Clonazepam Tablets, Usp

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

Clonazepam is 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).

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

Clonazepam tablets USP 1 mg are blue, round, flat faced, beveled edge, debossed with C 1 on one side and plain on the other. They are supplied as follows:

NDC 68071-5247-9 BOTTLES OF 90

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

Manufactured For:



Accord Healthcare, Inc.,



1009, Slater Road,



Suite 210-B,



Durham, NC 27703,



USA.

Manufactured By:



Intas Pharmaceuticals Limited,



Ahmedabad -380 009, India.

10 0533 2 682353

Issued April 2018

Clonazepam, a benzodiazepine, is available as scored tablets debossed with “1” and “2” containing 0.5 mg of clonazepam and unscored tablets debossed with “C 1” on 1 mg tablets and “C 2” on 2 mg tablets containing 1 mg or 2 mg of clonazepam. Each tablet contains anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and starch (corn), with the following colorants: 0.5 mg-FD&C Yellow No. 6 Lake and 1 mg- FD&C Blue No.2 Lake.

Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72 and the following structural formula:

Drug Interactions:

Labor and Delivery:

The effect of clonazepam on labor and delivery in humans has not been specifically studied; however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena (see PRECAUTIONS: Pregnancy).

Nursing Mothers:

The effects of clonazepam 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 clonazepam and any potential adverse effects on the breastfed infant from clonazepam or from the underlying maternal condition.

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 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.

Geriatric Use:

Clinical studies of clonazepam 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 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 and observed closely.

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/m ²) basis.

Controlled Substance Class:

Clonazepam is a Schedule IV controlled substance.

Physical and Psychological Dependence:

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, psychosis, hallucinations, behavioral disorder, mood changes, tremor, abdominal and muscle cramps) have occurred following abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving clonazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see CLINICAL PHARMACOLOGY: Clinical Trials), patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. However, there are not sufficient data from adequate and well-controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.

Pregnancy:

Pharmacokinetics in Demographic Subpopulations and in Disease States:

Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients. (see CONTRAINDICATIONS).

In children, clearance values of 0.42 ± 0.32 mL/min/kg (ages 2 – 18 years) and 0.88 ± 0.4 mL/min/kg (ages 7 – 12 years) were reported; these values decreased with increasing body weight. Ketogenic diet in children does not affect clonazepam concentrations.

Risks from Concomitant Use with Opioids: Concomitant use of benzodiazepines, including clonazepam, 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 clonazepam 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 is used with opioids (see PRECAUTIONS : Information for Patients and PRECAUTIONS : Drug Interactions).

Interference with Cognitive and Motor Performance: Since clonazepam 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 (see PRECAUTIONS: Drug Interactions and Information for Patients).

Clonazepam is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-V. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of clonazepam 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 CLINICAL PHARMACOLOGY: Clinical Trials).

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 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 for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Medication Guide

Clonazepam Tablets, USP

(kloe-NA-za-pam)

CIV

What is the most important information I should know about clonazepam tablets?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affects you.
• Clonazepam tablets may cause problems with your coordination, especially when you are walking or picking things up.

• Like other antiepileptic drugs, clonazepam tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
  
  

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

Stopping clonazepam tablets suddenly can cause serious problems. Stopping clonazepam tablets suddenly can cause seizures that will not stop (status epilepticus).

• Do not stop taking clonazepam all of a sudden. Stopping clonazepam tablets suddenly can cause seizures that do not stop, hearing or seeing things that are not there (hallucinations), shaking, and stomach and muscle cramps.
• Talk to your healthcare provider about slowly stopping clonazepam tablets to avoid withdrawal symptoms.
• Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.

Clonazepam tablets is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep clonazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away clonazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.

What is Clonazepam tablets?

Clonazepam tablets is a prescription medicine used alone or with other medicines to treat:

• certain types of seizure disorders (epilepsy) in adults and children
• panic disorder with or without fear of open spaces (agoraphobia) in adults
  
  It is not known if clonazepam tablets is safe or effective in treating panic disorder in children younger than 18 years old.

Who should not take Clonazepam tablets?

Do not take clonazepam tablets if you:

• are allergic to benzodiazepines
• have significant liver disease
• have an eye disease called acute narrow angle glaucoma

Ask your healthcare provider if you are not sure if you have any of the problems listed above.

Before you take clonazepam tablets, tell your healthcare provider if you:

• have liver or kidney problems
• have lung problems (respiratory disease)
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical problems
• are pregnant or plan to become pregnant. It is not known if clonazepam tablets can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking clonazepam tablets. You and your healthcare provider will decide if you should take clonazepam tablets while you are pregnant.

• Studies in pregnant animals have shown harmful effects of benzodiazepine medications (including the active ingredient in clonazepam tablets on the developing fetus.
• Children born to mothers receiving benzodiazepine medications including clonazepam tablets late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, hypothermia, and withdrawal symptoms.
• If you become pregnant while taking clonazepam tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking clonazepam tablets with certain other medicines can cause side effects or affect how well clonazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take clonazepam tablets?

