label

NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

KLONOPIN



TABLETS

(clonazepam)

Rx only

DESCRIPTION

Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation

containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation

containing 1 mg or 2 mg of clonazepam. Each tablet also contains lactose, magnesium

stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5

mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2

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

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 Klonopin 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, Klonopin 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 Klonopin 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 Klonopin 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 Klonopin 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: Klonopin 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,

Klonopin may be useful.

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 reestablish

efficacy.

Panic Disorder: Klonopin 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 Klonopin 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, ie, 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 Klonopin 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

Klonopin for extended periods should periodically reevaluate the long-term usefulness of

the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Klonopin 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 Klonopin 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 Klonopin therapy (see PRECAUTIONS: Drug

Interactions and Information for Patients).

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including Klonopin,

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.

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 (5-100 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

1.0

5.7

1.0

2.4

3.4

8.5

1.8

4.3

3.5

1.5

1.9

1.8

2.4

2.9

0.9

1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy

than in clinical trials for psychiatric or other conditions, but the absolute risk differences

were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Klonopin 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.

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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.

Pregnancy Risks: Data from several sources raise concerns about the use of Klonopin

during pregnancy.

Animal Findings: In three studies in which Klonopin 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/m

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/m

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 (eg, 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.

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 Klonopin in Women of Childbearing Potential: In general,

the use of Klonopin 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, Klonopin 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, Klonopin 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 Klonopin may produce absence status.

Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function

tests are advisable during long-term therapy with Klonopin.

Risks of Abrupt Withdrawal: The abrupt withdrawal of Klonopin, particularly in those

patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore,

when discontinuing Klonopin, gradual withdrawal is essential. While Klonopin is being

gradually withdrawn, the simultaneous substitution of another anticonvulsant may be

indicated.

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

Caution in Renally Impaired Patients: Metabolites of Klonopin 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: Klonopin 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, Klonopin should be used

with caution in patients with chronic respiratory diseases.

Information for Patients: A Klonopin Medication Guide must be given to the patient

each time Klonopin is dispensed, as required by law. Patients should be instructed to take

Klonopin only as prescribed. Physicians are advised to discuss the following issues with

patients for whom they prescribe Klonopin:

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 Klonopin therapy does not affect them adversely.

Suicidal Thinking and Behavior: Patients, their caregivers, and families should be

counseled that AEDs, including Klonopin, 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 Klonopin (see WARNINGS:

Pregnancy Risks). 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 not to breastfeed an infant if they are taking

Klonopin.

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 Klonopin.

Drug Interactions: Effect of Clonazepam on the Pharmacokinetics of Other Drugs:

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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.

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

max

clonazepam was 20% lower when the orally disintegrating tablet was given with

propantheline compared to when it was given alone.

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/m

basis), there was a decrease in the number of

pregnancies and in the number of offspring surviving until weaning.

Pregnancy: Teratogenic Effects: Pregnancy Category D (see WARNINGS: Pregnancy

Risks).

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

are advised to recommend that pregnant patients taking Klonopin 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 Klonopin on labor and delivery in humans has not

been specifically studied; however, perinatal complications have been reported in

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 Klonopin 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 Klonopin is important in pediatric patients being treated for

seizure disorder (see INDICATIONS AND USAGE and DOSAGE AND

ADMINISTRATION).

Safety and effectiveness in pediatric patients with panic disorder below the age of 18

have not been established.

Geriatric Use: Clinical studies of Klonopin 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 Klonopin 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 Klonopin and observed closely.

ADVERSE REACTIONS

The adverse experiences for Klonopin are provided separately for patients with seizure

disorders and with panic disorder.

Seizure Disorders: The most frequently occurring side effects of Klonopin 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:

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, hallucinations, hysteria, increased libido,

insomnia, psychosis (the behavior effects are more likely to occur in patients with a

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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

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

gastritis, increased appetite, nausea, sore gums

Genitourinary: Dysuria, enuresis, nocturia, urinary retention

Musculoskeletal: Muscle weakness, pains

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

or gain

Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia

Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline

phosphatase

Panic Disorder: Adverse events during exposure to Klonopin 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 Klonopin

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 Klonopin than that of placebo included the following:

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NDA 017533 Klonopin (clonazepam) tablets

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Table 2 Most Common Adverse Events (

≥

1%) Associated with

Discontinuation of Treatment

Adverse Event

Klonopin (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 Klonopin-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 Klonopin (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*

Clonazepam Maximum Daily Dose

Adverse Event

by Body System

1mg

n=96

2mg

n=129

3mg

n=113

≥

3mg

n=235

All

Klonopin

Groups

N=574

Placebo

N=294

Central & Peripheral Nervous

System

Somnolence†

Dizziness

Coordination Abnormal†

Ataxia†

Dysarthria†

Psychiatric

Depression

Memory Disturbance

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

Clonazepam Maximum Daily Dose

Adverse Event

by Body System

1mg

n=96

2mg

n=129

3mg

n=113

≥

3mg

n=235

All

Klonopin

Groups

N=574

Placebo

N=294

Nervousness

Intellectual Ability Reduced

Emotional Lability

Libido Decreased

Confusion

Respiratory System

Upper Respiratory Tract

Infection†

Sinusitis

Rhinitis

Coughing

Pharyngitis

Bronchitis

Gastrointestinal System

Constipation†

Appetite Decreased

Abdominal Pain†

Reference ID: 3398090

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

Clonazepam Maximum Daily Dose

Adverse Event

by Body System

1mg

n=96

2mg

n=129

3mg

n=113

≥

3mg

n=235

All

Klonopin

Groups

N=574

Placebo

N=294

Body as a Whole

Fatigue

Allergic Reaction

Musculoskeletal

Myalgia

Resistance Mechanism

Disorders

Influenza

Urinary System

Micturition Frequency

Urinary Tract Infection†

Vision Disorders

Blurred Vision

Reproductive Disorders‡

Female

Dysmenorrhea

Colpitis

Male

Ejaculation Delayed

Impotence

* Events reported by at least 1% of patients treated with Klonopin and for which the

incidence was greater than that for placebo.

† Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for

adverse event incidence was ≤0.10.

‡ Denominators for events in gender-specific systems are: n=240 (clonazepam), 102

(placebo) for male, and 334 (clonazepam), 192 (placebo) for female.

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

Commonly Observed Adverse Events:

Table 4 Incidence of Most Commonly Observed Adverse Events* in

Acute Therapy in Pool of 6- to 9-Week Trials

Adverse Event

(Genentech Preferred Term)

Clonazepam

(N=574)

Placebo

(N=294)

Somnolence

37%

10%

Depression

Coordination Abnormal

Ataxia

* Treatment-emergent events for which the incidence in the clonazepam patients was

≥5% and at least twice that in the placebo patients.

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 Klonopin-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 Klonopin-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 Klonopin in

Panic Disorder:

Following is a list of modified CIGY terms that reflect treatment-emergent adverse

events reported by patients treated with Klonopin at multiple doses during clinical trials.

