Clonazepam

• 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

  Risks from Concomitant Use with Opioids:

  Concomitant use of benzodiazepines, including clonazepam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for 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 clonazepam tablets 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 clonazepam tablets are used with opioids (see PRECAUTIONS: Information for Patientsand PRECAUTIONS: Drug Interactions).

  Abuse, Misuse, and Addiction:

  The use of benzodiazepines, including clonazepam tablets, 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 clonazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of clonazepam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clonazepam tablets 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 clonazepam tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION:

  Discontinuation or Dosage Reduction of Clonazepam Tablets

  )

  .

  
  
  

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

  Interference with Cognitive and Motor Performance:

  Since clonazepam tablets produce CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam tablets therapy (see PRECAUTIONS: Drug Interactionsand PRECAUTIONS: Information for Patients).

  Suicidal Behavior and Ideation:

  Antiepileptic drugs (AEDs), including clonazepam tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

  
  
  

  Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

  
  
  

  The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

  
  
  

  The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

  
  
  

  Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

  
  
  

  Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

  Indication	Placebo	Drug Patients	Relative Risk:	Risk Difference:
  	Patients with	with Events Per	Incidence of	Additional Drug
  	Events Per	1000 Patients	Events in Drug	Patients with
  	1000 Patients		Patients/Incidence	Events per 1000
  			in Placebo	Patients
  			Patients
  Epilepsy	1.0	3.4	3.5	2.4
  Psychiatric	5.7	8.5	1.5	2.9
  Other	1.0	1.8	1.9	0.9
  Total	2.4	4.3	1.8	1.9

  The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

  
  
  

  Anyone considering prescribing clonazepam tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and with an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

  
  
  

  Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

  Neonatal Sedation and Withdrawal Syndrome:

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

  and

  PRECAUTIONS

  General:

  Worsening of Seizures:

  When used in patients in whom several different types of seizure disorders coexist, clonazepam tablets may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam tablets may produce absence status.

  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.

  Laboratory Testing During Long-Term Therapy:

  Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam tablets.

  Psychiatric and Paradoxical Reactions:

  Paradoxical reactions, such as agitation, irritability, aggression, anxiety, anger, nightmares, hallucinations, and psychoses are known to occur when using benzodiazepines (see ADVERSE REACTIONS: Psychiatric). Should this occur, the use of the drug should be discontinued gradually (see WARNINGS: Dependence and Withdrawal Reactionsand DRUG ABUSE AND DEPENDENCE: Dependence). Paradoxical reactions are more likely to occur in children and in the elderly.
  
  

  
  
  Caution in Renally Impaired Patients:

  Metabolites of clonazepam tablets are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.

  Hypersalivation:

  Clonazepam tablets may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions.

  
  
  

  Respiratory Depression:

  Clonazepam tablets may cause respiratory depression and should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, sleep apnea).

  
  
  

  Porphyria:

  Clonazepam tablets may have a porphyrogenic effect and should be used with care in patients with porphyria.

  Information for Patients:

  A clonazepam tablets Medication Guide must be given to the patient each time clonazepam tablets are dispensed, as required by law. Patients should be instructed to take clonazepam tablets only as prescribed. Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam tablets:

  
  
  

  Risks from Concomitant Use with Opioids:

  Inform patients and caregivers that potentially fatal additive effects may occur if clonazepam tablets are used with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see WARNINGS:

  Risks from Concomitant Use with Opioids

  and PRECAUTIONS: Drug Interactions).

  Abuse, Misuse, and Addiction:

  Inform patients that the use of clonazepam tablets, 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 clonazepam tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of clonazepam tablets 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 clonazepam tablets may require a slow taper (see WARNINGS:

  Dependence and Withdrawal Reactions

  and DRUG ABUSE AND DEPENDENCE)

  .

  Interference With Cognitive and Motor Performance:

  Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam tablets therapy does not affect them adversely.

  Suicidal Thinking and Behavior:

  Patients, their caregivers, and families should be counseled that AEDs, including clonazepam tablets, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

  Pregnancy:

  Advise pregnant females that use of clonazepam tablets 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 Syndromeand 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 clonazepam tablets. 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 clonazepam tablets 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).