• Take clonazepam tablets exactly as your healthcare provider tells you. If you take clonazepam tablets for seizures, your healthcare provider may change the dose until you are taking the right amount of medicine to control your symptoms.
• Clonazepam is available as a tablet.
• Do not stop taking clonazepam tablets without first talking to your healthcare provider.

Stopping clonazepam tablets suddenly can cause serious problems.

• Clonazepam tablets should be taken with water and swallowed whole.
• If you take too much clonazepam tablets, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking clonazepam tablets?

• Clonazepam tablets can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affect you.
• Do not drink alcohol or take other medicines that may make you sleepy or dizzy while taking clonazepam tablets until you talk to your healthcare provider. When taken with alcohol or medicines that cause sleepiness or dizziness, clonazepam tablets may make your sleepiness or dizziness much worse.

What are the possible side effects of clonazepam tablets?

See “What is the most important information I should know about clonazepam tablets?”

Clonazepam tablets can also make your seizures happen more often or make them worse. Call your healthcare provider right away if your seizures get worse while taking clonazepam tablets.

The most common side effects of clonazepam tablets include:

• Drowsiness
• Problems with walking and coordination
• Dizziness
• Depression
• Fatigue
• Problems with memory

These are not all the possible side effects of clonazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store clonazepam tablets?

• Store clonazepam tablets between 59ºF to 86ºF (15ºC to 30ºC).

Keep clonazepam tablets and all medicines out of the reach of children.

General Information about clonazepam tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use clonazepam tablets for a condition for which it was not prescribed. Do not give clonazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about clonazepam tablets that is written for health professionals.

For more information, go to www.accordhealthcare.us or call Accord Healthcare Inc. at 1-866-941-7875.

What are the ingredients in clonazepam tablets?

Active Ingredient: clonazepam

Inactive Ingredients:

Tablets:

• 0.5 mg tablets contain anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, starch (corn) and FD&C Yellow No. 6 Lake.
• 1 mg tablets contain anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, starch (corn) and FD&C Blue No. 2 Lake.
• 2 mg tablets contain anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and starch (corn)

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Medication guide available at https://www.accordhealthcare.us/medication-guides

Manufactured For:

Accord Healthcare, Inc.,

1009, Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Ahmedabad -380 009, India.

10 0533 2 682353

Issued April 2018

The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.

Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.

Clonazepam is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam may be useful.

Some loss of effect may occur during the course of clonazepam treatment (see PRECAUTIONS : Loss of Effect).

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

Antiepileptic drugs (AEDs), including clonazepam, 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.

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 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.

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.

Drug Interactions:

Labor and Delivery:

The effect of clonazepam on labor and delivery in humans has not been specifically studied; however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena (see PRECAUTIONS: Pregnancy).

Nursing Mothers:

The effects of clonazepam 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 clonazepam and any potential adverse effects on the breastfed infant from clonazepam or from the underlying maternal condition.

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 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.

Geriatric Use:

Clinical studies of clonazepam 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 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 and observed closely.

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/m ²) basis.

Controlled Substance Class:

Clonazepam is a Schedule IV controlled substance.

Physical and Psychological Dependence:

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, psychosis, hallucinations, behavioral disorder, mood changes, tremor, abdominal and muscle cramps) have occurred following abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving clonazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see CLINICAL PHARMACOLOGY: Clinical Trials), patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. However, there are not sufficient data from adequate and well-controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.

Pregnancy:

Pharmacokinetics in Demographic Subpopulations and in Disease States:

Controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients. (see CONTRAINDICATIONS).

In children, clearance values of 0.42 ± 0.32 mL/min/kg (ages 2 – 18 years) and 0.88 ± 0.4 mL/min/kg (ages 7 – 12 years) were reported; these values decreased with increasing body weight. Ketogenic diet in children does not affect clonazepam concentrations.

Risks from Concomitant Use with Opioids: Concomitant use of benzodiazepines, including clonazepam, 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 clonazepam 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 is used with opioids (see PRECAUTIONS : Information for Patients and PRECAUTIONS : Drug Interactions).

Interference with Cognitive and Motor Performance: Since clonazepam 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 (see PRECAUTIONS: Drug Interactions and Information for Patients).

Clonazepam, a benzodiazepine, is available as scored tablets debossed with “1” and “2” containing 0.5 mg of clonazepam and unscored tablets debossed with “C 1” on 1 mg tablets and “C 2” on 2 mg tablets containing 1 mg or 2 mg of clonazepam. Each tablet contains anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and starch (corn), with the following colorants: 0.5 mg-FD&C Yellow No. 6 Lake and 1 mg- FD&C Blue No.2 Lake.

Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.72 and the following structural formula:

Clonazepam tablets USP 1 mg are blue, round, flat faced, beveled edge, debossed with C 1 on one side and plain on the other. They are supplied as follows:

NDC 68071-5247-9 BOTTLES OF 90

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

Manufactured For:



Accord Healthcare, Inc.,



1009, Slater Road,



Suite 210-B,



Durham, NC 27703,



USA.

Manufactured By:



Intas Pharmaceuticals Limited,



Ahmedabad -380 009, India.

