NOVATRIL

A benzodiazepine used to treat various seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop.

Label 18, 22, 23, 24 The agent has also been indicated for treating panic disorder.

Label 7, 18, 22, 23, 24 The mechanism of action appears to involve the enhancement of gamma-aminobutyric acid receptor responses.

Label 7, 8, 18, 22, 23, 24 Since being first patented in and then released for sale from Roche in the US in 1975, 16, 17 clonazepam has experienced a storied history in the treatment of the aforementioned medical conditions.

Now available as a generic medication, the agent continues to see exceptionally high use as millions of prescriptions are written for the medication internationally every year.

Unfortunately, however, like most benzodiazepines, clonazepam use has also been associated with recreational use and drug abuse.

Clonazepam is indicated as monotherapy or as an adjunct in the treatment of Lennox-Gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures.

Label 23 Furthermore, clonazepam may also be of some value in patients with absence spells (petit mal) who have failed to respond to succinimides.

Label 23 Additionally, clonazepam is also indicated for the treatment of panic disorder, with or without agoraphobia, as defined in the DSM-V. Label Alternatively, some regional prescribing information note that clonazepam is indicated for all clinical forms of epileptic disease and seizures in adults, especially absence seizures (petit mal) including atypical absence; primary or secondarily generalised tonic-clonic (grand mal), tonic or clonic seizures; partial (focal) seizures with elementary or complex symptomatology; various forms of myoclonic seizures, myoclonus and associated abnormal movements. 18, 24 Such regional label data also has clonazepam indicated for most types of epilepsy in infants and children, especially absences (petit mal), myoclonic seizures and tonic-clonic fits, whether due to primary generalized epilepsy or to secondary generalization of partial epilepsy.

The pharmacodynamic properties of clonazepam are common among benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects 6, 18, 22, 23.

Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations, as well as irregular spikes and waves Label 6, 18, 22, 23.

Moreover, the agent can also decrease the frequency, amplitude, duration, and spread of discharge in minor motor seizures Label 22.

EEG abnormalities are more readily suppressed by clonazepam than are focal EEG abnormalities such as focal spikes 18.

Clonazepam has beneficial effects in generalized and focal epilepsies 18.

Clonazepam is rapidly and almost entirely absorbed after oral administration as tablets Label 22, 24.

Peak plasma concentrations of clonazepam administered by the oral route are reached within 1-4 hours and the associated absorption half-life is about 25 minutes Label 22, 24.

The absolute bioavailability is approximately 90%.

• but with substantially large differences between individuals Label 22, 24.

Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures 22, 24.

The apparent volume of distribution has been documented as approximately 3 L/kg 22, 24.

Clonazepam is metabolized principally in the liver 22, 24.

The metabolic pathways include hydroxylation, reduction of the nitro groups to amine groups, and the addition of acetate to the amino grouping 22, 24.

In particular, clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamido-clonazepam 22, 24.

Hydroxylation at the

C-3 position also occurs 22, 24.

Hepatic cytochrome

P450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites 22, 24.

Hover over products below to view reaction partners Clonazepam 7-amino-clonazepam 3-hydroxy-7-amino-clonazepam 7-acetamido-clonazepam 3-hydroxy-7-acetamido-clonazepam 3-hydroxy-clonazepam glucuronyl-3-hydroxy-clonazepam.

Approximately 50-70% of a clonazepam dose is excreted in the urine and 10-30% is excreted in the feces as metabolites 22, 24.

The excretion of unchanged clonazepam in the urine is typically less than 2% of the administered dose 22, 24.

Metabolites of clonazepam are present in urine as both free and conjugated (glucuronide and sulfate) compounds 22, 24.

The mean elimination half-life determined for clonazepam is independent of the dose given and has been documented as being about 30-40 hours 22, 24.

The documented clearance for clonazepam is approximately 55 ml/min regardless of gender 22.

Nevertheless, clearance values normalized by weight decline with increasing body weight 22.

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Benzodiazepines like clonazepam commonly cause drowsiness, ataxia, dysarthria, and nystagmus.

Overdose with clonazepam is generally not life-threatening if the drug is taken alone, but may lead to areflexia, apnea, hypotension, cardiorespiratory depression, and coma.

Coma, if it does occur, usually lasts a few hours but it can become more protracted and cyclical, especially in elderly patients.

Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations.

Benzodiazepine respiratory depressant effects are more serious when compounded in patients with respiratory disease.

An increased risk of congenital malformations associated with the use of benzodiazepine drugs like clonazepam has been suggested in several studies Label 22, 24.

There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy Label 22, 24.

There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy Label 22, 24.

In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period Label 22, 24.

In general, it is best for patients who are of childbearing potential and also use benzodiazepines like clonazepam to discuss such matters with their health care professionals as careful consideration must be undertaken regarding the intersection of the risks of untreated seizure potential in the patient and any possible toxicity to the fetus Label 22, 24.

Although the active ingredient of clonazepam has been found to pass into the maternal milk in small amounts only, mothers receiving clonazepam should not breast-feed their infants Label 22, 24.

Since the possibility that adverse effects on the physical or mental development of the child could become apparent only after a number of years, the risk-benefit consideration of the long-term use of clonazepam in pediatric patients younger than five years of age is important Label 22, 24.

The pharmacological effects of benzodiazepines like clonazepam appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms, and organ function Label 22, 24.

In general elderly patients should be started on the lowest possible dose of clonazepam and observed closely Label 22, 24.

There is an increased risk for falls and fractures among elderly and debilitated benzodiazepine users Label 22, 24.

The risk is increased in those taking concomitant sedatives, including substances like benzodiazepines, alcoholic beverages, and so on Label 22, 24.

Some oral

LD50 values documented are >4000 mg/kg for the mouse model, >4000 mg/kg for the adult rat model, and >2000 mg/kg for the rabbit model 22.

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.

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.

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.

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.

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) .

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

Interference with Cognitive and Motor Performance

Since clonazepam tablets produces 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 therapy.

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 Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 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.

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.

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.

Clonazepam tablets are contraindicated in patients with the following conditions: History of sensitivity to benzodiazepines Clinical or biochemical evidence of significant liver disease Acute narrow angle glaucoma (it may be used in patients with open angle glaucoma who are receiving appropriate therapy).

Clonazepam is available as a tablet.

The tablets should be administered with water by swallowing the tablet whole.

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.

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 mg 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 mg 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.

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.

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 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 mg 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.

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

There is no clinical trial experience with clonazepam tablets in panic disorder patients 65 years of age and older.

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 Reactions and DRUG ABUSE AND DEPENDENCE: Dependence.

Clonazepam tablets

USP 0.5 mg are orange, round, flat faced, beveled edge, scored, debossed with “1” and “2” on one side and plain on other.

They are supplied as follows

NDC: 70518-1801-00 NDC: 70518-1801-01 OUTER PACKAGING: 100 in 1 BOX INNER PACKAGING: 1 in 1 POUCH Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). .

Suite #4 Indiana, PA 1-724-465-8762.

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 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.

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.

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.

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.

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.

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/m 2 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 and 100 times the MRHD of 4 mg/day for panic disorder, respectively, on a mg/m 2 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.

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.

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

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 USAGE and DOSAGE AND ADMINISTRATION.

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

Clinical studies of clonazepam tablets did not include sufficient numbers of subjects aged 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.