All reported events are included except those already listed in Table 3 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 Klonopin, 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

Cardiovascular Disorders: chest pain, hypotension postural

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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

Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation,

stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel

movements frequent, pain pelvic, dyspepsia, hemorrhoids

Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness

Heart Rate and Rhythm Disorders: palpitation

Metabolic and Nutritional Disorders: thirst, gout

Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain

leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,

arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee

Platelet, Bleeding and Clotting Disorders: bleeding dermal

Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization,

dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased,

aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal,

illusion, nightmares, sleep disorder, suicide ideation, yawning

Reproductive Disorders, Female: breast pain, menstrual irregularity

Reproductive Disorders, Male: ejaculation decreased

Resistance Mechanism Disorders: infection mycotic, infection viral, infection

streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis

Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed,

pneumonia, pleurisy

Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact,

flushing, pruritus, pustular reaction, skin burns, skin disorder

Special Senses Other, Disorders: taste loss

Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder

dysfunction, urinary retention, urinary tract bleeding, urine discoloration

Vascular (Extracardiac) Disorders: thrombophlebitis leg

Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual

field defect, xerophthalmia

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class: Clonazepam is a Schedule IV controlled substance.

Physical and Psychological Dependence: Withdrawal symptoms, similar in character to

those noted with barbiturates and alcohol (eg, convulsions, psychosis, hallucinations,

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 (eg, 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.

Reference ID: 3398090

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

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 Klonopin to an existing anticonvulsant

regimen.

Pediatric Patients: Klonopin 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 Klonopin in seizure disorder

patients 65 years of age and older. In general, elderly patients should be started on low

doses of Klonopin 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

Klonopin for extended periods should periodically reevaluate the long-term usefulness of

the drug for the individual patient.

Pediatric Patients: There is no clinical trial experience with Klonopin in panic disorder

patients under 18 years of age.

Reference ID: 3398090

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Labeling Text October 2013

Geriatric Patients: There is no clinical trial experience with Klonopin in panic disorder

patients 65 years of age and older. In general, elderly patients should be started on low

doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).

HOW SUPPLIED

Klonopin tablets are available as scored tablets with a K-shaped perforation—0.5 mg,

orange (NDC 0004-0068-01); and unscored tablets with a K-shaped perforation—1 mg,

blue (NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottles of 100.

Imprint on tablets:

0.5 mg — 1/2 KLONOPIN (front)

ROCHE (scored side)

1 mg — 1 KLONOPIN (front)

ROCHE (reverse side)

2 mg — 2 KLONOPIN (front)

ROCHE (reverse side)

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Revised: Month Year

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NDA 017533 Klonopin (clonazepam) tablets

FDA Approved Medication Guide October 2013

Medication Guide

KLONOPIN



(KLON-oh-pin)

(clonazepam)

Tablets

Read this Medication Guide before you start taking KLONOPIN and each time

you get a refill. There may be new information. This information does not take the

place of talking to your healthcare provider about your medical condition or

treatment.

KLONOPIN can cause serious side effects. Because stopping KLONOPIN

suddenly can also cause serious problems, do not stop taking KLONOPIN without

talking to your healthcare provider first.

What is the most important information I should know about KLONOPIN?

Do not stop taking KLONOPIN without first talking to your healthcare

provider. Stopping KLONOPIN suddenly can cause serious problems.

KLONOPIN can cause serious side effects, including:

1. KLONOPIN can slow your thinking and motor skills

• Do not drive, operate heavy machinery, or do other dangerous activities

until you know how KLONOPIN affects you.

• Do not drink alcohol or take other drugs that may make you sleepy or

dizzy while taking KLONOPIN until you talk to your healthcare

provider. When taken with alcohol or drugs that cause sleepiness or

dizziness, KLONOPIN may make your sleepiness or dizziness worse.

2. Like other antiepileptic drugs, KLONOPIN 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

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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 KLONOPIN without first talking to a healthcare provider.

Stopping KLONOPIN suddenly can cause serious problems. Stopping

KLONOPIN suddenly can cause seizures that will not stop (status

epilepticus).

KLONOPIN may harm your unborn or developing baby.

• If you take KLONOPIN during pregnancy, your baby is at risk for serious

birth defects. These defects can happen as early as in the first month of

pregnancy, even before you know you are pregnant. Birth defects may

occur even in children born to women who are not taking any medicines

and do not have other risk factors.

• Children born to mothers receiving benzodiazepine medications (including

KLONOPIN) late in pregnancy may be at some risk of experiencing

breathing problems, feeding problems, hypothermia, and withdrawal

symptoms.

• Tell your healthcare provider right away if you become pregnant while

taking KLONOPIN. You and your healthcare provider should decide if

you will take KLONOPIN while you are pregnant.

• If you become pregnant while taking KLONOPIN, 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.

• KLONOPIN can pass into breast milk. Talk to your healthcare provider

about the best way to feed your baby if you take KLONOPIN. You and

your healthcare provider should decide if you will take KLONOPIN or

breast feed. You should not do both.

4. KLONOPIN can cause abuse and dependence.

• Do not stop taking KLONOPIN all of a sudden. Stopping KLONOPIN

suddenly can cause seizures that do not stop, hearing or seeing things that

are not there (hallucinations), shaking, and stomach and muscle cramps.

Reference ID: 3398090

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o Talk to your doctor about slowly stopping KLONOPIN to avoid

getting sick with withdrawal symptoms.

o 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.

KLONOPIN is a federally controlled substance (C-IV) because it can be

abused or lead to dependence. Keep KLONOPIN in a safe place to prevent

misuse and abuse. Selling or giving away KLONOPIN may harm others, and

is against the law. Tell your doctor if you have ever abused or been

dependent on alcohol, prescription medicines or street drugs.

What is KLONOPIN?

KLONOPIN is a prescription medicine used alone or with other medicines to

treat:

• certain types of seizure disorders (epilepsy) in adults and children

• panic disorder with or without fear of open spaces (agoraphobia) in adults

It is not known if KLONOPIN is safe or effective in treating panic disorder in

children younger than 18 years old.

Who should not take KLONOPIN?

Do not take KLONOPIN 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.

What should I tell my healthcare provider before taking KLONOPIN?

Before you take KLONOPIN, 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 conditions

Tell your healthcare provider about all the medicines you take, including

prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking KLONOPIN with certain other medicines can cause side effects or affect

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how well they work. Do not start or stop other medicines without talking to your

healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare

provider and pharmacist when you get a new medicine.

How should I take KLONOPIN?

• Take KLONOPIN exactly as your healthcare provider tells you.

KLONOPIN is available as a tablet.

• Do not stop taking KLONOPIN without first talking to your healthcare

provider. Stopping KLONOPIN suddenly can cause serious problems.

• KLONOPIN tablets should be taken with water and swallowed whole.

• If you take too much KLONOPIN, call your healthcare provider or local

Poison Control Center right away.

What should I avoid while taking KLONOPIN?

• KLONOPIN can slow your thinking and motor skills. Do not drive,

operate heavy machinery, or do other dangerous activities until you know

how KLONOPIN affects you.

• Do not drink alcohol or take other drugs that may make you sleepy or

dizzy while taking KLONOPIN until you talk to your healthcare

provider. When taken with alcohol or drugs that cause sleepiness or

dizziness, KLONOPIN may make your sleepiness or dizziness worse.

What are the possible side effects of KLONOPIN?

See “What is the most important information I should know about

KLONOPIN?”

KLONOPIN 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

KLONOPIN.

The most common side effects of KLONOPIN include:

• Drowsiness

• Problems with walking and coordination

• Dizziness

• Depression

• Fatigue

• Problems with memory

These are not all the possible side effects of KLONOPIN. For more information,

ask your healthcare provider or pharmacist.

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Tell your healthcare provider if you have any side effect that bothers you or that

does not go away.

Call your doctor for medical advice about side effects. You may report side

effects to FDA at 1-800-FDA-1088.

How should I store KLONOPIN?

• Store KLONOPIN between 59°F to 86°F (15°C to 30°C)

Keep KLONOPIN and all medicines out of the reach of children.

