CLONEX 0.5 MG

333603200-02

PATIENT LEAFLET IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) – 1986

The medicine is dispensed with a doctor's prescription only

Clonex

0.5 mg

Tablets

Each tablet contains:

Clonazepam 0.5 mg

Clonex

®

2 mg

Tablets

Each tablet contains:

Clonazepam 2 mg

For information regarding inactive ingredients and allergens, see

section 2 - “Important information about some of the ingredients

of the medicine” and section 6 - “Additional information”.

Read the entire leaflet carefully before using the medicine.

This leaflet contains concise information about the medicine. If you

have additional questions, refer to the doctor or the pharmacist.

This medicine has been prescribed for your treatment. Do not

pass it on to others. It may harm them even if it seems to you

that their medical condition is similar.

Taking this medicine together with opioid medicines, with

other medicines that depress the central nervous system

(including drugs) or with alcohol, may cause a sensation of

deep drowsiness, breathing difficulties (respiratory depression),

coma and death.

1. What is the medicine intended for?

For treatment of certain kinds of seizures (epilepsy).

For treatment of anxiety attacks.

Therapeutic class: Benzodiazepines.

2. Before using the medicine

Do not use this medicine if:

You are sensitive (allergic) to the active ingredient or to

other preparations from the benzodiazepines group, or to

any of the other ingredients this medicine contains (see

section 6 – “Additional information”).

You have a severe hepatic disease.

You have an eye disease called acute narrow-angle

glaucoma.

Ask the doctor if you are uncertain whether you have any of

the abovementioned conditions.

Special warnings regarding the use of the medicine

Before treatment with Clonex, inform the doctor about

your medical condition, including if:

You have liver or kidney problems.

You have lung problems (airway diseases).

You have or have had depression, mood problems, or suicidal

thoughts or behavior.

You have any other medical issue.

You are or have been addicted to alcohol, medicines or drugs.

You are pregnant, planning to become pregnant, breastfeeding

or planning to breastfeed. See more information under the

section “Pregnancy and breastfeeding”.

Suicidal thoughts or actions

Similar to other anticonvulsants, Clonex may cause suicidal

thoughts or actions in a very small number of people, about 1

in 500. For a list of possible symptoms, see section 4 under the

title “Severe side effects”.

How can I be aware of early symptoms of suicidal thoughts

or actions?

You should notice any change, especially a sudden change

in mood, behavior, thoughts or emotions.

All appointments to see the treating doctor should be kept

as planned.

Consult the treating doctor between appointments as necessary,

especially if you are worried about the symptoms.

Suicidal thoughts or actions can be caused by non-pharmacological

reasons. If you have suicidal thoughts or actions, the treating

doctor may look at other reasons for them.

Additional warnings

Do not stop taking Clonex without consulting with the doctor.

Suddenly stopping to take Clonex may cause severe side

effects, including a prolonged epileptic seizure (status

epilepticus). See more information in section 3 under the

title “If you stop taking the medicine”.

Clonex may lead to dependence and abuse. The medicine

should be kept at a safe place to prevent wrong use and abuse.

Physical dependence is not the same thing as addiction to

the medicine. The doctor will be able to tell you about the

differences between physical dependence and addiction.

Clonex may cause drowsiness or dizziness and slow down

thinking and motor skills. Improvement is possible over time.

Coordination problems are also possible, especially when

walking or lifting objects.

Do not drive and operate machinery until you know how

the medicine affects you. See also the section “Driving and

operating machinery”.

Children and adolescents

No information is available regarding safety and efficacy of the

medicine in treating panic states in children under 18 years of age.

Drug-drug interactions

If you are taking or have recently taken other medicines

including non-prescription medicines and food supplements,

tell the doctor or the pharmacist. Especially if you are taking:

Taking this medicine with certain other medicines may cause

side effects or affect the way Clonex or the other medicines

work. Do not start or stop taking other medicines without

consulting with the treating doctor.

Do not take this medicine together with opioid medicines,

with other medicines that depress the central nervous system

(including drugs) or with alcohol - see the boxed warning in

the beginning of this leaflet.