10 0533 2 682353

Issued April 2018

Clonazepam is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-V. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of clonazepam 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 CLINICAL PHARMACOLOGY: Clinical Trials).

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 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 for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Medication Guide

Clonazepam Tablets, USP

(kloe-NA-za-pam)

CIV

What is the most important information I should know about clonazepam tablets?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affects you.
• Clonazepam tablets may cause problems with your coordination, especially when you are walking or picking things up.

• Like other antiepileptic drugs, clonazepam tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempt to commit suicide
• new or worse depression
• new or worse anxiety
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
  
  

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

Stopping clonazepam tablets suddenly can cause serious problems. Stopping clonazepam tablets suddenly can cause seizures that will not stop (status epilepticus).

• Do not stop taking clonazepam all of a sudden. Stopping clonazepam tablets suddenly can cause seizures that do not stop, hearing or seeing things that are not there (hallucinations), shaking, and stomach and muscle cramps.
• Talk to your healthcare provider about slowly stopping clonazepam tablets to avoid withdrawal symptoms.
• Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.

Clonazepam tablets is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep clonazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away clonazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.

What is Clonazepam tablets?

Clonazepam tablets is a prescription medicine used alone or with other medicines to treat:

• certain types of seizure disorders (epilepsy) in adults and children
• panic disorder with or without fear of open spaces (agoraphobia) in adults
  
  It is not known if clonazepam tablets is safe or effective in treating panic disorder in children younger than 18 years old.

Who should not take Clonazepam tablets?

Do not take clonazepam tablets if you:

• are allergic to benzodiazepines
• have significant liver disease
• have an eye disease called acute narrow angle glaucoma

Ask your healthcare provider if you are not sure if you have any of the problems listed above.

Before you take clonazepam tablets, tell your healthcare provider if you:

• have liver or kidney problems
• have lung problems (respiratory disease)
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical problems
• are pregnant or plan to become pregnant. It is not known if clonazepam tablets can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking clonazepam tablets. You and your healthcare provider will decide if you should take clonazepam tablets while you are pregnant.

• Studies in pregnant animals have shown harmful effects of benzodiazepine medications (including the active ingredient in clonazepam tablets on the developing fetus.
• Children born to mothers receiving benzodiazepine medications including clonazepam tablets late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, hypothermia, and withdrawal symptoms.
• If you become pregnant while taking clonazepam tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking clonazepam tablets with certain other medicines can cause side effects or affect how well clonazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take clonazepam tablets?

• Take clonazepam tablets exactly as your healthcare provider tells you. If you take clonazepam tablets for seizures, your healthcare provider may change the dose until you are taking the right amount of medicine to control your symptoms.
• Clonazepam is available as a tablet.
• Do not stop taking clonazepam tablets without first talking to your healthcare provider.

Stopping clonazepam tablets suddenly can cause serious problems.

• Clonazepam tablets should be taken with water and swallowed whole.
• If you take too much clonazepam tablets, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking clonazepam tablets?

• Clonazepam tablets can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how clonazepam tablets affect you.
• Do not drink alcohol or take other medicines that may make you sleepy or dizzy while taking clonazepam tablets until you talk to your healthcare provider. When taken with alcohol or medicines that cause sleepiness or dizziness, clonazepam tablets may make your sleepiness or dizziness much worse.

What are the possible side effects of clonazepam tablets?

See “What is the most important information I should know about clonazepam tablets?”

Clonazepam tablets can also make your seizures happen more often or make them worse. Call your healthcare provider right away if your seizures get worse while taking clonazepam tablets.

The most common side effects of clonazepam tablets include:

• Drowsiness
• Problems with walking and coordination
• Dizziness
• Depression
• Fatigue
• Problems with memory

These are not all the possible side effects of clonazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store clonazepam tablets?

• Store clonazepam tablets between 59ºF to 86ºF (15ºC to 30ºC).

Keep clonazepam tablets and all medicines out of the reach of children.

General Information about clonazepam tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use clonazepam tablets for a condition for which it was not prescribed. Do not give clonazepam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about clonazepam tablets that is written for health professionals.

For more information, go to www.accordhealthcare.us or call Accord Healthcare Inc. at 1-866-941-7875.

What are the ingredients in clonazepam tablets?

Active Ingredient: clonazepam

Inactive Ingredients:

Tablets:

• 0.5 mg tablets contain anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, starch (corn) and FD&C Yellow No. 6 Lake.
• 1 mg tablets contain anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, starch (corn) and FD&C Blue No. 2 Lake.
• 2 mg tablets contain anhydrous lactose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and starch (corn)

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Medication guide available at https://www.accordhealthcare.us/medication-guides

Manufactured For:

Accord Healthcare, Inc.,

1009, Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Ahmedabad -380 009, India.

10 0533 2 682353

Issued April 2018

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

Clonazepam is 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).

The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.

Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.

Clonazepam is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic, and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam may be useful.

Some loss of effect may occur during the course of clonazepam treatment (see PRECAUTIONS : Loss of Effect).

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

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

Antiepileptic drugs (AEDs), including clonazepam, 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.

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 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.

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.