General Information about KLONOPIN

Medicines are sometimes prescribed for purposes other than those listed in a

Medication Guide. Do not use KLONOPIN for a condition for which it was not

prescribed. Do not give KLONOPIN to other people, even if they have the same

symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about

KLONOPIN. If you would like more information, talk with your healthcare

provider. You can ask your pharmacist or healthcare provider for information

about KLONOPIN that is written for health professionals.

For more information, go to www.gene.com/gene/products/information/klonopin

or call 1-888-835-2555.

What are the ingredients in KLONOPIN?

Active ingredient: clonazepam

Inactive ingredients:

• Tablets:

o 0.5 mg tablets contain lactose, magnesium stearate,

microcrystalline cellulose, corn starch, FD&C Yellow No. 6 Lake

o 1 mg tablets contain lactose, magnesium stearate, microcrystalline

cellulose, corn starch, FD&C Blue No. 1 Lake and FD&C Blue

No. 2 Lake

o 2 mg tablets contain lactose, magnesium stearate, microcrystalline

cellulose, corn starch

Issued: Month Year

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

Administration.

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For additional copies of this Medication Guide, please call 1-877-436-3683 or visit

www.gene.com/gene/products/information/klonopin.

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Klonopin (clonazepam) tablets NDA 017533

Klonopin (clonazepam) wafers NDA 020813

FDA Approved Labeling Text October 2013

2 KLONOPIN



TABLETS

3 (clonazepam)

4 KLONOPIN



WAFERS

5 (clonazepam orally disintegrating tablets)

6 Rx only

7 DESCRIPTION

8 Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation

9 containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation

10 containing 1 mg or 2 mg of clonazepam. Each tablet also contains lactose, magnesium

11 stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5

12 mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2

13 Lake.

14 Klonopin is also available as an orally disintegrating tablet containing 0.125 mg, 0.25

15 mg, 0.5 mg, 1 mg or 2 mg clonazepam. Each orally disintegrating tablet also contains

16 gelatin, mannitol, methylparaben sodium, propylparaben sodium and xanthan gum.

17 Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-

18 benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of

19 315.72 and the following structural formula:

21 CLINICAL PHARMACOLOGY

22 Pharmacodynamics: The precise mechanism by which clonazepam exerts its antiseizure

23 and antipanic effects is unknown, although it is believed to be related to its ability to

24 enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory

25 neurotransmitter in the central nervous system. Convulsions produced in rodents by

26 pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are

27 convulsions produced by photic stimulation in susceptible baboons. A taming effect in

28 aggressive primates, muscle weakness and hypnosis are also produced. In humans,

29 clonazepam is capable of suppressing the spike and wave discharge in absence seizures

30 (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in

31 minor motor seizures.

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Klonopin (clonazepam) tablets NDA 017533

Klonopin (clonazepam) wafers NDA 020813

FDA Approved Labeling Text October 2013

32 Pharmacokinetics: Clonazepam is rapidly and completely absorbed after oral

33 administration. The absolute bioavailability of clonazepam is about 90%. Maximum

34 plasma concentrations of clonazepam are reached within 1 to 4 hours after oral

35 administration. Clonazepam is approximately 85% bound to plasma proteins.

36 Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being

37 excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group

38 to the 4-amino derivative. This derivative can be acetylated, hydroxylated and

39 glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in

40 clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically

41 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the

42 dosing range. There is no evidence that clonazepam induces its own metabolism or that

43 of other drugs in humans.

44 Pharmacokinetics in Demographic Subpopulations and in Disease States: Controlled

45 studies examining the influence of gender and age on clonazepam pharmacokinetics have

46 not been conducted, nor have the effects of renal or liver disease on clonazepam

47 pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is

48 possible that liver disease will impair clonazepam elimination. Thus, caution should be

49 exercised when administering clonazepam to these patients.

50 Clinical Trials: Panic Disorder: The effectiveness of Klonopin in the treatment of panic

51 disorder was demonstrated in two double-blind, placebo-controlled studies of adult

52 outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without

53 agoraphobia. In these studies, Klonopin was shown to be significantly more effective

54 than placebo in treating panic disorder on change from baseline in panic attack frequency,

55 the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global

56 Impression Improvement Score.

57 Study 1 was a 9-week, fixed-dose study involving Klonopin doses of 0.5, 1, 2, 3 or 4

58 mg/day or placebo. This study was conducted in four phases: a 1-week placebo lead-in, a

59 3-week upward titration, a 6-week fixed dose and a 7-week discontinuance phase. A

60 significant difference from placebo was observed consistently only for the 1 mg/day

61 group. The difference between the 1 mg dose group and placebo in reduction from

62 baseline in the number of full panic attacks was approximately 1 panic attack per week.

63 At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic

64 attacks, compared to 56% of placebo-treated patients.

65 Study 2 was a 6-week, flexible-dose study involving Klonopin in a dose range of 0.5 to 4

66 mg/day or placebo. This study was conducted in three phases: a 1-week placebo lead-in, a

67 6-week optimal-dose and a 6-week discontinuance phase. The mean clonazepam dose

68 during the optimal dosing period was 2.3 mg/day. The difference between Klonopin and

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

70 1 panic attack per week. At endpoint, 62% of patients receiving clonazepam were free of

71 full panic attacks, compared to 37% of placebo-treated patients.

72 Subgroup analyses did not indicate that there were any differences in treatment outcomes

73 as a function of race or gender.

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74 INDICATIONS AND USAGE

75 Seizure Disorders: Klonopin is useful alone or as an adjunct in the treatment of the

76 Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In

77 patients with absence seizures (petit mal) who have failed to respond to succinimides,

78 Klonopin may be useful.

79 In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often

80 within 3 months of administration. In some cases, dosage adjustment may reestablish

81 efficacy.

82 Panic Disorder: Klonopin is indicated for the treatment of panic disorder, with or

83 without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the

84 occurrence of unexpected panic attacks and associated concern about having additional

85 attacks, worry about the implications or consequences of the attacks, and/or a significant

86 change in behavior related to the attacks.

87 The efficacy of Klonopin was established in two 6- to 9-week trials in panic disorder

88 patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see

89 CLINICAL PHARMACOLOGY: Clinical Trials).

90 Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a

91 discrete period of intense fear or discomfort in which four (or more) of the following

92 symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations,

93 pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4)

94 sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or

95 discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or

96 faint; (9) derealization (feelings of unreality) or depersonalization (being detached from

97 oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or

98 tingling sensations); (13) chills or hot flushes.

99 The effectiveness of Klonopin in long-term use, that is, for more than 9 weeks, has not

100 been systematically studied in controlled clinical trials. The physician who elects to use

101 Klonopin for extended periods should periodically reevaluate the long-term usefulness of

102 the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

103 CONTRAINDICATIONS

104 Klonopin should not be used in patients with a history of sensitivity to benzodiazepines,

105 nor in patients with clinical or biochemical evidence of significant liver disease. It may

106 be used in patients with open angle glaucoma who are receiving appropriate therapy but

107 is contraindicated in acute narrow angle glaucoma.

108 WARNINGS

109 Interference With Cognitive and Motor Performance: Since Klonopin produces CNS

110 depression, patients receiving this drug should be cautioned against engaging in

111 hazardous occupations requiring mental alertness, such as operating machinery or driving

112 a motor vehicle. They should also be warned about the concomitant use of alcohol or

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113 other CNS-depressant drugs during Klonopin therapy (see PRECAUTIONS: Drug

114 Interactions and Information for Patients).

115 Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including Klonopin,

116 increase the risk of suicidal thoughts or behavior in patients taking these drugs for any

117 indication. Patients treated with any AED for any indication should be monitored for the

118 emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual

119 changes in mood or behavior.