  Concomitant Medication:

  Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.

  Alcohol:

  Patients should be advised to avoid alcohol while taking clonazepam tablets.

  Drug Interactions:

  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 GABA_Asites, 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.

  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:

  Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.

  
  
  

  In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the C_maxof clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.

  
  
  

  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.

  Pharmacodynamic Interactions:

  The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

  Carcinogenesis, Mutagenesis, Impairment of Fertility:

  Carcinogenesis

  Carcinogenicity studies have not been conducted with clonazepam.

  
  
  

  Mutagenesis

  The data currently available are not sufficient to determine the genotoxic potential of clonazepam.

  
  
  

  Impairment of Fertility

  In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day, there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning. The lowest dose tested is approximately 5 and 24 times the maximum recommended human dose (MRHD) of 20 mg/day for seizure disorders and 4 mg/day for panic disorder, respectively, on a body surface area (mg/m²) basis.

  Pregnancy:

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as clonazepam tablets, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking clonazepam tablets 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 clonazepam tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to clonazepam tablets 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.

  
  
  

  Animal Data

  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/m²basis. 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/m²basis).

  
  
  

  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:

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

  
  
  

  Clinical Considerations

  Infants exposed to clonazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain.

  Pediatric Use:

  Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam tablets is important in pediatric patients being treated for seizure disorder (see INDICATIONS AND USAGEand DOSAGE AND ADMINISTRATION).

  
  
  

  Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.

  Geriatric Use:

  Clinical studies of clonazepam tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

  
  
  

  Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam tablets are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection.

  
  
  

  Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam tablets and observed closely.

  ).

• The use of benzodiazepines, including clonazepam tablets, 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 clonazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see

  WARNINGS

  Risks from Concomitant Use with Opioids:

  Concomitant use of benzodiazepines, including clonazepam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for 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 clonazepam tablets 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 clonazepam tablets are used with opioids (see PRECAUTIONS: Information for Patientsand PRECAUTIONS: Drug Interactions).

  Abuse, Misuse, and Addiction:

  The use of benzodiazepines, including clonazepam tablets, 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 clonazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of clonazepam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clonazepam tablets 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 clonazepam tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION:

  Discontinuation or Dosage Reduction of Clonazepam Tablets

  )

  .

  
  
  

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

  Interference with Cognitive and Motor Performance:

  Since clonazepam tablets produce CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam tablets therapy (see PRECAUTIONS: Drug Interactionsand PRECAUTIONS: Information for Patients).

  Suicidal Behavior and Ideation:

  Antiepileptic drugs (AEDs), including clonazepam tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

  
  
  

  Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

  
  
  

  The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

  
  
  

  The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

  
  
  

  Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

  
  
  

  Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

  Indication	Placebo	Drug Patients	Relative Risk:	Risk Difference:
  	Patients with	with Events Per	Incidence of	Additional Drug
  	Events Per	1000 Patients	Events in Drug	Patients with
  	1000 Patients		Patients/Incidence	Events per 1000
  			in Placebo	Patients
  			Patients
  Epilepsy	1.0	3.4	3.5	2.4
  Psychiatric	5.7	8.5	1.5	2.9
  Other	1.0	1.8	1.9	0.9
  Total	2.4	4.3	1.8	1.9

  The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

  
  
  

  Anyone considering prescribing clonazepam tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and with an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

  
  
  

  Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

  Neonatal Sedation and Withdrawal Syndrome:

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

  )

  .

• The continued use of benzodiazepines, including clonazepam tablets, 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 clonazepam tablets 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 clonazepam tablets or reduce the dosage (see 

  DOSAGE AND ADMINISTRATION

  Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.

  
  
  

  Seizure Disorders:

  The use of multiple anticonvulsants may result in an increase of CNS depressant adverse effects. This should be considered before adding clonazepam tablets to an existing anticonvulsant regimen.

  Adults:

  The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

  
  
  

  Pediatric Patients:

  Clonazepam tablets are administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.