Do not take this medicine together with alcohol or other

medicines that can cause drowsiness or dizziness without

consulting with the treating doctor. When taken with alcohol

or medicines that cause drowsiness or dizziness, Clonex

may aggravate the drowsiness or dizziness.

Use of the medicine and alcohol consumption

Do not drink alcohol while taking Clonex without consulting with

the treating doctor. Alcohol consumption while taking Clonex

may aggravate the drowsiness or dizziness.

Pregnancy and breastfeeding

Pregnancy

If you are pregnant, planning to become pregnant or think

you might be pregnant, consult with a doctor before taking

this medicine. It is unknown whether the medicine might

harm the fetus.

If you become pregnant while taking Clonex, inform the

treating doctor immediately. You and the treating doctor

need to decide whether you should continue to take Clonex

during the pregnancy.

Animal studies have shown harmful effects of medicines from

the benzodiazepines group (including medicines containing

clonazepam, which is the active ingredient in Clonex) on the

developing fetus.

Children born to mothers who received medicines from the

benzodiazepines group (including medicines containing

clonazepam) during the late stages of pregnancy may be at

risk for breathing problems, feeding problems, hypothermia

and withdrawal symptoms.

Breastfeeding

If you are breastfeeding or are planning to breastfeed, consult

with the doctor before using the medicine. The medicine can

pass into breastmilk. If you are taking Clonex, you and the

treating doctor should decide what would be the right way

for you to feed your baby.

Driving and operating machinery

The medicine may cause drowsiness or dizziness and slow

down thinking and motor skills. Do not drive, operate heavy

machinery or perform other dangerous activities until you know

how the medicine affects you.

Important information about some of the ingredients of

the medicine

Clonex contains lactose. If your doctor told you that you have

intolerance to certain types of sugar, consult a doctor before

taking this medicine.

Clonex 0.5 mg contains FCF (Sunset yellow FCF – E 110) which

may cause allergic reactions.

3. How should you use the medicine?

Always use the medicine according to the doctor’s instructions.

Check with the doctor or pharmacist if you are uncertain about

the dosage and how to use the medicine.

The dosage and treatment regimen will be determined only

by the doctor.

If you are taking this medicine to prevent seizures, your doctor

may adjust the dosage until you find the suitable dose for you

for controlling the seizures.

Do not exceed the recommended dose.

The medicine should be taken with water.

No information is available regarding chewing or crushing

the tablet.

Clonex 0.5 mg - the tablet may be halved.

Clonex 2 mg - the tablet may be divided into 4 parts.

If you accidentally took a higher dose or if a child accidentally

swallowed the medicine, immediately contact a doctor or proceed

to a hospital emergency room and bring the package of the

medicine with you.

If you forgot to take this medicine at the required time, take

your dose as soon as you remember, but under no circumstances

should you take two doses at the same time.

Follow the treatment as recommended by the doctor.

Even if there is an improvement in your health, do not stop

treatment with the medicine without consulting the doctor.

If you stop taking the medicine

Do not stop taking the medicine without consulting a doctor.

Suddenly stopping to take the medicine may cause serious

problems, such as: continuous convulsions (status epilepticus),

hallucinations (hearing or seeing things that do not exist),

abdominal and muscle tremors and cramps.

Consult with the doctor regarding gradually stopping the

medicine, to avoid withdrawal symptoms.

Do not take medicines in the dark! Check the label and

the dose every time you take the medicine. Wear glasses

if you need them.

If you have any other questions regarding use of the medicine,

consult the doctor or the pharmacist.

4. Side effects

As with any medicine, using Clonex may cause side effects in

some users. Do not be alarmed when reading the list of side

effects. You may not experience any of them.