120 Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy)

121 of 11 different AEDs showed that patients randomized to one of the AEDs had

122 approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal

123 thinking or behavior compared to patients randomized to placebo. In these trials, which

124 had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal

125 behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24%

126 among 16,029 placebo-treated patients, representing an increase of approximately one

127 case of suicidal thinking or behavior for every 530 patients treated. There were four

128 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the

129 number is too small to allow any conclusion about drug effect on suicide.

130 The increased risk of suicidal thoughts or behavior with AEDs was observed as early as

131 one week after starting drug treatment with AEDs and persisted for the duration of

132 treatment assessed. Because most trials included in the analysis did not extend beyond 24

133 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

134 The risk of suicidal thoughts or behavior was generally consistent among drugs in the

135 data analyzed. The finding of increased risk with AEDs of varying mechanisms of action

136 and across a range of indications suggests that the risk applies to all AEDs used for any

137 indication. The risk did not vary substantially by age (5-100 years) in the clinical trials

138 analyzed.

139 Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

140 Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled

141 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

1.0

5.7

1.0

2.4

3.4

8.5

1.8

4.3

3.5

1.5

1.9

1.8

2.4

2.9

0.9

1.9

142

143 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy

144 than in clinical trials for psychiatric or other conditions, but the absolute risk differences

145 were similar for the epilepsy and psychiatric indications.

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146 Anyone considering prescribing Klonopin or any other AED must balance the risk of

147 suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other

148 illnesses for which AEDs are prescribed are themselves associated with morbidity and

149 mortality and an increased risk of suicidal thoughts and behavior. Should suicidal

150 thoughts and behavior emerge during treatment, the prescriber needs to consider whether

151 the emergence of these symptoms in any given patient may be related to the illness being

152 treated.

153 Patients, their caregivers, and families should be informed that AEDs increase the risk of

154 suicidal thoughts and behavior and should be advised of the need to be alert for the

155 emergence or worsening of the signs and symptoms of depression, any unusual changes

156 in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about

157 self-harm. Behaviors of concern should be reported immediately to healthcare providers.

158 Pregnancy Risks: Data from several sources raise concerns about the use of Klonopin

159 during pregnancy.

160 Animal Findings: In three studies in which Klonopin was administered orally to pregnant

161 rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the

162

163

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/m

basis) during the period

164 of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused

165 sternebrae and limb defects) was observed in a low, non-dose-related incidence in

166 exposed litters from all dosage groups. Reductions in maternal weight gain occurred at

167 dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one

168 study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were

169 observed in mice and rats following administration during organogenesis of oral doses up

170 to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum

171

172

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/m

basis).

173 General Concerns and Considerations About Anticonvulsants: Recent reports suggest an

174 association between the use of anticonvulsant drugs by women with epilepsy and an

175 elevated incidence of birth defects in children born to these women. Data are more

176 extensive with respect to diphenylhydantoin and phenobarbital, but these are also the

177 most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a

178 possible similar association with the use of all known anticonvulsant drugs.

179 In children of women treated with drugs for epilepsy, reports suggesting an elevated

180 incidence of birth defects cannot be regarded as adequate to prove a definite cause and

181 effect relationship. There are intrinsic methodologic problems in obtaining adequate data

182 on drug teratogenicity in humans; the possibility also exists that other factors (eg, genetic

183 factors or the epileptic condition itself) may be more important than drug therapy in

184 leading to birth defects. The great majority of mothers on anticonvulsant medication

185 deliver normal infants. It is important to note that anticonvulsant drugs should not be

186 discontinued in patients in whom the drug is administered to prevent seizures because of

187 the strong possibility of precipitating status epilepticus with attendant hypoxia and threat

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188 to life. In individual cases where the severity and frequency of the seizure disorder are

189 such that the removal of medication does not pose a serious threat to the patient,

190 discontinuation of the drug may be considered prior to and during pregnancy; however, it

191 cannot be said with any confidence that even mild seizures do not pose some hazards to

192 the developing embryo or fetus.

193 General Concerns About Benzodiazepines: An increased risk of congenital

194 malformations associated with the use of benzodiazepine drugs has been suggested in

195 several studies.

196 There may also be non-teratogenic risks associated with the use of benzodiazepines

197 during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding

198 difficulties, and hypothermia in children born to mothers who have been receiving

199 benzodiazepines late in pregnancy. In addition, children born to mothers receiving

200 benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal

201 symptoms during the postnatal period.

202 Advice Regarding the Use of Klonopin in Women of Childbearing Potential: In general,

203 the use of Klonopin in women of childbearing potential, and more specifically during

204 known pregnancy, should be considered only when the clinical situation warrants the risk

205 to the fetus.

206 The specific considerations addressed above regarding the use of anticonvulsants for

207 epilepsy in women of childbearing potential should be weighed in treating or counseling

208 these women.

209 Because of experience with other members of the benzodiazepine class, Klonopin is

210 assumed to be capable of causing an increased risk of congenital abnormalities when

211 administered to a pregnant woman during the first trimester. Because use of these drugs

212 is rarely a matter of urgency in the treatment of panic disorder, their use during the first

213 trimester should almost always be avoided. The possibility that a woman of childbearing

214 potential may be pregnant at the time of institution of therapy should be considered. If

215 this drug is used during pregnancy, or if the patient becomes pregnant while taking this

216 drug, the patient should be apprised of the potential hazard to the fetus. Patients should

217 also be advised that if they become pregnant during therapy or intend to become

218 pregnant, they should communicate with their physician about the desirability of

219 discontinuing the drug.

220 Withdrawal Symptoms: Withdrawal symptoms of the barbiturate type have occurred

221 after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

222 PRECAUTIONS

223 General: Worsening of Seizures: When used in patients in whom several different types

224 of seizure disorders coexist, Klonopin may increase the incidence or precipitate the onset

225 of generalized tonic-clonic seizures (grand mal). This may require the addition of

226 appropriate anticonvulsants or an increase in their dosages. The concomitant use of

227 valproic acid and Klonopin may produce absence status.

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228 Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function

229 tests are advisable during long-term therapy with Klonopin.

230 Risks of Abrupt Withdrawal: The abrupt withdrawal of Klonopin, particularly in those

231 patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore,

232 when discontinuing Klonopin, gradual withdrawal is essential. While Klonopin is being

233 gradually withdrawn, the simultaneous substitution of another anticonvulsant may be

234 indicated.

235 Caution in Renally Impaired Patients: Metabolites of Klonopin are excreted by the

236 kidneys; to avoid their excess accumulation, caution should be exercised in the

237 administration of the drug to patients with impaired renal function.

238 Hypersalivation: Klonopin may produce an increase in salivation. This should be

239 considered before giving the drug to patients who have difficulty handling secretions.

240 Because of this and the possibility of respiratory depression, Klonopin should be used

241 with caution in patients with chronic respiratory diseases.

242 Information for Patients: A Klonopin Medication Guide must be given to the patient

243 each time Klonopin is dispensed, as required by law. Patients should be instructed to take

244 Klonopin only as prescribed. Physicians are advised to discuss the following issues with

245 patients for whom they prescribe Klonopin:

246 Dose Changes: To assure the safe and effective use of benzodiazepines, patients should

247 be informed that, since benzodiazepines may produce psychological and physical

248 dependence, it is advisable that they consult with their physician before either increasing

249 the dose or abruptly discontinuing this drug.

