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Guide
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.
ONFI (NDA-202067)
(CLOBAZAM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/12/2024 (SUPPL-8)
5 Warnings and Precautions
5.7 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Multiorgan HypersensitivityNewly added subsection:
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including ONFI. 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. ONFI 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 GUIDEAdditions and/or revisions underlined:
…
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
…
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. ONFI should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.7)].
…
01/13/2023 (SUPPL-7)
5 Warnings and Precautions
5.8 Neonatal Sedation and Withdrawal SyndromeNewly added subsection:
Use of ONFI 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 ONFI during pregnancy or labor for signs of sedation and monitor neonates exposed to ONFI 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 PregnancyAdditions and/or revisions underlined:
Pregnancy Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as ONFI, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking ONFI 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).
…
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 of 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 ONFI during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to ONFI 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 benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.
Additions and/or revisions underlined:
Risk Summary
ONFI 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 ONFI and any potential adverse effects on the breastfed infant from ONFI 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 ONFI. Infants exposed to ONFI 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 GUIDEAdditions and/or revisions underlined:
…
are pregnant or plan to become pregnant.
Taking ONFI 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 while taking ONFI.
If you become pregnant while taking ONFI, 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. ONFI can pass into breast milk.
Breastfeeding during treatment with ONFI 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 ONFI.
Additions and/or revisions underlined:
Pregnancy
Advise pregnant females that the use of ONFI 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 (5.8) 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 ONFI. 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 ONFI, is excreted in breast milk. Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who have been administered ONFI to observe their infants for 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-6)
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 ONFI, exposes users
to risks of abuse, misuse, and addiction, which can lead to
overdose or death. Before prescribing ONFI and throughout
treatment, assess each patient’s risk for abuse, misuse, and
addiction (5.2).
• Abrupt discontinuation or rapid dosage reduction of ONFI
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
ONFI or reduce the dosage (2.2, 5.3).
5 Warnings and Precautions
5.2 Abuse, Misuse, and Addiction(Newly added section)
The use of benzodiazepines, including ONFI, 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 ONFI and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of ONFI, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of ONFI 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.
(Newly added section)
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue ONFI 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 ONFI, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of ONFI 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)
(Newly added information)
Abuse, Misuse, and Addiction
Inform patients that the use of ONFI, 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 ONFI may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of ONFI 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 ONFI may require a slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].
06/15/2018 (SUPPL-5)
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes-please refer to labeling)
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
ONFI is excreted in human milk. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as ONFI, may have effects of lethargy, somnolence and poor sucking. The effect of ONFI on milk production is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ONFI and any potential adverse effects on the breastfed infant from ONFI or from the underlying maternal condition. If exposing a breastfed infant to ONFI, observe for any potential adverse effects.
Clinical Considerations
Monitoring for Adverse Reactions
Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with ONFI. Monitor breastfed infants for possible sedation and poor sucking.
Data
Scientific literature on ONFI use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk.
(Newly Added Subsection)
Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Pregnancy
Advise pregnant women and women of childbearing potential that the use of ONFI during pregnancy can cause fetal harm which may occur early in pregnancy before many women know they are pregnant. Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options.
Advise patients that there is a pregnancy exposure registry that collects information about the safety of antiepileptic drugs during pregnancy.
Nursing
Counsel patients that ONFI is excreted in breast milk. Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy and counsel nursing mothers to observe their infants for poor sucking and somnolence.
12/16/2016 (SUPPL-4)
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
5.1 Risks from Concomitant Use with Opioids
(new subsection added)
Concomitant use of benzodiazepines, including ONFI, 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 ONFI 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 ONFI is used with opioids.
(new subsection added)
Since ONFI has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
6 Adverse Reactions
(addition underlined)
• Risks from Concomitant Use with Opioids.
7 Drug Interactions
7.1 Opioids(new subsection added)
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.
(new subsection added)
Concomitant use of ONFI with other CNS depressants may increase the risk of sedation and somnolence.
Alcohol, as a CNS depressant, will interact with ONFI in a similar way and also increases clobazam’s maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(additions underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide and
Instructions for Use).
Risks from Concomitant Use with Opioids
Inform patients and caregivers that potentially fatal additive effects may occur if ONFI is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider.
Hypersensitivity
Inform patients or caregivers that ONFI is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.
(additions underlined)
• ONFI is a benzodiazepine medicine. Benzodiazepines can cause severe drowsiness, breathing problems (respiratory depression), coma, and death when taken with opioid medicines.
• ONFI can make you sleepy or dizzy and can slow your thinking and motor skills. This may get better over time.
· ONFI may cause problems with your coordination, especially when you are walking or picking things up.
· Serious skin reactions have been seen when ONFI is taken with other medicines and may require stopping its use. Do not stop taking ONFI without first talking to your healthcare provider.