Severe side effects

Refer to a doctor immediately if one or more of the following

symptoms occur, especially if these are new symptoms, if

the symptoms worsen or if they concern you:

Suicidal thoughts or actions

Thoughts of suicide or death

Suicide attempt

Appearance of depression or worsening of existing

depression

Appearance of anxiety or worsening of existing anxiety

Emotional turmoil or restlessness

Anxiety attacks

Sleeping problems (insomnia)

Appearance of irritability or worsening of irritability

Aggressive, angry or violent behavior

Dangerous impulsive behavior

An extreme increase in activity and speech (mania)

Other abnormal changes in behavior or mood

Clonex may cause worsening of seizures or increased

frequency of seizures. Contact the doctor immediately

if your seizures worsen due to taking Clonex.

The most frequent side effects:

Drowsiness

Walking and coordination problems

Dizziness

Depression

Tiredness

Memory impairment

Additional side effects:

Palpitations, hair loss, excessive hairiness in women, rash,

edema in the ankle and the face, lack of appetite (anorexia),

coated tongue, constipation, diarrhea, dry mouth, involuntary

excretion of stool, gastritis, increased appetite, nausea, sensitive

gums, pain while urinating, wetting, bedwetting, urinary retention,

anemia, leukopenia, thrombocytopenia, eosinophilia, enlarged

liver, transient elevation in serum levels of transaminases and

alkaline phosphatase, muscle weakness, pain, dehydration,

general deterioration, fever, lymph nodes enlargement

(lymphadenopathy), weight loss or weight gain, abnormal eye

movements, loss of voice, chorea-like movements, coma, double

vision, mispronunciation in speech, dysdiadochokinesis, lack

of expression, headache, mild paralysis affecting half of the

body, hypotonia, nystagmus, respiratory depression, slurred

speech, tremor, confusion, amnesia, hysteria, increased libido,

psychosis (behavioral effects occur more in patients with a history

of psychiatric disorders). The following paradoxical reactions

have been observed: agitation, aggression, hostility, nightmares,

abnormal dreams and hallucinations. Chest congestion, rhinitis,

shortness of breath, excessive secretions in the upper airways.

If a side effect occurs, if one of the side effects worsens, or

if you suffer from a side effect not mentioned in this leaflet,

consult your doctor.

Reporting side effects

Side effects may be reported to the Ministry of Health by clicking

on the link "report side effects due to medicinal treatment" found

on the Ministry of Health website homepage (www.health.gov.il),

which will direct you to the online form for reporting side effects,

or by clicking on the following link:

https://sideeffects.health.gov.il/

5. How to store the medicine?

Avoid poisoning! This medicine and any other medicine must

be kept in a closed place out of the reach and sight of children

and/or infants to avoid poisoning. Do not induce vomiting

without an explicit instruction from the doctor.

Do not use the medicine after the expiry date (exp. date)

appearing on the package. The expiry date refers to the last

day of that month.

Keep in a dry place under 25°C.

6. Additional information

In addition to the active ingredient, the medicine also

contains:

Clonex 0.5 mg:

Starch, Lactose Monohydrate, Talc, Magnesium Stearate,

Color FD&C Yellow No. 6 (E 110), Color D&C Yellow No. 10.

Clonex 2 mg:

Lactose Monohydrate, Starch, Talc, Magnesium Stearate.

What does the medicine look like and what are the contents

of the package

Clonex 0.5 mg:

A light orange, round, flat beveled tablet. Bisected on one side,

plain on the other.

Clonex 2 mg:

A white, round, flat beveled tablet. Quadrisected on one side,

engraved "TEVA" on the other.

Each package contains 30 or 100 tablets packed in a blister.

Not all package sizes may be marketed.

Name and address of the Manufacturer and Marketing

Authorization Holder:

Teva Pharmaceutical Industries Ltd., P.O. box 3190, Petah Tikva.

The format of this leaflet was determined by the Ministry of Health

and its content was checked and approved in March 2013, and

edited in February 2020.

Registration numbers of the medicine in the national drug

registry of the Ministry of Health:

Clonex 0.5 mg: 027.85.22043

Clonex 2 mg:

035.99.22044

CLONEX PIL MW0520

Clonex 0.5mg, 2mg, HS 02/2020, Notification

SUMMARY OF PRODUCT CHARACTERISTICS

CLONEX

®

NAME OF THE MEDICINAL PRODUCT

Clonex

0.5 mg

Clonex

2 mg

Tablets

QUALITATIVE AND QUANTITATIVE COMPOSITION

Clonex 0.5 mg - each tablet contains clonazepam 0.5 mg

Excipient with known effect:

75 mg of lactose monohydrate and 0.188 mg of color FD&C Yellow No. 6.