250 Interference With Cognitive and Motor Performance: Because benzodiazepines have the

251 potential to impair judgment, thinking or motor skills, patients should be cautioned about

252 operating hazardous machinery, including automobiles, until they are reasonably certain

253 that Klonopin therapy does not affect them adversely.

254 Suicidal Thinking and Behavior: Patients, their caregivers, and families should be

255 counseled that AEDs, including Klonopin, may increase the risk of suicidal thoughts and

256 behavior and should be advised of the need to be alert for the emergence or worsening of

257 symptoms of depression, any unusual changes in mood or behavior, or the emergence of

258 suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be

259 reported immediately to healthcare providers.

260 Pregnancy: Patients should be advised to notify their physician if they become pregnant

261 or intend to become pregnant during therapy with Klonopin (see WARNINGS:

262 Pregnancy Risks). Patients should be encouraged to enroll in the North American

263 Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry

264 is collecting information about the safety of antiepileptic drugs during pregnancy. To

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

266 Pregnancy).

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267 Nursing: Patients should be advised not to breastfeed an infant if they are taking

268 Klonopin.

269 Concomitant Medication: Patients should be advised to inform their physicians if they are

270 taking, or plan to take, any prescription or over-the-counter drugs, since there is a

271 potential for interactions.

272 Alcohol: Patients should be advised to avoid alcohol while taking Klonopin.

273 Drug Interactions: Effect of Clonazepam on the Pharmacokinetics of Other Drugs:

274 Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine

275 or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not

276 been investigated.

277 Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Literature reports suggest

278 that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam

279 pharmacokinetics.

280 In a study in which the 2 mg clonazepam orally disintegrating tablet was administered

281 with and without propantheline (an anticholinergic agent with multiple effects on the GI

282 tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the C

max

283 clonazepam was 20% lower when the orally disintegrating tablet was given with

284 propantheline compared to when it was given alone.

285 Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450

286 inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam

287 metabolism, causing an approximately 30% decrease in plasma clonazepam levels.

288 Although clinical studies have not been performed, based on the involvement of the

289 cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme

290 system, notably oral antifungal agents, should be used cautiously in patients receiving

291 clonazepam.

292 Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class

293 of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics,

294 antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of

295 antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and

296 by other anticonvulsant drugs.

297 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not

298 been conducted with clonazepam.

299 The data currently available are not sufficient to determine the genotoxic potential of

300 clonazepam.

301 In a two-generation fertility study in which clonazepam was given orally to rats at 10 and

302 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum

303

304

recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic

disorder, respectively, on a mg/m

basis), there was a decrease in the number of

305 pregnancies and in the number of offspring surviving until weaning.

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306 Pregnancy: Teratogenic Effects: Pregnancy Category D (see WARNINGS: Pregnancy

307 Risks).

308 To provide information regarding the effects of in utero exposure to Klonopin, physicians

309 are advised to recommend that pregnant patients taking Klonopin enroll in the NAAED

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

311 and must be done by patients themselves. Information on this registry can also be found

312 at the website http://www.aedpregnancyregistry.org/.

313 Labor and Delivery: The effect of Klonopin on labor and delivery in humans has not

314 been specifically studied; however, perinatal complications have been reported in

315 children born to mothers who have been receiving benzodiazepines late in pregnancy,

316 including findings suggestive of either excess benzodiazepine exposure or of withdrawal

317 phenomena (see WARNINGS: Pregnancy Risks).

318 Nursing Mothers: Mothers receiving Klonopin should not breastfeed their infants.

319 Pediatric Use: Because of the possibility that adverse effects on physical or mental

320 development could become apparent only after many years, a benefit-risk consideration

321 of the long-term use of Klonopin is important in pediatric patients being treated for

322 seizure disorder (see INDICATIONS AND USAGE and DOSAGE AND

323 ADMINISTRATION).

324 Safety and effectiveness in pediatric patients with panic disorder below the age of 18

325 have not been established.

326 Geriatric Use: Clinical studies of Klonopin did not include sufficient numbers of subjects

327 aged 65 and over to determine whether they respond differently from younger subjects.

328 Other reported clinical experience has not identified differences in responses between the

329 elderly and younger patients. In general, dose selection for an elderly patient should be

330 cautious, usually starting at the low end of the dosing range, reflecting the greater

331 frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or

332 other drug therapy.

333 Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will

334 impair clonazepam elimination. Metabolites of Klonopin are excreted by the kidneys; to

335 avoid their excess accumulation, caution should be exercised in the administration of the

336 drug to patients with impaired renal function. Because elderly patients are more likely to

337 have decreased hepatic and/or renal function, care should be taken in dose selection, and

338 it may be useful to assess hepatic and/or renal function at the time of dose selection.

339 Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients

340 generally should be started on low doses of Klonopin and observed closely.

341 ADVERSE REACTIONS

342 The adverse experiences for Klonopin are provided separately for patients with seizure

343 disorders and with panic disorder.

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344 Seizure Disorders: The most frequently occurring side effects of Klonopin are referable

345 to CNS depression. Experience in treatment of seizures has shown that drowsiness has

346 occurred in approximately 50% of patients and ataxia in approximately 30%. In some

347 cases, these may diminish with time; behavior problems have been noted in

348 approximately 25% of patients. Others, listed by system, are:

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

350 dysarthria, dysdiadochokinesis, ‘‘glassy-eyed’’ appearance, headache, hemiparesis,

351 hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo

352 Psychiatric: Confusion, depression, amnesia, hallucinations, hysteria, increased libido,

353 insomnia, psychosis (the behavior effects are more likely to occur in patients with a

354 history of psychiatric disturbances). The following paradoxical reactions have been

355 observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility,

356 anxiety, sleep disturbances, nightmares and vivid dreams

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

358 respiratory passages

359 Cardiovascular: Palpitations

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

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

362 gastritis, increased appetite, nausea, sore gums

363 Genitourinary: Dysuria, enuresis, nocturia, urinary retention

364 Musculoskeletal: Muscle weakness, pains

365 Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss

366 or gain

367 Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia

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

369 phosphatase

370 Panic Disorder: Adverse events during exposure to Klonopin were obtained by

371 spontaneous report and recorded by clinical investigators using terminology of their own

372 choosing. Consequently, it is not possible to provide a meaningful estimate of the

373 proportion of individuals experiencing adverse events without first grouping similar types

374 of events into a smaller number of standardized event categories. In the tables and

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

376 adverse events, except in certain cases in which redundant terms were collapsed into

377 more meaningful terms, as noted below.

378 The stated frequencies of adverse events represent the proportion of individuals who

379 experienced, at least once, a treatment-emergent adverse event of the type listed. An

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380 event was considered treatment-emergent if it occurred for the first time or worsened

381 while receiving therapy following baseline evaluation.

382

383

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

385 Adverse Events Associated With Discontinuation of Treatment:

386 Overall, the incidence of discontinuation due to adverse events was 17% in Klonopin

387 compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most

388 common events (≥1%) associated with discontinuation and a dropout rate twice or greater

389 for Klonopin than that of placebo included the following:

390 Table 2 Most Common Adverse Events (

≥

1%) Associated with

391 Discontinuation of Treatment

Adverse Event

Klonopin (N=574)

Placebo (N=294)

Somnolence

Depression

Dizziness

<1%

Nervousness

Ataxia

Intellectual Ability Reduced

392 Adverse Events Occurring at an Incidence of 1% or More Among Klonopin-Treated

393 Patients:

394 Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent

395 adverse events that occurred during acute therapy of panic disorder from a pool of two 6-

396 to 9-week trials. Events reported in 1% or more of patients treated with Klonopin (doses

397 ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in

398 placebo-treated patients are included.

