CLONAZEPAM tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
CLONAZEPAM (UNII: 5PE9FDE8GB) (CLONAZEPAM - UNII:5PE9FDE8GB)
Available from:
Teva Pharmaceuticals USA, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Clonazepam tablets are 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 tablets may be useful. Some loss of effect may occur during the course of clonazepam treatment (see PRECAUTIONS: Loss of Effect ). Clonazepam tablets are 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 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 CLINICAL PHARMACOLOGY, Clinical Trials ). Panic disorder (DSM-V) is charact
Product summary:
Clonazepam tablets USP 0.5 mg are available as yellow, round, flat beveled, tablets. Scored and debossed with "832" above the score on one side, debossed with "TEVA" on the other side. Packaged in bottles of 100 (NDC 0093-0832-01) with a child-resistant closure, in bottles of 500 (NDC 0093-0832-05) and 1000 (NDC 0093-0832-10). Clonazepam tablets USP 1 mg are available as mottled green, round, flat beveled tablets. Debossed with "833" on one side and debossed with "TEVA" on the other side. Packaged in bottles of 100 (NDC 0093-3212-01) with a child-resistant closure, in bottles of 500 (NDC 0093-3212-05) and 1000 (NDC 0093-3212-10). Clonazepam tablets USP 2 mg are available as white to off-white, round, flat beveled tablets. Debossed with "834" on one side and debossed with "TEVA" on the other side. Packaged in bottles of 100 (NDC 0093-3213-01) with a child-resistant closure, in bottles of 500 (NDC 0093-3213-05). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Manufactured In Czech Republic By: Teva Czech Industries, s.r.o. Opava-Komarov, Czech Republic Manufactured For: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. W 2/2018
Authorization status:
Abbreviated New Drug Application
Authorization number:
0093-0832-01, 0093-0832-05, 0093-3212-01, 0093-3212-05, 0093-3213-01, 0093-3213-05

Teva Pharmaceuticals USA, Inc.

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MEDICATION GUIDE

Clonazepam (klo-NAY-zeh-pam) Tablets USP, for oral use, CIV

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

Clonazepam tablets are a benzodiazepine medicine. Benzodiazepines can cause severe drowsiness,

breathing problems (respiratory depression), coma, and death when taken with opioid medicines.

Clonazepam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. This

may get better over time.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how

clonazepam tablets affect you.

Clonazepam tablets may cause problems with your coordination, especially when you are

walking or picking things up.

Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking clonazepam

tablets until you talk to your healthcare provider. When taken with alcohol or drugs that cause

sleepiness or dizziness, clonazepam tablets may make your sleepiness or dizziness worse.

Like other antiepileptic drugs, clonazepam tablets may cause suicidal thoughts or actions in a very

small number of people, about 1 in 500.

Call a 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

feeling agitated or restless

panic attacks

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.

Do not stop clonazepam tablets without first talking to a healthcare provider.

Stopping clonazepam tablets suddenly can cause serious problems. Stopping clonazepam

tablets suddenly can cause seizures that will not stop (status epilepticus).

Clonazepam tablets can cause abuse and dependence.

Do not stop taking clonazepam tablets 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 doctor about slowly stopping clonazepam tablets to avoid getting sick with

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 are 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 are clonazepam tablets?

Clonazepam tablets are 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 are 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.

are breastfeeding or plan to breastfeed. Clonazepam can pass into breast milk. You and your

healthcare provider should decide how you will feed your baby while you take clonazepam tablets.

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 many 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 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. You may also report side effects to

Teva Pharmaceuticals USA, Inc. at 1-888-838-2872.

How should I store clonazepam tablets?

Store clonazepam tablets between 68° to 77°F (20° to 25°C)

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

General Information about the safe and effect use of 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 they were not prescribed. Do not give clonazepam tablets to

other people, even if they have the same symptoms that you have. They may harm them.

You can ask your pharmacist or healthcare provider for information about clonazepam tablets that is written

for health professionals.

What are the ingredients in clonazepam tablets USP?

Active ingredient: clonazepam, USP

Inactive ingredients:

0.5 mg tablets contain corn starch, lactose monohydrate, magnesium stearate, microcrystalline

cellulose, povidone, and Yellow D&C No. 10 Aluminum Lake

1 mg tablets contain corn starch, FD&C Blue No. 1 Aluminum Lake, lactose monohydrate,

magnesium stearate, microcrystalline cellulose, povidone, and Yellow D&C No. 10 Aluminum Lake

2 mg tablets contain corn starch, lactose monohydrate, magnesium stearate, microcrystalline

cellulose, and povidone

Manufactured In Czech Republic By:

Teva Czech Industries, s.r.o.