  
  
  

  Geriatric Patients:

  There is no clinical trial experience with clonazepam tablets in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely (see PRECAUTIONS: Geriatric Use).

  
  
  

  Panic Disorder:

  Adults:

  The initial dose for adults with panic disorder is 0.25 mg twice daily. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects. Nevertheless, it is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 to 0.25 mg twice daily every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.

  
  
  

  Treatment should be discontinued gradually, with a decrease of 0.125 mg twice daily every 3 days, until the drug is completely withdrawn.

  
  
  

  There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

  Pediatric Patients:

  There is no clinical trial experience with clonazepam tablets in panic disorder patients under 18 years of age.

  
  
  

  Geriatric Patients:

  There is no clinical trial experience with clonazepam tablets in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam tablets and observed closely (see PRECAUTIONS: Geriatric Use).

  
  
  

  Discontinuation or Dosage Reduction of Clonazepam Tablets:

  To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clonazepam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactionsand DRUG ABUSE AND DEPENDENCE: Dependence).

  and

  WARNINGS

  Risks from Concomitant Use with Opioids:

  Concomitant use of benzodiazepines, including clonazepam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for 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 clonazepam tablets 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 clonazepam tablets are used with opioids (see PRECAUTIONS: Information for Patientsand PRECAUTIONS: Drug Interactions).

  Abuse, Misuse, and Addiction:

  The use of benzodiazepines, including clonazepam tablets, 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 clonazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of clonazepam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clonazepam tablets 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 clonazepam tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION:

  Discontinuation or Dosage Reduction of Clonazepam Tablets

  )

  .

  
  
  

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

  Interference with Cognitive and Motor Performance:

  Since clonazepam tablets produce CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam tablets therapy (see PRECAUTIONS: Drug Interactionsand PRECAUTIONS: Information for Patients).

  Suicidal Behavior and Ideation:

  Antiepileptic drugs (AEDs), including clonazepam tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

  
  
  

  Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

  
  
  

  The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

  
  
  

  The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

  
  
  

  Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

  
  
  

  Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

  Indication	Placebo	Drug Patients	Relative Risk:	Risk Difference:
  	Patients with	with Events Per	Incidence of	Additional Drug
  	Events Per	1000 Patients	Events in Drug	Patients with
  	1000 Patients		Patients/Incidence	Events per 1000
  			in Placebo	Patients
  			Patients
  Epilepsy	1.0	3.4	3.5	2.4
  Psychiatric	5.7	8.5	1.5	2.9
  Other	1.0	1.8	1.9	0.9
  Total	2.4	4.3	1.8	1.9

  The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

  
  
  

  Anyone considering prescribing clonazepam tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and with an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

  
  
  

  Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

  Neonatal Sedation and Withdrawal Syndrome:

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

  )

  .

Some loss of effect may occur during the course of clonazepam treatment (see 

The efficacy of clonazepam tablets was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see 

Panic disorder (DSM-V) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The effectiveness of clonazepam tablets in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see

Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.

The use of multiple anticonvulsants may result in an increase of CNS depressant adverse effects. This should be considered before adding clonazepam tablets to an existing anticonvulsant regimen.

Treatment should be discontinued gradually, with a decrease of 0.125 mg twice daily every 3 days, until the drug is completely withdrawn.

There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clonazepam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see 

The adverse experiences for clonazepam tablets are provided separately for patients with seizure disorders and with panic disorder.

The following paradoxical reactions have been observed: irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, abnormal dreams, hallucinations.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Overall, the incidence of discontinuation due to adverse events was 17% in clonazepam tablets compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most common events (≥ 1%) associated with discontinuation and a dropout rate twice or greater for clonazepam tablets than that of placebo included the following:

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6- to 9-week trials. Events reported in 1% or more of patients treated with clonazepam tablets (doses ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.

The prescriber should be aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied.

In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of clonazepam tablets-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of clonazepam tablets-treated patients compared to 1% of placebo-treated patients. While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression.

Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam tablets at multiple doses during clinical trials. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the events occurred during treatment with clonazepam tablets, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients.

In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the C_max of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.

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.