Clonex 2 mg - each tablet contains clonazepam 2 mg

Excipient with known effect:

120 mg of lactose monohydrate.

For the full list of excipients, see "DESCRIPTION"

THERAPEUTIC INDICATIONS

Typical or atypical petit mal, Lennox - Gastaut syndrome (petit mal variant),

generalized primary or secondary tonic-clonic seizures including grand mal

and focal seizures.

Panic disorder.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound

sedation, respiratory depression, coma, and death (see WARNINGS and

PRECAUTIONS).

Reserve concomitant prescribing of these drugs for use in patients for

whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and

sedation.

DESCRIPTION

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

benzodiazepine.

Each tablet of Clonex 0.5 mg also contains starch, lactose monohydrate, talc,

magnesium stearate, color FD&C yellow No. 6 and color D&C yellow No. 10.

Each tablet of Clonex 2 mg also contains lactose monohydrate, starch, talc and

magnesium stearate.

Clonex 0.5mg, 2mg, HS 02/2020, Notification

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

benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following

structural formula:

M.W. 315.72

CLINICAL PHARMACOLOGY

Pharmacodynamics

The precise mechanism by which clonazepam exerts its antiseizure and antipanic

effects is unknown, although it is believed to be related to its ability to enhance the

activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in

the central nervous system.

Pharmacokinetics

Clonazepam is rapidly and completely absorbed after oral administration. The

absolute bioavailability of clonazepam is about 90%. Maximum plasma

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

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

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

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

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

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

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

typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent

throughout the dosing range. There is no evidence that clonazepam induces its own

metabolism or that of other drugs in humans.

Pharmacokinetics in Demographic Subpopulations and in Disease States

Controlled studies examining the influence of gender and age on clonazepam

pharmacokinetics have not been conducted, nor have the effects of renal or liver

disease on clonazepam pharmacokinetics been studied. Because clonazepam

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

elimination. Thus, caution should be exercised when administering clonazepam to

these patients (see CONTRAINDICATIONS).

Clonex 0.5mg, 2mg, HS 02/2020, Notification

In children, clearance values of 0.42 ± 0.32 mL/min/kg (ages 2 to 18 years) and 0.88

± 0.4 mL/min/kg (ages 7 to 12 years) were reported; these values decreased with

increasing body weight. Ketogenic diet in children does not affect clonazepam

concentrations.

Clinical Trials

Panic Disorder

The effectiveness of clonazepam in the treatment of panic disorder was

demonstrated in two double-blind, placebo-controlled studies of adult outpatients who

had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia. In

these studies, clonazepam was shown to be significantly more effective than placebo

in treating panic disorder on change from baseline in panic attack frequency, the

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

Impression Improvement Score.

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

4 mg/day or placebo. This study was conducted in four phases: a 1 week placebo

lead-in, a 3 week upward titration, a 6 week fixed dose, and a 7 week discontinuance

phase. A significant difference from placebo was observed consistently only for the 1

mg/day group. The difference between the 1 mg dose group and placebo in reduction

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

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

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

Study 2 was a 6 week, flexible-dose study involving clonazepam in a dose range of

0.5 to 4 mg/day or placebo. This study was conducted in three phases: a 1 week

placebo lead-in, a 6 week optimal-dose, and a 6 week discontinuance phase. The

mean clonazepam dose during the optimal dosing period was 2.3 mg/day. The

difference between clonazepam and placebo in reduction from baseline in the

number of full panic attacks was approximately 1 panic attack per week. At endpoint,

62% of patients receiving clonazepam were free of full panic attacks, compared to

37% of placebo-treated patients.

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

outcomes as a function of race or gender.