399 The prescriber should be aware that the figures in Table 3 cannot be used to predict the

400 incidence of side effects in the course of usual medical practice where patient

401 characteristics and other factors differ from those that prevailed in the clinical trials.

402 Similarly, the cited frequencies cannot be compared with figures obtained from other

403 clinical investigations involving different treatments, uses and investigators. The cited

404 figures, however, do provide the prescribing physician with some basis for estimating the

405 relative contribution of drug and nondrug factors to the side effect incidence in the

406 population studied.

407 Table 3 Treatment-Emergent Adverse Event Incidence in 6- to 9-

408 Week Placebo-Controlled Clinical Trials*

Clonazepam Maximum Daily Dose

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Adverse Event

by Body System

1mg

n=96

2mg

n=129

3mg

n=113

≥

3mg

n=235

All

Klonopin

Groups

N=574

Placebo

N=294

Central & Peripheral Nervous

System

Somnolence†

Dizziness

Coordination Abnormal†

Ataxia†

Dysarthria†

Psychiatric

Depression

Memory Disturbance

Nervousness

Intellectual Ability Reduced

Emotional Lability

Libido Decreased

Confusion

Respiratory System

Upper Respiratory Tract

Infection†

Sinusitis

Rhinitis

Coughing

Pharyngitis

Bronchitis

Gastrointestinal System

Constipation†

Appetite Decreased

Abdominal Pain†

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Clonazepam Maximum Daily Dose

Adverse Event

by Body System

1mg

n=96

2mg

n=129

3mg

n=113

≥

3mg

n=235

All

Klonopin

Groups

N=574

Placebo

N=294

Body as a Whole

Fatigue

Allergic Reaction

Musculoskeletal

Myalgia

Resistance Mechanism

Disorders

Influenza

Urinary System

Micturition Frequency

Urinary Tract Infection†

Vision Disorders

Blurred Vision

Reproductive Disorders‡

Female

Dysmenorrhea

Colpitis

Male

Ejaculation Delayed

Impotence

409 * Events reported by at least 1% of patients treated with Klonopin and for which the

410 incidence was greater than that for placebo.

411 † Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for

412 adverse event incidence was ≤0.10.

413 ‡ Denominators for events in gender-specific systems are: n=240 (clonazepam), 102

414 (placebo) for male, and 334 (clonazepam), 192 (placebo) for female.

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Klonopin (clonazepam) tablets NDA 017533

Klonopin (clonazepam) wafers NDA 020813

FDA Approved Labeling Text October 2013

415 Commonly Observed Adverse Events:

416 Table 4 Incidence of Most Commonly Observed Adverse Events* in

417 Acute Therapy in Pool of 6- to 9-Week Trials

Adverse Event

(Genentech Preferred Term)

Clonazepam

(N=574)

Placebo

(N=294)

Somnolence

37%

10%

Depression

Coordination Abnormal

Ataxia

418 * Treatment-emergent events for which the incidence in the clonazepam patients was

419 ≥5% and at least twice that in the placebo patients.

420 Treatment-Emergent Depressive Symptoms:

421 In the pool of two short-term placebo-controlled trials, adverse events classified under the

422 preferred term “depression” were reported in 7% of Klonopin-treated patients compared

423 to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these

424 same trials, adverse events classified under the preferred term “depression” were reported

425 as leading to discontinuation in 4% of Klonopin-treated patients compared to 1% of

426 placebo-treated patients. While these findings are noteworthy, Hamilton Depression

427 Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D

428 scores in the clonazepam group than the placebo group suggesting that clonazepam-

429 treated patients were not experiencing a worsening or emergence of clinical depression.

430 Other Adverse Events Observed During the Premarketing Evaluation of Klonopin in

431 Panic Disorder:

432 Following is a list of modified CIGY terms that reflect treatment-emergent adverse

433 events reported by patients treated with Klonopin at multiple doses during clinical trials.

434 All reported events are included except those already listed in Table 3 or elsewhere in

435 labeling, those events for which a drug cause was remote, those event terms which were

436 so general as to be uninformative, and events reported only once and which did not have

437 a substantial probability of being acutely life-threatening. It is important to emphasize

438 that, although the events occurred during treatment with Klonopin, they were not

439 necessarily caused by it.

440 Events are further categorized by body system and listed in order of decreasing

441 frequency. These adverse events were reported infrequently, which is defined as

442 occurring in 1/100 to 1/1000 patients.

443 Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever,

444 shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain,

445 cellulitis, inflammation localized

446 Cardiovascular Disorders: chest pain, hypotension postural

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447 Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness,

448 feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness,

449 hyperactivity, hypoesthesia, tongue thick, twitching

450 Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation,

451 stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel

452 movements frequent, pain pelvic, dyspepsia, hemorrhoids

453 Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness

454 Heart Rate and Rhythm Disorders: palpitation

455 Metabolic and Nutritional Disorders: thirst, gout

456 Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain

457 leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,

458 arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee

459 Platelet, Bleeding and Clotting Disorders: bleeding dermal

460 Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization,

461 dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased,

462 aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal,

463 illusion, nightmares, sleep disorder, suicide ideation, yawning

464 Reproductive Disorders, Female: breast pain, menstrual irregularity

465 Reproductive Disorders, Male: ejaculation decreased

466 Resistance Mechanism Disorders: infection mycotic, infection viral, infection

467 streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis

468 Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed,

469 pneumonia, pleurisy

470 Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact,

471 flushing, pruritus, pustular reaction, skin burns, skin disorder

472 Special Senses Other, Disorders: taste loss

473 Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder

474 dysfunction, urinary retention, urinary tract bleeding, urine discoloration

475 Vascular (Extracardiac) Disorders: thrombophlebitis leg

476 Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual

477 field defect, xerophthalmia

478 DRUG ABUSE AND DEPENDENCE

479 Controlled Substance Class: Clonazepam is a Schedule IV controlled substance.

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FDA Approved Labeling Text October 2013

480 Physical and Psychological Dependence: Withdrawal symptoms, similar in character to

481 those noted with barbiturates and alcohol (eg, convulsions, psychosis, hallucinations,

482 behavioral disorder, tremor, abdominal and muscle cramps) have occurred following

483 abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have

484 usually been limited to those patients who received excessive doses over an extended

485 period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia)

486 have been reported following abrupt discontinuance of benzodiazepines taken

487 continuously at therapeutic levels for several months. Consequently, after extended

488 therapy, abrupt discontinuation should generally be avoided and a gradual dosage

489 tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone

490 individuals (such as drug addicts or alcoholics) should be under careful surveillance when

491 receiving clonazepam or other psychotropic agents because of the predisposition of such

492 patients to habituation and dependence.

493 Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see

494 CLINICAL PHARMACOLOGY: Clinical Trials), patients were gradually withdrawn

495 during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance

496 period was associated with good tolerability and a very modest clinical deterioration,

497 without evidence of a significant rebound phenomenon. However, there are not sufficient

498 data from adequate and well-controlled long-term clonazepam studies in patients with

499 panic disorder to accurately estimate the risks of withdrawal symptoms and dependence

500 that may be associated with such use.

