United States - English - NLM (National Library of Medicine)
Teva Pharmaceuticals USA, Inc.
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
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
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
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
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
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:
problems with walking and coordination
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
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
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
Document Id: c19156ff-3055-469c-8a6a-fc28ba371124
Set id: 8069b1a0-7c06-4252-b44e-e2eef065d9b8
Effective Time: 20180228
Teva Pharmaceuticals USA, Inc.
CLONAZEPAM- clonazepam tablet
Teva Pharmaceuticals USA, Inc.
CLONAZEPAM TABLETS USP CIV
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.
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
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.
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.
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
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
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).
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).
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
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
Relative Risk: Incidence of
Events in Drug
Patients/Incidence in Placebo
Patients with Events
per 1000 Patients
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 of the barbiturate type have occurred after the discontinuation of benzodiazepines
(see DRUG ABUSE AND DEPENDENCE).
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
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.
Clonazepam may produce an increase in salivation. This should be considered before giving the drug to
patients who have difficulty handling secretions.
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).
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
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).
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.
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:
Patients should be advised to notify their physician if they are breastfeeding or intend to breastfeed
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.
Patients should be advised to avoid alcohol while taking clonazepam.
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
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.
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
Carcinogenicity studies have not been conducted with clonazepam.
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.
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
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
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).
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.
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
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.
The adverse experiences for clonazepam are provided separately for patients with seizure disorders
and with panic disorder.
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:
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
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
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
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
Table 2: Most Common Adverse Events (≥ 1%) Associated With Discontinuation of Treatment
Clonazepam (N = 574)
Placebo (N = 294)
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
Table 3: Treatment-Emergent Adverse Event Incidence in 6 to 9 Week Placebo-Controlled