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.

DIASTAT (NDA-020648)

(DIAZEPAM)

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

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01/13/2023 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Newly added information:

Pregnancy

Advise pregnant females that use of DIASTAT 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.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant while taking DIASTAT. The registry is collecting information about the safety of antiepileptic drugs during pregnancy (see PRECAUTIONS: Pregnancy).

Lactation

Counsel patients that diazepam, the active ingredient in DIASTAT, is present in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or plan to breastfeed. Instruct breastfeeding patients who take DIASTAT to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS: Nursing Mothers).

WARNINGS

Newly added information:

Neonatal Sedation and Withdrawal Syndrome

Use of DIASTAT 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 DIASTAT during pregnancy or labor for signs of sedation and monitor neonates exposed to DIASTAT during pregnancy for signs of withdrawal; manage these neonates accordingly.

8 Use in Specific Populations

Pregnancy

Extensive changes; please refer to label

02/05/2021 (SUPPL-21)

Approved Drug Label (PDF)

Boxed Warning

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

misuse, and addiction (see WARNINGS).

• The continued use of benzodiazepines may lead to clinically significant physical dependence.

The risks of dependence and withdrawal increase with longer treatment duration and

higher daily dose. Although DIASTAT is indicated only for intermittent use (see

INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more

frequently than recommended, abrupt discontinuation or rapid dosage reduction of

DIASTAT may precipitate acute withdrawal reactions, which can be life-threatening. For

patients using DIASTAT more frequently than recommended, to reduce the risk of

withdrawal reactions, use a gradual taper to discontinue DIASTAT (see WARNINGS).

5 Warnings and Precautions

Precautions

(Newly added information)

Abuse, Misuse, and Addiction: Inform patients that the use of DIASTAT more frequently than recommended, 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 use of DIASTAT more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage

reduction of DIASTAT 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 (see WARNINGS, Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE).

Warnings

(Newly added information)

Abuse, Misuse, and Addiction

The use of benzodiazepines, including DIASTAT, 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 DIASTAT and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of DIASTAT, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of DIASTAT along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; 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 After Use of DIASTAT More Frequently Than Recommended

For patients using DIASTAT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue DIASTAT (a patient-specific plan should be used to taper the dose).

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 may lead to clinically significant physical dependence. Although DIASTAT is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of DIASTAT, 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).

6 Adverse Reactions

(Newly added information)

To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321- 4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

12/16/2016 (SUPPL-14)

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

PRECAUTIONS

(additions underlined)

Information to Be Communicated by the Prescriber to Patients and Caregivers

Risks from Concomitant Use with Opioids: Inform patients and caregivers that potentially fatal additive effects may occur if Diastat or Diastat AcuDial is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider .

Administration: Prescribers are strongly advised to take all reasonable steps to ensure that caregivers fully understand their role and obligations vis a vis the administration of Diazepam rectal gel to individuals in their care. Prescribers should routinely discuss the steps in the Patient/Caregiver Package Insert (see Patient/Caregiver Insert printed at the end of the product labeling and also included in the product carton). The successful and safe use of Diazepam rectal gel depends in large measure on the competence and performance of the caregiver.

Prescribers should advise caregivers that they expect to be informed immediately if a patient develops any new findings which are not typical of the patient’s characteristic seizure episode.

WARNINGS

(additions underlined)

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including Diastat and Diastat AcuDial, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids 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 Diastat or Diastat AcuDial 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 Diastat or Diastat AcuDial is used with opioids.

7 Drug Interactions

(additions underlined)

There have been no clinical studies or reports in literature to evaluate the interaction of rectally administered diazepam with other drugs. As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Effect of Concomitant Use of Benzodiazepines and 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 follow patients closely for respiratory depression and sedation.

Other Psychotropic Agents or Other CNS Depressants: If Diazepam rectal gel is to be combined with other psychotropic agents or other CNS depressants, careful consideration should be given to the pharmacology of the agents to be employed particularly with known compounds which may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

Cimetidine: The clearance of diazepam and certain other benzodiazepines can be delayed in association with cimetidine administration. The clinical significance of this is unclear.

Valproate: Valproate may potentiate the CNS-depressant effects of diazepam.