CONTRAINDICATIONS

Clonazepam is contraindicated in patients with the following conditions:

Hypersensitivity to the active substance or to any of the excipients listed in

DESCRIPTION

History of sensitivity to benzodiazepines

Clinical or biochemical evidence of significant liver disease

Acute narrow angle glaucoma (it may be used in patients with open angle

glaucoma who are receiving appropriate therapy).

Clonex 0.5mg, 2mg, HS 02/2020, Notification

WARNINGS

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including clonazepam, and opioids may result

in profound sedation, respiratory depression, coma, and death. Because of these

risks, reserve concomitant prescribing of benzodiazepines and opioids for use in

patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics

and benzodiazepines increases the risk of drug-related mortality compared to use of

opioids alone. If a decision is made to prescribe clonazepam concomitantly with

opioids, prescribe the lowest effective dosages and minimum durations of

concomitant use, and follow patients closely for signs and symptoms of respiratory

depression and sedation. Advise both patients and caregivers about the risks of

respiratory depression and sedation when clonazepam is used with opioids (see

PRECAUTIONS, Information for Patients and PRECAUTIONS, Drug

Interactions).

Interference with Cognitive and Motor Performance

Since clonazepam produces CNS depression, patients receiving this drug should be

cautioned against engaging in hazardous occupations requiring mental alertness,

such as operating machinery or driving a motor vehicle. They should also be warned

about the concomitant use of alcohol or other CNS-depressant drugs during

clonazepam therapy (see PRECAUTIONS: Drug Interactions and PRECAUTIONS:

Information for Patients).

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including clonazepam, increase the risk of suicidal

thoughts or behavior in patients taking these drugs for any indication. Patients

treated with any AED for any indication should be monitored for the emergence or

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

in mood or behavior.

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

therapy) of 11 different AEDs showed that patients randomized to one of the AEDs

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

suicidal thinking or behavior compared to patients randomized to placebo. In these

trials, which had a median treatment duration of 12 weeks, the estimated incidence

rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%

compared to 0.24% among 16,029 placebo-treated patients, representing an

increase of approximately one case of suicidal thinking or behavior for every 530

patients treated. There were four suicides in drug-treated patients in the trials and

none in placebo-treated patients, but the number is too small to allow any conclusion

about drug effect on suicide.

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

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

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

Clonex 0.5mg, 2mg, HS 02/2020, Notification

beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could

not be assessed.

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

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

action and across a range of indications suggests that the risk applies to all AEDs

used for any indication. The risk did not vary substantially by age (5 to 100 years) in

the clinical trials analyzed.

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

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo

Patients

with Events

Per 1000

Patients

Drug

Patients

with Events

Per 1000

Patients

Relative Risk: Incidence

of Events in Drug

Patients/Incidence in

Placebo Patients

Risk Difference:

Additional Drug

Patients with

Events per 1000

Patients

Epilepsy

Psychiatric

Other

Total

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

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

differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing clonazepam or any other AED must balance the risk

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

other illnesses for which AEDs are prescribed are themselves associated with

morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber

needs to consider whether the emergence of these symptoms in any given patient

may be related to the illness being treated.

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

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

for the emergence or worsening of the signs and symptoms of depression, any

unusual changes in mood or behavior, or the emergence of suicidal thoughts,

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

immediately to healthcare providers.

Withdrawal Symptoms

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation

of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

Clonex 0.5mg, 2mg, HS 02/2020, Notification

PRECAUTIONS

General

Worsening of Seizures

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

clonazepam may increase the incidence or precipitate the onset of generalized tonic-

clonic seizures (grand mal). This may require the addition of appropriate

anticonvulsants or an increase in their dosages. The concomitant use of valproic acid

and clonazepam may produce absence status.

Loss of Effect: In some studies, up to 30% of patients who initially responded have

shown a loss of anticonvulsant activity, often within 3 months of administration. In

some cases, dosage adjustment may reestablish efficacy.

Laboratory Testing During Long-Term Therapy

Periodic blood counts and liver function tests are advisable during long-term therapy

with clonazepam.

