Clonazepam has been related to the side effect of Obtundation. If you are taking Clonazepam and have experienced Obtundation this information may be of use to you.
IMPORTANT NOTE: The following information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist or other healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Consult your healthcare professional before using this drug.
Clonazepam Tablets USP, a benzodiazepine, is available as scored tablets containing 0.5 mg of clonazepam and unscored tablets
containing 1 mg or 2 mg of clonazepam. Each tablet also contains colloidal silicon dioxide, croscarmellose sodium, lactose
monohydrate, magnesium stearate and microcrystalline cellulose, with the following colorants: 0.5 mg – D&C Yellow #10 aluminum
lake; 1 mg – FD&C Blue #1 aluminum lake.
Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-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:
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. Convulsions produced in rodents by pentylenetetrazol or to a lesser extent, electrical stimulation
are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates,
muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge
in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.
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.
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 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.
In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration.
In some cases, dosage adjustment may re-establish efficacy.
Panic Disorder:
Clonazepam is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. 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-IV) 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 one-self);
(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 (seeDOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical
or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving
appropriate therapy but is contraindicated in acute narrow angle glaucoma.
WARNINGS
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).
Pregnancy Risks:
Data from several sources raise concerns about the use of clonazepam during pregnancy.
Animal Findings:
In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low
dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum
dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae
and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups. Reductions
in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one
study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were observed in mice and rats following administration
during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended
human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively,
on a mg/m2 basis).
General Concerns and Considerations About Anticonvulsants:
Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence
of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital,
but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar
association with the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggesting an elevated incidence of birth defects cannot be
regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining
adequate data on drug teratogenicity in humans; the possibility also exists that other factors (e.g., genetic factors or the
epileptic condition itself) may be more important than drug therapy in leading to birth defects. The great majority of mothers
on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued
in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure
disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug
may be considered prior to and during pregnancy; however, it cannot be said with any confidence that even mild seizures do
not pose some hazards to the developing embryo or fetus.
General Concerns About Benzodiazepines:
An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several
studies.
There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports
of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving
benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be
at some risk of experiencing withdrawal symptoms during the postnatal period.
Advice Regarding the Use of Clonazepam in Women of Childbearing Potential:
In general, the use of clonazepam in women of childbearing potential, and more specifically during known pregnancy, should
be considered only when the clinical situation warrants the risk to the fetus.
The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential
should be weighed in treating or counseling these women.
Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased
risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs
is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always
be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should
be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient
should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during
therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing
the drug.
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.
Laboratory Testing During Long-Term Therapy:
Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.
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. Because of this and the possibility of respiratory depression, clonazepam should be used with caution
in patients with chronic respiratory diseases.
Information for Patients:
Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam:
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 judgement, 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.
Pregnancy:
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with
clonazepam (see WARNINGS).
Nursing:
Patients should be advised not to breastfeed an infant if they are taking clonazepam.
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 Clonazepam on the Pharmacokinetics of Other Drugs:
Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. 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.
Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine
and phenobarbital, induce clonazepam metabolism, causing an approximately 30% 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, should be used cautiously in patients receiving clonazepam.
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:
Carcinogenicity studies have not been conducted with clonazepam.
The data currently available are not sufficient to determine the genotoxic potential of clonazepam.
In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day (low dose approximately
5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder,
respectively, on a mg/m2 basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning.
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 WARNINGS:Pregnancy Risks).
Nursing Mothers:
Mothers receiving clonazepam should not breastfeed their infants.
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 sections).
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 functions 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, are:
Psychiatric: Confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis, suicidal attempt (the behavior
effects are more likely to occur in patients with a history of psychiatric disturbances). The following paradoxical reactions
have been observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances,
nightmares and vivid dreams.
Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages
Cardiovascular: Palpitations
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase
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:
Adverse Event
Clonazepam (N=574)
Placebo (N=294)
Somnolence
7%
1%
Depression
4%
1%
Dizziness
1%
<1%
Nervousness
1%
0%
Ataxia
1%
0%
Intellectual Ability Reduced
1%
0%
Adverse Events Occurring at an Incidence of 1% or More Among Clonazepam-Treated Patients:
Table 1 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 1 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 1. Treatment-Emergent Adverse Event Incidence in 6- to 9-Week Placebo-Controlled Clinical Trials*
Treatment-emergent events for which the incidence in the clonazepam patients was ≥5% and at least twice that in the placebo
patients.
Somnolence
37%
10%
Depression
7%
1%
Coordination Abnormal
6%
0%
Ataxia
5%
0%
Treatment-Emergent Depressive Symptoms:
In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term "depression" were
reported in 7% of clonazepam-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose
relatedness. In these same trials, adverse events classified under the preferred term "depression" were reported as leading
to discontinuation in 4% of clonazepam-treated patients compared to 1% of placebo-treated patients. While these findings are
noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores
in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening
or emergence of clinical depression.
Other Adverse Events Observed During the Premarketing Evaluation of Clonazepam in Panic Disorder:
Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with
clonazepam at multiple doses during clinical trials. All reported events are included except those already listed in Table
1 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be
uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening.
It is important to emphasize that, although the events occurred during treatment with clonazepam, they were not necessarily
caused by it.
Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported
infrequently, which is defined as occurring in 1/100 to 1/1000 patients.
Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital,
injury, malaise, pain, cellulitis, inflammation localized
Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness,
hyperactivity, hypoesthesia, tongue thick, twitching
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, psychosis, hallucinations,
behavioral disorder, 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.
OVERDOSAGE
Human Experience:
Symptoms of clonazepam overdosage, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished
reflexes.
Overdose Management:
Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric
lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use
of levarterenol or metaraminol. Dialysis is of no known value.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative
effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior
to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous
access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients
treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects
for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine
users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.
Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine
effect in such patients may provoke seizures.
Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.
DOSAGE AND ADMINISTRATION
Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.
Seizure Disorders:
Adults:
The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased
in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further
increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose
is 20 mg.
The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before
adding clonazepam to an existing anticonvulsant regimen.
Pediatric Patients:
Clonazepam is administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years
of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or
three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance
dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further
increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the
largest dose should be given before retiring.
Geriatric Patients:
There is no clinical trial experience with clonazepam in seizure disorder patients 65 years of age and older. In general,
elderly patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS: Geriatric Use).
Panic Disorder:
Adults:
The initial dose for adults with panic disorder is 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day
may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal
effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and
were associated with more adverse effects. Nevertheless, it is possible that some individual patients may benefit from doses
of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 to 0.25 mg bid
every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience
of somnolence, administration of one dose at bedtime may be desirable.
Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn.
There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain
on it. Therefore, the physician who elects to use clonazepam for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Pediatric Patients:
There is no clinical trial experience with clonazepam in panic disorder patients under 18 years of age.
Geriatric Patients:
There is no clinical trial experience with clonazepam in panic disorder patients 65 years of age and older. In general, elderly
patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS: Geriatric Use).
HOW SUPPLIED
Clonazepam Tablets, USP are available as:
0.5 mg: light yellow, flat-faced beveled edge tablets, scored, debossed "2530" on one side and debossed "V" on the reverse
side, supplied in bottles of 10, 30, 60, 90, 100, 120, 500 and 1000.
1 mg: light blue, flat-faced beveled edge tablets, unscored, debossed "2531" on one side and debossed "V" on the reverse side,
supplied in bottles of 10, 30, 60, 90, 100, 120, 500 and 1000.
2 mg: white, flat-faced beveled edge tablets, unscored, debossed "2532" on one side and debossed "V" on the reverse side,
supplied in bottles of 10, 30, 60, 90, 100, 500 and 1000.
Dispense in a tight, light-resistant container as defined in the USP/NF.
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].
Manufactured for: QUALITEST PHARMACEUTICALS Huntsville, AL 35811
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