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.

SYMPAZAN (NDA-210833)

(CLOBAZAM)

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

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03/12/2024 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Multiorgan Hypersensitivity

Newly added subsection:

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including clobazam. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. SYMPAZAN should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications (4)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.7)]

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about SYMPAZAN?

…

A serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Call your healthcare provider right away if you have:
- a skin rash
- fever or swollen glands that do not go away
- swelling of your face
- shortness of breath
- dark urine
- yellowing of the skin or whites of the eyes

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

DRESS/Multiorgan Hypersensitivity

Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately. SYMPAZAN should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.7)].

…

01/13/2023 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Neonatal Sedation and Withdrawal Syndrome

Newly added subsection:

Use of SYMPAZAN 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 SYMPAZAN during pregnancy or labor for signs of sedation and monitor neonates exposed to SYMPAZAN 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 (5.8)]

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 AEDs, such as SYMPAZAN®, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN® enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at 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 (5.8) 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 clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [see Animal Data].

Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines 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 defect, 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%-4% and 15% -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 SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8)].

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

SYMPAZAN® is excreted in human milk (see Data). 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 clobazam on milk production.

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

Clinical Considerations

Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with clobazam. Infants exposed to SYMPAZAN 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 SYMPAZAN, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant.
- Taking SYMPAZAN 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 SYMPAZAN.
- If you become pregnant while taking SYMPAZAN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888- 233-2334. For more information about the registry go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
Are breastfeeding or plan to breastfeed. SYMPAZAN can pass into breast milk.
- Breastfeeding during treatment with SYMPAZAN may cause your baby to have sleepiness, feeding problems, and decreased weight gain.
- Talk to your healthcare provider about the best way to feed your baby if you take SYMPAZAN.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Pregnancy

Advise pregnant females that the use of SYMPAZAN® late in pregnancy can result in 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 (5.8) and Use in Specific Populations (8.1)]. Instruct patients to notify 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 SYMPAZAN. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Counsel patients that clobazam, the active ingredient in SYMPAZAN®, is excreted in breast milk. Instruct patients to notify their healthcare provider if they are breast feeding or intend to breastfeed. Instruct breastfeeding patients who take SYMPAZAN to monitor their 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)].

03/16/2021 (SUPPL-2)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Effect of Other Drugs on SYMPAZAN

(Additions and/or revisions underlined)

Strong and Moderate Inhibitors of CYP2C19

Coadministration with strong or moderate inhibitors of CYP2C19 may result in increased exposure to N- desmethylclobazam, the active metabolite of clobazam. This may increase the risk of dose-related adverse reactions. Dosage adjustment of SYMPAZAN® may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole) [see Clinical Pharmacology (12.3)].

Effect of Cannabidiol on SYMPAZAN®

Coadministration of cannabidiol, a CYP3A4 and CYP2C19 substrate and a CYP2C19 inhibitor, with clobazam may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions (5.4, 5.5), Clinical Pharmacology (12.3)]. Consider a reduction in dosage of cannabidiol or clobazam if adverse reactions known to occur with SYMPAZAN are experienced.

02/05/2021 (SUPPL-3)

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.

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. (5.1, 7.1)

• The use of benzodiazepines, including SYMPAZAN, exposes users

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

overdose or death. Before prescribing SYMPAZAN and

throughout treatment, assess each patient’s risk for abuse, misuse,

and addiction (5.2).

• Abrupt discontinuation or rapid dosage reduction of SYMPAZAN

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 SYMPAZAN (2.2,

5.3).

5 Warnings and Precautions

5.2 Abuse, Misuse, and Addiction

(Newly added section)

The use of benzodiazepines, including SYMPAZAN, 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 SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of SYMPAZAN, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SYMPAZAN 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.

5.3 Dependence and Withdrawal Reactions

(Newly added section)

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN or reduce the dosage

[see Dosage and Administration (2.2)].

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

Clinically significant adverse reactions that appear in other sections of the labeling include the following:

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 [see Warnings and Precautions (5.3)]

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

Medication Guide

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Newly added information)

Abuse, Misuse, and Addiction

Inform patients that the use of SYMPAZAN, 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

Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure. Inform patients that the continued use of SYMPAZAN may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of SYMPAZAN 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 SYMPAZAN may require a slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].