501 OVERDOSAGE

502 Human Experience: Symptoms of clonazepam overdosage, like those produced by other

503 CNS depressants, include somnolence, confusion, coma and diminished reflexes.

504 Overdose Management: Treatment includes monitoring of respiration, pulse and blood

505 pressure, general supportive measures and immediate gastric lavage. Intravenous fluids

506 should be administered and an adequate airway maintained. Hypotension may be

507 combated by the use of levarterenol or metaraminol. Dialysis is of no known value.

508 Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete

509 or partial reversal of the sedative effects of benzodiazepines and may be used in

510 situations when an overdose with a benzodiazepine is known or suspected. Prior to the

511 administration of flumazenil, necessary measures should be instituted to secure airway,

512 ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a

513 substitute for, proper management of benzodiazepine overdose. Patients treated with

514 flumazenil should be monitored for resedation, respiratory depression and other residual

515 benzodiazepine effects for an appropriate period after treatment. The prescriber should

516 be aware of a risk of seizure in association with flumazenil treatment, particularly in

517 long-term benzodiazepine users and in cyclic antidepressant overdose. The complete

518 flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and

519 PRECAUTIONS, should be consulted prior to use.

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520 Flumazenil is not indicated in patients with epilepsy who have been treated with

521 benzodiazepines. Antagonism of the benzodiazepine effect in such patients may

522 provoke seizures.

523 Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.

524 DOSAGE AND ADMINISTRATION

525 Clonazepam is available as a tablet or an orally disintegrating tablet (wafer). The tablets

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

527 disintegrating tablet should be administered as follows: After opening the pouch, peel

528 back the foil on the blister. Do not push tablet through foil. Immediately upon opening

529 the blister, using dry hands, remove the tablet and place it in the mouth. Tablet

530 disintegration occurs rapidly in saliva so it can be easily swallowed with or without

531 water.

532

533 Seizure Disorders: Adults: The initial dose for adults with seizure disorders should not

534 exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of

535 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects

536 preclude any further increase. Maintenance dosage must be individualized for each

537 patient depending upon response. Maximum recommended daily dose is 20 mg.

538 The use of multiple anticonvulsants may result in an increase of depressant adverse

539 effects. This should be considered before adding Klonopin to an existing anticonvulsant

540 regimen.

541 Pediatric Patients: Klonopin is administered orally. In order to minimize drowsiness, the

542 initial dose for infants and children (up to 10 years of age or 30 kg of body weight)

543 should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in

544 two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg

545 every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has

546 been reached, unless seizures are controlled or side effects preclude further increase.

547 Whenever possible, the daily dose should be divided into three equal doses. If doses are

548 not equally divided, the largest dose should be given before retiring.

549 Geriatric Patients: There is no clinical trial experience with Klonopin in seizure disorder

550 patients 65 years of age and older. In general, elderly patients should be started on low

551 doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).

552 Panic Disorder: Adults: The initial dose for adults with panic disorder is 0.25 mg bid. An

553 increase to the target dose for most patients of 1 mg/day may be made after 3 days. The

554 recommended dose of 1 mg/day is based on the results from a fixed dose study in which

555 the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study

556 were less effective than the 1 mg/day dose and were associated with more adverse

557 effects. Nevertheless, it is possible that some individual patients may benefit from doses

558 of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased

559 in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or

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FDA Approved Labeling Text October 2013

560 until side effects make further increases undesired. To reduce the inconvenience of

561 somnolence, administration of one dose at bedtime may be desirable.

562 Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every

563 3 days, until the drug is completely withdrawn.

564 There is no body of evidence available to answer the question of how long the patient

565 treated with clonazepam should remain on it. Therefore, the physician who elects to use

566 Klonopin for extended periods should periodically reevaluate the long-term usefulness of

567 the drug for the individual patient.

568 Pediatric Patients: There is no clinical trial experience with Klonopin in panic disorder

569 patients under 18 years of age.

570 Geriatric Patients: There is no clinical trial experience with Klonopin in panic disorder

571 patients 65 years of age and older. In general, elderly patients should be started on low

572 doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).

573 HOW SUPPLIED

574 Klonopin tablets are available as scored tablets with a K-shaped perforation—0.5 mg,

575 orange (NDC 0004-0068-01); and unscored tablets with a K-shaped perforation—1 mg,

576 blue (NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottles of 100.

577 Imprint on tablets:

578 0.5 mg — 1/2 KLONOPIN (front)

579 ROCHE (scored side)

580 1 mg — 1 KLONOPIN (front)

581 ROCHE (reverse side)

582 2 mg — 2 KLONOPIN (front)

583 ROCHE (reverse side)

584 Klonopin Wafers (clonazepam orally disintegrating tablets) are white, round and

585 debossed with the tablet strength expressed as a fraction or whole number (1/8, 1/4, 1/2,

586 1, or 2). The tablets are available in blister packages of 60 (10 pouches/carton) as

587 follows:

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FDA Approved Labeling Text October 2013

588 0.125 mg debossed 1/8, (NDC 0004-0279-22)

589 0.25 mg debossed 1/4, (NDC 0004-0280-22)

590 0.5 mg debossed 1/2, (NDC 0004-0281-22)

591 1 mg debossed 1, (NDC 0004-0282-22)

592 2 mg debossed 2, (NDC 0004-0283-22)

593 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

594

595

596

597 Revised: Month Year

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FDA Approved MG Text October 2013

1 Medication Guide

2 KLONOPIN



(KLON-oh-pin)

3 (clonazepam)

4 Tablets and Wafers

6 Read this Medication Guide before you start taking KLONOPIN and each time

7 you get a refill. There may be new information. This information does not take the

8 place of talking to your healthcare provider about your medical condition or

9 treatment.

10 KLONOPIN can cause serious side effects. Because stopping KLONOPIN

11 suddenly can also cause serious problems, do not stop taking KLONOPIN without

12 talking to your healthcare provider first.

13 What is the most important information I should know about KLONOPIN?

14 Do not stop taking KLONOPIN without first talking to your healthcare

15 provider. Stopping KLONOPIN suddenly can cause serious problems.

16 KLONOPIN can cause serious side effects, including:

17 1. KLONOPIN can slow your thinking and motor skills

18 • Do not drive, operate heavy machinery, or do other dangerous activities

19 until you know how KLONOPIN affects you.

20 • Do not drink alcohol or take other drugs that may make you sleepy or

21 dizzy while taking KLONOPIN until you talk to your healthcare

22 provider. When taken with alcohol or drugs that cause sleepiness or

23 dizziness, KLONOPIN may make your sleepiness or dizziness worse.

24 2. Like other antiepileptic drugs, KLONOPIN may cause suicidal thoughts

25 or actions in a very small number of people, about 1 in 500.

26 Call a healthcare provider right away if you have any of these

27 symptoms, especially if they are new, worse, or worry you:

28  thoughts about suicide or dying

29  attempt to commit suicide

30  new or worse depression

31  new or worse anxiety

32  feeling agitated or restless

33  panic attacks

34  trouble sleeping (insomnia)

35  new or worse irritability

36  acting aggressive, being angry, or violent

37  acting on dangerous impulses

38  an extreme increase in activity and talking (mania)

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39  other unusual changes in behavior or mood

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

41 • Pay attention to any changes, especially sudden changes, in mood,

42 behaviors, thoughts, or feelings.

43 • Keep all follow-up visits with your healthcare provider as scheduled.

44 Call your healthcare provider between visits as needed, especially if you are

45 worried about symptoms.

47 Suicidal thoughts or actions can be caused by things other than medicines. If

48 you have suicidal thoughts or actions, your healthcare provider may check

49 for other causes.

50 Do not stop KLONOPIN without first talking to a healthcare provider.

51 Stopping KLONOPIN suddenly can cause serious problems. Stopping

52 KLONOPIN suddenly can cause seizures that will not stop (status

53 epilepticus).

