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.

SEIZALAM (NDA-209566)

(MIDAZOLAM HYDROCHLORIDE)

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

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01/13/2023 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Neonatal Sedation and Withdrawal Syndrome

Newly added subsection:

Use of SEIZALAM 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 Use in Specific Populations (8.1)]. Monitor neonates exposed to SEIZALAM during pregnancy or labor for signs of sedation and monitor neonates exposed to SEIZALAM during pregnancy for signs of withdrawal; manage these neonates accordingly.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.9)]

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as SEIZALAM, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women who are taking SEIZALAM during pregnancy enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

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 and Precautions (5.9) 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).

Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in adverse effects on development (see Animal Data). Data for other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background 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 SEIZALAM during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to SEIZALAM during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9)].

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.

…

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Midazolam is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of midazolam on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SEIZALAM and any potential adverse effects on the breastfed child from SEIZALAM or from the underlying maternal condition.

Clinical Considerations

Infants exposed to SEIZALAM 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)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise pregnant females that the use of SEIZALAM 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 and Precautions (5.9) and Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Counsel patients that midazolam, the active ingredient in SEIZALAM, is excreted in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who have been administered SEIZALAM to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see Use in Specific Populations (8.2)].

02/05/2021 (SUPPL-1)

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

See full prescribing information for complete boxed warning.

• Concomitant use of benzodiazepines and opioids may result in

profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation. (5.1, 7.1)

• The use of benzodiazepines, including SEIZALAM, exposes users to

risks of abuse, misuse, and addiction, which can lead to overdose or

death. Before prescribing SEIZALAM and throughout treatment,

assess each patient’s risk for abuse, misuse, and addiction. (5.2)

• Although SEIZALAM is indicated only for intermittent use (1, 2), if

used more frequently than recommended, abrupt discontinuation or

rapid dosage reduction of SEIZALAM may precipitate acute

withdrawal reactions, which can be life-threatening. For patients

using SEIZALAM more frequently than recommended, to reduce

the risk of withdrawal reactions, use a gradual taper to discontinue

SEIZALAM. (5.3)

5 Warnings and Precautions

5.2 Abuse, Misuse, and Addiction

(Newly added section)

The use of benzodiazepines, including SEIZALAM, 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 (9.2)].

Before prescribing SEIZALAM and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of SEIZALAM, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SEIZALAM 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.

5.3 Dependence and Withdrawal Reactions After Use of SEIZALAM More Frequently Than Recommended

(Newly added section)

For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue SEIZALAM (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 SEIZALAM is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2)], if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of SEIZALAM, 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 (9.3)].

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 (9.3)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed in greater detail in other sections:

Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]
Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]
Dependence and Withdrawal Reactions After Use of SEIZALAM More Frequently Than Recommended

[see Warnings and Precautions (5.3)]

Risks of Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.4)]
Other Adverse Reactions [see Warnings and Precautions (5.5)]
Risks from Concomitant Use of Central Nervous System Depressants [see Warnings and Precautions (5.6)]
Impaired Cognitive Function [see Warnings and Precautions (5.7)]
Glaucoma [see Warnings and Precautions (5.8)]
Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.9)]

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

Patient Counseling Information

(Newly added information)

Abuse, Misuse, and Addiction

Inform patients that the use of SEIZALAM 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 and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Inform patients that use of SEIZALAM more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of SEIZALAM 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 and Precautions (5.3) and Drug Abuse and Dependence (9.3)].