Opava-Komarov, Czech Republic

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

For more information, call 1-888-838-2872.

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

Rev. F 2/2018

Revised: 2/2018

Document Id: c19156ff-3055-469c-8a6a-fc28ba371124

34391-3

Set id: 8069b1a0-7c06-4252-b44e-e2eef065d9b8

Version: 5

Effective Time: 20180228

Teva Pharmaceuticals USA, Inc.

CLONAZEPAM- clonazepam tablet

Teva Pharmaceuticals USA, Inc.

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CLONAZEPAM TABLETS USP CIV

Rx only

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation,

respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS).

Reserve concomitant prescribing of these drugs for use in patients for whom alternative

treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

DESCRIPTION

Each tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg clonazepam, USP, a benzodiazepine.

Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline

cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake.

Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No.

1 Aluminum Lake.

Chemically, clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one.

It is a light yellow crystalline powder. It has the following structural formula:

H ClN O M.W. 315.72

CLINICAL PHARMACOLOGY

Pharmacodynamics

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.

Pharmacokinetics

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.

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 to 18 years) and 0.88 ± 0.4 mL/min/kg

(ages 7 to 12 years) were reported; these values decreased with increasing body weight. Ketogenic diet

in children does not affect clonazepam concentrations.

Clinical Trials

Panic Disorder

The effectiveness of clonazepam in the treatment of panic disorder was demonstrated in two double-

blind, placebo-controlled studies of adult outpatients who had a primary diagnosis of panic disorder

(DSM-IIIR) with or without agoraphobia. In these studies, clonazepam was shown to be significantly

more effective than placebo in treating panic disorder on change from baseline in panic attack

frequency, the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global

Impression Improvement Score.

Study 1 was a 9 week, fixed-dose study involving clonazepam doses of 0.5, 1, 2, 3 or 4 mg/day or

placebo. This study was conducted in four phases: a 1 week placebo lead-in, a 3 week upward titration,

a 6 week fixed dose, and a 7 week discontinuance phase. A significant difference from placebo was

observed consistently only for the 1 mg/day group. The difference between the 1 mg dose group and

placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack

per week. At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic attacks,

compared to 56% of placebo-treated patients.

Study 2 was a 6 week, flexible-dose study involving clonazepam in a dose range of 0.5 to 4 mg/day or

placebo. This study was conducted in three phases: a 1 week placebo lead-in, a 6 week optimal-dose,

and a 6 week discontinuance phase. The mean clonazepam dose during the optimal dosing period was

2.3 mg/day. The difference between clonazepam and placebo in reduction from baseline in the number

of full panic attacks was approximately 1 panic attack per week. At endpoint, 62% of patients receiving

clonazepam were free of full panic attacks, compared to 37% of placebo-treated patients.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function

of race or gender.

INDICATIONS AND USAGE

Seizure Disorders

Clonazepam tablets are 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 tablets may be useful.

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

Effect).

Panic Disorder

Clonazepam tablets are 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 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 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 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 DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

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).

WARNINGS

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

PRECAUTIONS: Information for Patients).

Suicidal Behavior and Ideation

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.

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

Psychiatric

Other

Total

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 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.

Withdrawal Symptoms

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines

(see DRUG ABUSE AND DEPENDENCE).

PRECAUTIONS

General

Worsening of Seizures

When used in patients in whom several different types of seizure disorders coexist, clonazepam 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 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.

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 PRECAUTIONS: Risks of Abrupt Withdrawaland DRUG ABUSE

AND DEPENDENCE: Physical and Psychological Dependence). Paradoxical reactions are more likely to

occur in children and in the elderly.

Risks of Abrupt Withdrawal

The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy,

may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is

essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another

anticonvulsant may be indicated.

Caution in Renally Impaired Patients

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.

Hypersalivation

Clonazepam may produce an increase in salivation. This should be considered before giving the drug to

patients who have difficulty handling secretions.

Respiratory Depression

Clonazepam 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 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 only as prescribed.

Physicians are advised to discuss the following issues with patients for whom they prescribe

clonazepam:

Risks from Concomitant Use with Opioids

Inform patients and caregivers that potentially fatal additive effects may occur if clonazepam is used

with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see

WARNINGS, Risks from Concomitant Use With Opioidsand PRECAUTIONS, Drug Interactions).