Psychiatric and Paradoxical Reactions: Paradoxical reactions, such as agitation,

irritability, aggression, anxiety, anger, nightmares, hallucinations, and psychoses are

known to occur when using benzodiazepines (see ADVERSE REACTIONS:

Psychiatric). Should this occur, the use of the drug should be discontinued gradually

(see PRECAUTIONS: Risks of Abrupt Withdrawal and DRUG ABUSE AND

DEPENDENCE: Physical and Psychological Dependence). Paradoxical reactions are

more likely to occur in children and in the elderly.

Risks of Abrupt Withdrawal

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

high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing

clonazepam, gradual withdrawal is essential. While clonazepam is being gradually

withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.

Caution in Renally Impaired Patients

Metabolites of clonazepam are excreted by the kidneys; to avoid their excess

accumulation, caution should be exercised in the administration of the drug to

patients with impaired renal function.

Hypersalivation

Clonazepam may produce an increase in salivation. This should be considered

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

Respiratory Depression

Clonazepam may cause respiratory depression and should be used with caution in

patients with compromised respiratory function (e.g., chronic obstructive pulmonary

disease, sleep apnea).

Porphyria

Clonex 0.5mg, 2mg, HS 02/2020, Notification

Clonazepam may have a porphyrogenic effect and should be used with care in

patients with porphyria.

Inactive ingredients

Clonex 0.5 mg and Clonex 2 mg contain lactose monohydrate. Patients with rare

hereditary problems of galactose intolerance, total lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

Clonex 0.5 mg and contains color FD&C yellow No. 6 (E 110) which may cause

allergic reactions.

Information for Patients

Patients should be instructed to take clonazepam only as prescribed. Physicians are

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

clonazepam:

Risks from Concomitant Use with Opioids

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

clonazepam is used with opioids and not to use such drugs concomitantly unless

supervised by a health care provider (see WARNINGS, Risks from Concomitant

Use With Opioids and PRECAUTIONS, Drug Interactions).

Dose Changes

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

informed that, since benzodiazepines may produce psychological and physical

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

increasing the dose or abruptly discontinuing this drug.

Interference with Cognitive and Motor Performance

Because benzodiazepines have the potential to impair judgment, thinking or motor

skills, patients should be cautioned about operating hazardous machinery, including

automobiles, until they are reasonably certain that clonazepam therapy does not

affect them adversely.

Suicidal Thinking and Behavior

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

clonazepam, may increase the risk of suicidal thoughts and behavior and should be

advised of the need to be alert for the emergence or worsening of symptoms of

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

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

reported immediately to healthcare providers.

Pregnancy

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

to become pregnant during therapy with clonazepam (see PRECAUTIONS:

Pregnancy).

Nursing

Clonex 0.5mg, 2mg, HS 02/2020, Notification

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

to breastfeed during therapy.

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to

take, any prescription or over-the-counter drugs, since there is a potential for

interactions.

Alcohol

Patients should be advised to avoid alcohol while taking clonazepam.

Drug Interactions

Effect of Concomitant Use of Benzodiazepines and Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory

depression because of actions at different receptor sites in the CNS that control

respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily

at mu receptors. When benzodiazepines and opioids are combined, the potential for

benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Limit dosage and duration of concomitant use of benzodiazepines and opioids, and

follow patients closely for respiratory depression and sedation.

Effect of Clonazepam on the Pharmacokinetics of Other Drugs

Clonazepam does not appear to alter the pharmacokinetics of carbamazepine or

phenobarbital. Clonazepam has the potential to influence concentrations of

phenytoin. Monitoring of phenytoin concentration is recommended when clonazepam

is coadministrated with phenytoin. The effect of clonazepam on the metabolism of

other drugs has not been investigated.

Effect of Other Drugs on the Pharmacokinetics of Clonazepam

Literature reports suggest that ranitidine, an agent that decreases stomach acidity,

does not greatly alter clonazepam pharmacokinetics.

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

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

GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax

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

propantheline compared to when it was given alone.

The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) and

fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbamate (CYP2C19

inhibitor and CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam.