54 3. KLONOPIN may harm your unborn or developing baby.

55 • If you take KLONOPIN during pregnancy, your baby is at risk for serious

56 birth defects. These defects can happen as early as in the first month of

57 pregnancy, even before you know you are pregnant. Birth defects may

58 occur even in children born to women who are not taking any medicines

59 and do not have other risk factors.

60 • Children born to mothers receiving benzodiazepine medications (including

61 KLONOPIN) late in pregnancy may be at some risk of experiencing

62 breathing problems, feeding problems, hypothermia, and withdrawal

63 symptoms.

64 • Tell your healthcare provider right away if you become pregnant while

65 taking KLONOPIN. You and your healthcare provider should decide if

66 you will take KLONOPIN while you are pregnant.

67 • If you become pregnant while taking KLONOPIN, talk to your healthcare

68 provider about registering with the North American Antiepileptic Drug

69 Pregnancy Registry. You can register by calling 1-888-233-2334. The

70 purpose of this registry is to collect information about the safety of

71 antiepileptic drugs during pregnancy.

72 • KLONOPIN can pass into breast milk. Talk to your healthcare provider

73 about the best way to feed your baby if you take KLONOPIN. You and

74 your healthcare provider should decide if you will take KLONOPIN or

75 breast feed. You should not do both.

76 4. KLONOPIN can cause abuse and dependence.

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77 • Do not stop taking KLONOPIN all of a sudden. Stopping KLONOPIN

78 suddenly can cause seizures that do not stop, hearing or seeing things that

79 are not there (hallucinations), shaking, and stomach and muscle cramps.

80 o Talk to your doctor about slowly stopping KLONOPIN to avoid

81 getting sick with withdrawal symptoms.

82 o Physical dependence is not the same as drug addiction. Your

83 healthcare provider can tell you more about the differences

84 between physical dependence and drug addiction.

85 KLONOPIN is a federally controlled substance (C-IV) because it can be

86 abused or lead to dependence. Keep KLONOPIN in a safe place to prevent

87 misuse and abuse. Selling or giving away KLONOPIN may harm others, and

88 is against the law. Tell your doctor if you have ever abused or been

89 dependent on alcohol, prescription medicines or street drugs.

90 What is KLONOPIN?

91 KLONOPIN is a prescription medicine used alone or with other medicines to

92 treat:

93 • certain types of seizure disorders (epilepsy) in adults and children

94 • panic disorder with or without fear of open spaces (agoraphobia) in adults

95 It is not known if KLONOPIN is safe or effective in treating panic disorder in

96 children younger than 18 years old.

97 Who should not take KLONOPIN?

98 Do not take KLONOPIN if you:

99 • are allergic to benzodiazepines

100 • have significant liver disease

101 • have an eye disease called acute narrow angle glaucoma

102 Ask your healthcare provider if you are not sure if you have any of the

103 problems listed above.

104 What should I tell my healthcare provider before taking KLONOPIN?

105 Before you take KLONOPIN, tell your healthcare provider if you:

106 • have liver or kidney problems

107 • have lung problems (respiratory disease)

108 • have or have had depression, mood problems, or suicidal thoughts or

109 behavior

110 • have any other medical conditions

111

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112 Tell your healthcare provider about all the medicines you take, including

113 prescription and non-prescription medicines, vitamins, and herbal supplements.

114 Taking KLONOPIN with certain other medicines can cause side effects or affect

115 how well they work. Do not start or stop other medicines without talking to your

116 healthcare provider.

117 Know the medicines you take. Keep a list of them and show it to your healthcare

118 provider and pharmacist when you get a new medicine.

119 How should I take KLONOPIN?

120 • Take KLONOPIN exactly as your healthcare provider tells you.

121 KLONOPIN is available as a tablet or as an orally disintegrating tablet

122 (wafer).

123 • Do not stop taking KLONOPIN without first talking to your healthcare

124 provider. Stopping KLONOPIN suddenly can cause serious problems.

125 • KLONOPIN tablets should be taken with water and swallowed whole.

126 • KLONOPIN wafers can be taken with or without water.

127 o Do not open the pouch until you are ready to take KLONOPIN.

128 o After opening the pouch, peel back the foil on the blister pack.

129 o Do not push the wafer through the foil.

130 o After opening the blister pack, with dry hands, take the wafer and

131 place it in your mouth.

132 o The wafer will melt quickly.

133 • If you take too much KLONOPIN, call your healthcare provider or local

134 Poison Control Center right away.

135 What should I avoid while taking KLONOPIN?

136 • KLONOPIN can slow your thinking and motor skills. Do not drive,

137 operate heavy machinery, or do other dangerous activities until you know

138 how KLONOPIN affects you.

139 • Do not drink alcohol or take other drugs that may make you sleepy or

140 dizzy while taking KLONOPIN until you talk to your healthcare

141 provider. When taken with alcohol or drugs that cause sleepiness or

142 dizziness, KLONOPIN may make your sleepiness or dizziness worse.

143 What are the possible side effects of KLONOPIN?

144 See “What is the most important information I should know about

145 KLONOPIN?”

146 KLONOPIN can also make your seizures happen more often or make them worse.

147 Call your healthcare provider right away if your seizures get worse while taking

148 KLONOPIN.

149 The most common side effects of KLONOPIN include:

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150 • Drowsiness

151 • Problems with walking and coordination

152 • Dizziness

153 • Depression

154 • Fatigue

155 • Problems with memory

156 These are not all the possible side effects of KLONOPIN. For more information,

157 ask your healthcare provider or pharmacist.

158 Tell your healthcare provider if you have any side effect that bothers you or that

159 does not go away.

160 Call your doctor for medical advice about side effects. You may report side

161 effects to FDA at 1-800-FDA-1088.

162 How should I store KLONOPIN?

163 • Store KLONOPIN between 59°F to 86°F (15°C to 30°C)

164 Keep KLONOPIN and all medicines out of the reach of children.

165 General Information about KLONOPIN

166 Medicines are sometimes prescribed for purposes other than those listed in a

167 Medication Guide. Do not use KLONOPIN for a condition for which it was not

168 prescribed. Do not give KLONOPIN to other people, even if they have the same

169 symptoms that you have. It may harm them.

170 This Medication Guide summarizes the most important information about

171 KLONOPIN. If you would like more information, talk with your healthcare

172 provider. You can ask your pharmacist or healthcare provider for information

173 about KLONOPIN that is written for health professionals.

174 For more information, go to www.gene.com/gene/products/information/klonopin

175 or call 1-888-835-2555.

176 What are the ingredients in KLONOPIN?

177 Active ingredient: clonazepam

178 Inactive ingredients:

179 • Tablets:

180 o 0.5 mg tablets contain lactose, magnesium stearate,

181 microcrystalline cellulose, corn starch, FD&C Yellow No. 6 Lake

182 o 1 mg tablets contain lactose, magnesium stearate, microcrystalline

183 cellulose, corn starch, FD&C Blue No. 1 Lake and FD&C Blue

184 No. 2 Lake

185 o 2 mg tablets contain lactose, magnesium stearate, microcrystalline

186 cellulose, corn starch

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187 • Wafers: gelatin, mannitol, methylparaben sodium, propylparaben sodium

188

189

and xanthan gum

190 Issued: Month Year

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

192 Administration.

193

194

196 For additional copies of this Medication Guide, please call 1-877-436-3683 or visit

197 www.gene.com/gene/products/information/klonopin.

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