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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.
KLONOPIN (NDA-017533)
(CLONAZEPAM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
01/13/2023 (SUPPL-62)
5 Warnings and Precautions
PRECAUTIONSNewly added information:
Pregnancy: Advise pregnant females that use of Klonopin 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 Klonopin. This registry is collecting information about the safety of antiepileptic drugs during pregnancy (see PRECAUTIONS: Pregnancy).
Nursing: Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who take Klonopin 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).
Newly added information:
Neonatal Sedation and Withdrawal Syndrome: Use of Klonopin 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 Klonopin during pregnancy or labor for signs of sedation and monitor neonates exposed to Klonopin during pregnancy for signs of withdrawal; manage these neonates accordingly.
8 Use in Specific Populations
Nursing MothersAdditions and revisions underlined:
Risk Summary
Clonazepam 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 clonazepam on milk production.
Clinical Considerations
Infants exposed to Klonopin through breast milk should be monitored for sedation, poor feeding and poor weight gain.
Newly added information:
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as Klonopin, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking Klonopin enroll in the 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: Neonatal Sedation and Withdrawal Syndrome, 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 clonazepam to pregnant rabbits during the period of organogenesis resulted in developmental toxicity, including increased incidences of fetal malformations, at doses similar to or below 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 risk of major birth defects and of 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 Klonopin during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Klonopin 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideAdditions and revisions underlined:
o Taking KLONOPIN 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).
o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with KLONOPIN.
o Breastfeeding during treatment with KLONOPIN may cause your baby to have sleepiness,feeding problems, and decreased weight gain.
o Talk to your healthcare provider about the best way to feed your baby while you take KLONOPIN.
02/05/2021 (SUPPL-61)
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 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 Klonopin, 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 Klonopin and
throughout treatment, assess each patient’s risk for abuse, misuse, and
addiction (see WARNINGS).
• The continued use of benzodiazepines, including Klonopin, 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 Klonopin 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
Klonopin or reduce the dosage (see DOSAGE AND ADMINISTRATION and
WARNINGS).
5 Warnings and Precautions
Warnings(Newly added information)
Abuse, Misuse, and Addiction: The use of benzodiazepines, including KLONOPIN, 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 KLONOPIN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of KLONOPIN, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of KLONOPIN 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 KLONOPIN or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of KLONOPIN).
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 KLONOPIN, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of KLONOPIN 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: 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).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Information for PatientsInformation for Patients
(Newly added information)
Abuse, Misuse, and Addiction: Inform patients that the use of KLONOPIN, 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 the continued use of KLONOPIN may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of KLONOPIN 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 KLONOPIN may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE).
10/25/2017 (SUPPL-59)
5 Warnings and Precautions
PRECAUTIONS(Additions and/or revisions are underlined)
General:
Loss of Effect: In some studies, up to 30% of patients who initially responded have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.
Psychiatric and Paradoxical Reactions: Paradoxical reactions, such as agitation, irritability, aggression, anxiety, anger, nightmares, hallucinations, and psychoses are known to occur when using benzodiazepines. Should this occur, the use of the drug should be discontinued gradually. Paradoxical reactions are more likely to occur in children and in the elderly.
Respiratory Depression: Klonopin may cause respiratory depression and should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, sleep apnea).
Information for Patients
(Additions and/or revisions are underlined)
Nursing: Patients should be advised to notify their physician if they are breastfeeding or intend to breastfeed during therapy.
6 Adverse Reactions
(Additions and/or revisions are underlined)
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, aggression, apathy, disturbance in attention, excitement, anger…
7 Drug Interactions
(Additions and/or revisions are underlined)
Effect of Clonazepam on the Pharmacokinetics of Other Drugs: Clonazepam does not appear to alter the pharmacokinetics of carbamazepine or phenobarbital. Clonazepam has the potential to influence concentrations of phenytoin. Monitoring of phenytoin concentration is recommended when clonazepam is co-administrated with phenytoin. The effect of clonazepam on the metabolism of other drugs has not been investigated.