Cytochrome P-450 inducers, such as phenytoin, carbamazepine, lamotrigine, and

phenobarbital induce clonazepam metabolism, causing an approximately 38%

decrease in plasma clonazepam levels. Although clinical studies have not been

performed, based on the involvement of the cytochrome P-450 3A family in

clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal

agents (e.g., fluconazole), should be used cautiously in patients receiving

Clonex 0.5mg, 2mg, HS 02/2020, Notification

clonazepam because they may impair the metabolism of clonazepam leading to

exaggerated concentrations and effects.

Pharmacodynamic Interactions

The CNS-depressant action of the benzodiazepine class of drugs may be potentiated

by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the

phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents,

monoamine oxidase inhibitors and the tricyclic antidepressants, and by other

anticonvulsant drugs.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies have not been conducted with clonazepam.

Mutagenesis

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

clonazepam.

Impairment of Fertility

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

and 100 mg/kg/day, there was a decrease in the number of pregnancies and in the

number of offspring surviving until weaning. The lowest dose tested is approximately

5 and 24 times the maximum recommended human dose (MRHD) of 20 mg/day for

seizure disorders and 4 mg/day for panic disorder, respectively, on a body surface

area (mg/m2) basis.

Pregnancy

There are no adequate and well-controlled studies of clonazepam in pregnant

women. Available human data on the risk of teratogenicity are inconclusive. There is

insufficient evidence in humans to assess the effect of benzodiazepine exposure

during pregnancy on neurodevelopment. Administration of benzodiazepines

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

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

mothers who have taken benzodiazepines during the later stages of pregnancy can

develop dependence, and subsequently withdrawal, during the postnatal period.

In three studies in which clonazepam was administered orally to pregnant rabbits at

doses of 0.2, 1, 5, or 10 mg/kg/day during the period of organogenesis, a similar

pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb

defects) was observed at all doses, in a low, non-dose-related incidence. The lowest

dose tested is less than the maximum recommended human dose (MRHD) of 20

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

on a mg/m2 basis. Reductions in maternal weight gain occurred at doses of 5

mg/kg/day or greater and reduction in embryofetal growth occurred in one study at a

dose of 10 mg/kg/day.

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

oral administration of clonazepam during organogenesis of doses up to 15 or 40

Clonex 0.5mg, 2mg, HS 02/2020, Notification

mg/kg/day, respectively (4 and 20 times the MRHD of 20 mg/day for seizure

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

respectively, on a mg/m2 basis).

Data for other benzodiazepines suggest the possibility of adverse developmental

effects (long-term effects on neurobehavioral and immunological function) in animals

following prenatal exposure to benzodiazepines.

Labor and Delivery

The effect of clonazepam on labor and delivery in humans has not been specifically

studied; however, perinatal complications have been reported in children born to

mothers who have been receiving benzodiazepines late in pregnancy, including

findings suggestive of either excess benzodiazepine exposure or of withdrawal

phenomena (see PRECAUTIONS: Pregnancy).

Nursing Mothers

The effects of clonazepam on the breastfed infant and on milk production are

unknown. The developmental and health benefits of breastfeeding should be

considered along with the mother's clinical need for clonazepam and any potential

adverse effects on the breastfed infant from clonazepam or from the underlying

maternal condition.

Pediatric Use

Because of the possibility that adverse effects on physical or mental development

could become apparent only after many years, a benefit-risk consideration of the

long-term use of clonazepam is important in pediatric patients being treated for

seizure disorder (see INDICATIONS AND USAGE and DOSAGE AND

ADMINISTRATION).

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

have not been established.

Geriatric Use

Clinical studies of clonazepam did not include sufficient numbers of subjects aged 65

and over to determine whether they respond differently from younger subjects. Other

reported clinical experience has not identified differences in responses between the

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

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

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

disease or other drug therapy.

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

will impair clonazepam elimination. Metabolites of clonazepam are excreted by the

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

administration of the drug to patients with impaired renal function. Because elderly

patients are more likely to have decreased hepatic and/or renal function, care should

be taken in dose selection, and it may be useful to assess hepatic and/or renal

function at the time of dose selection.