used with opioids or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider (see WARNINGS and PRECAUTIONS, Drug Interactions).

Medication Guide

(Extensive changes; please refer to label)

12/16/2016 (SUPPL-66)

Boxed Warning

(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

(additions underlined)

Concomitant use of benzodiazepines, including Librax, 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 Librax 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. Advise both patients and caregivers about the risks of respiratory depression and sedation when Librax is used with opioids.

7 Drug Interactions

(additions underlined)

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 follow patients closely for respiratory depression and sedation.

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

17 Patient Counceling Information

(additions underlined)

To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.

MEDICATION GUIDE

(new section added, please refer to label)