Effect of Other Drugs on the Pharmacokinetics of Clonazepam: …The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) and fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbamate (CYP2C19 inhibitor and CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam. Cytochrome P- 450 inducers, such as phenytoin, carbamazepine, lamotrigine, and phenobarbital induce clonazepam metabolism, causing an approximately 38% decrease in plasma clonazepam levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents (e.g., fluconazole), should be used cautiously in patients receiving clonazepam because they may impair the metabolism of clonazepam leading to exaggerated concentrations and effects.
8 Use in Specific Populations
(Additions and/or revisions are underlined)
Pregnancy: There are no adequate and well-controlled studies of Klonopin in pregnant women. Available human data on the risk of teratogenicity are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure duringpregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5, or 10 mg/kg/day during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed at all doses, in a low, non-dose-related incidence. The lowest dose tested is less than the maximum recommended human dose (MRHD) of 20 mg/day for seizure disorders and similar to the MRHD of 4 mg/day for panic disorder, on a mg/m2 basis. Reductions in maternal weight gain occurred at doses of 5 mg/kg/day or greater and reduction in embryofetal growth occurred in one study at a dose of 10 mg/kg/day.
No adverse maternal or embryofetal effects were observed in mice or rats following oral administration of clonazepam during organogenesis of doses up to 15 or 40 mg/kg/day, respectively (4 and 20 times the MRHD of 20 mg/day for seizure disorders and 20 and 100 times the MRHD of 4 mg/day for panic disorder, respectively, on a mg/meter squared basis).
Data for other benzodiazepines suggest the possibility of adverse developmental effects (long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines.
Nursing Mothers: The effects of Klonopin on the breastfed infant and on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Klonopin and any potential adverse effects on the breastfed infant from Klonopin or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE KLONOPIN (KLON-oh-pin) (clonazepam)12/16/2016 (SUPPL-58)
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 (see WARNINGS and PRECAUTIONS).
· 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)
Risks from Concomitant Use With Opioids: Inform patients and caregivers that potentially fatal additive effects may occur if Klonopin is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider.
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.
(additions underlined)
Risks from Concomitant Use With Opioids: Concomitant use of benzodiazepines, including Klonopin, 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 Klonopin 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 Klonopin is used with opioids.
6 Adverse Reactions
(Extensive changes to table 3; please refer to label)
7 Drug Interactions
(additions underlined)
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(additions underlined)
What is the most important information I should know about KLONOPIN?
· Do not stop taking KLONOPIN without first talking to your healthcare provider. Stopping
KLONOPIN suddenly can cause serious side effects.
· KLONOPIN is a benzodiazepine medicine. Benzodiazepines can cause severe drowsiness, breathing problems (respiratory depression), coma, and death when taken with opioid medicines.
KLONOPIN can
1. make you sleepy or dizzy and can slow your thinking and motor skills. This may get better over time.
· Do not drive, operate heavy machinery, or do other dangerous activities until you know how
KLONOPIN affects you.
· KLONOPIN may cause problems with your coordination, especially when you are walking or picking things up.
Before you take KLONOPIN, tell your healthcare provider about all your medical conditions, including if you:
· have liver or kidney problems
· have lung problems (respiratory disease)
· have or have had depression, mood problems, or suicidal thoughts or behavior
Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.
Taking KLONOPIN with certain other medicines can cause side effects or affect how well KLONOPIN or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
What should I avoid while taking KLONOPIN?
· KLONOPIN can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how KLONOPIN affects you.
· Do not drink alcohol or take other medicines that may make you sleepy or dizzy while taking KLONOPIN until you talk to your healthcare provider. When taken with alcohol or medicines that cause sleepiness or dizziness, KLONOPIN may make your sleepiness or dizziness much worse.
03/25/2016 (SUPPL-55)
5 Warnings and Precautions
- Respiratory Compromise: Klonopin should be used with caution in patients with compromised respiratory function.
- Porphyria: Klonopin may have a porphyrogenic effect and should be used with care in patients with porphyria.