Dose Changes

To assure the safe and effective use of benzodiazepines, patients should be informed that, since

benzodiazepines may produce psychological and physical dependence, it is advisable that they consult

with their physician before either increasing the dose or abruptly discontinuing this drug.

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 therapy does not affect them adversely.

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including clonazepam, 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

Patients should be advised to notify their physician if they become pregnant or intend to become

pregnant during therapy with clonazepam (see PRECAUTIONS: Pregnancy). Patients should be

encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they

become pregnant. This registry is collecting information about the safety of antiepileptic drugs during

pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS:

Pregnancy).

Nursing

Patients should be advised to notify their physician if they are breastfeeding or intend to breastfeed

during therapy.

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.

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 sites, and opioids interact primarily at mu receptors. When benzodiazepines and

opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related

respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and

opioids, and follow patients closely for respiratory depression and sedation.

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 coadministrated 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

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.

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/m ) basis.

Pregnancy

There are no adequate and well-controlled studies of clonazepam in pregnant women. Available human

data on the risk of teratogenicity are inconclusive. There is insufficient evidence in humans to assess

the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of

benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia,

hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have

taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently

withdrawal, during the postnatal period.

In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5, or

10 mg/kg/day during the period of organogenesis, a similar pattern of malformations (cleft palate, open

eyelid, fused sternebrae and limb defects) was observed at all doses, in a low, non-dose-related

incidence. The lowest dose tested is less than the maximum recommended human dose (MRHD) of 20

mg/day for seizure disorders and similar to the MRHD of 4 mg/day for panic disorder, on a mg/m

basis. Reductions in maternal weight gain occurred at doses of 5 mg/kg/day or greater and reduction in

embryofetal growth occurred in one study at a dose of 10 mg/kg/day.

No adverse maternal or embryofetal effects were observed in mice or rats following oral administration

of clonazepam during organogenesis of doses up to 15 or 40 mg/kg/day, respectively (4 and 20 times

the MRHD of 20 mg/day for seizure disorders and 20 and 100 times the MRHD of 4 mg/day for panic

disorder, respectively, on a mg/m 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.

To provide information regarding the effects of in utero exposure to clonazepam, physicians are

advised to recommend that pregnant patients taking clonazepam enroll in the NAAED Pregnancy

Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by

patients themselves. Information on this registry can also be found at the website

http://www.aedpregnancyregistry.org/.

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

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 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.

ADVERSE REACTIONS

The adverse experiences for clonazepam are provided separately for patients with seizure disorders

and with panic disorder.

Seizure Disorders

The most frequently occurring side effects of clonazepam are referable to CNS depression.

Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of

patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior

problems have been noted in approximately 25% of patients. Others, listed by system, including those

identified during postapproval use of clonazepam are:

Cardiovascular: Palpitations

Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema

Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis,

increased appetite, nausea, sore gums

Genitourinary: Dysuria, enuresis, nocturia, urinary retention

Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia

Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase

Musculoskeletal: Muscle weakness, pains

Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain

Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria,

dysdiadochokinesis, “glassy-eyed” appearance, headache, hemiparesis, hypotonia, nystagmus,

respiratory depression, slurred speech, tremor, vertigo

Psychiatric: Confusion, depression, amnesia, hysteria, increased libido, insomnia, psychosis (the

behavior effects are more likely to occur in patients with a history of psychiatric disturbances).

The following paradoxical reactions have been observed: irritability, aggression, agitation,

nervousness, hostility, anxiety, sleep disturbances, nightmares, abnormal dreams and hallucinations.

Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory

passages

Panic Disorder

Adverse events during exposure to clonazepam were obtained by spontaneous report and recorded by

clinical investigators using terminology of their own choosing. Consequently, it is not possible to

provide a meaningful estimate of the proportion of individuals experiencing adverse events without first

grouping similar types of events into a smaller number of standardized event categories. In the tables

and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse

events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as

noted below.

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.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials

Adverse Events Associated with Discontinuation of Treatment

Overall, the incidence of discontinuation due to adverse events was 17% in clonazepam 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 than that of placebo included the

following:

Table 2: Most Common Adverse Events (≥ 1%) Associated With Discontinuation of Treatment

Adverse Event

Clonazepam (N = 574)

Placebo (N = 294)

Somnolence

Depression

Dizziness

< 1%

Nervousness

Ataxia

Intellectual Ability Reduced

Adverse Events Occurring at an Incidence of 1% or More among Clonazepam-Treated Patients

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 (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.

Table 3: Treatment-Emergent Adverse Event Incidence in 6 to 9 Week Placebo-Controlled

Clinical Trials

*

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