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Zepran® (Clorazepate dipotassium) Tablet
Generic Name: clorazepate dipotassium
Brand Name(s): Zepran®
Common Use: Anti Anxiety MEDICATION GUIDE
Anti Anxiety
Zepran® belongs to a class of drugs known as benzodiazepines. It
is used in the treatment of anxiety disorders and for short-term
relief of the symptoms of anxiety.
It is also used to relieve the symptoms of acute alcohol
withdrawal and to help in treating certain convulsive disorders
such as epilepsy.
Zepran® can be habit-forming if taken regularly over a long
period. You may experience withdrawal symptoms if you stop using
this drug abruptly. Consult your doctor before discontinuing
Zepran® or making any change in your dose.
Zepran® should be taken exactly as prescribed by your doctor.
If you miss a dose take it as soon as you remember if it is
within an hour or so of your scheduled time. If you do not
remember until later, skip the dose you missed and go back to
your regular schedule. Do not take 2 doses at once.
Adverse Effects:
Side effects cannot be anticipated. If any develop or change in
intensity, inform your doctor as soon as possible. Only your
doctor can determine if it is safe for you to continue taking
Zepran®.
More common side effects may include:
Drowsiness
Less common or rare side effects may include:
Blurred vision, depression, difficulty in sleeping or falling
asleep, dizziness, dry mouth, double vision, fatigue, genital
and urinary tract disorders, headache, irritability, lack of
muscle coordination, mental confusion, nervousness, tremors,
skin rashes, slurred speech, stomach and intestinal disorders,
tremor
Side effects due to rapid decrease or abrupt withdrawal from
Zepran® may include:
Abdominal cramps, convulsions, diarrhea, difficulty in sleeping
or falling asleep, hallucinations, impaired memory,
irritability, muscle aches, nervousness, tremors, vomiting
Do not take this medication if you have the eye condition known
as acute narrow-angle glaucoma.
Anxiety or tension related to everyday stress usually does not
require treatment with such a strong drug. Discuss your symptoms
thoroughly with your doctor.
Zepran® is not recommended for use in more serious conditions
such as depression or severe psychological disorders.
Warnings:
Zepran® may cause you to become drowsy or less alert; therefore,
you should not drive or operate dangerous machinery or
participate in any hazardous activity that requires full mental
alertness until you know how this drug affects you.
If you are being treated for anxiety associated with depression,
your doctor will have you take a low dose of this medication. Do
not increase your dose without consulting your doctor.
The elderly and people in a weakened condition are more apt to
become unsteady or oversedated when taking Zepran®.
Food and drug interactions:
Zepran® slows down the central nervous system and may intensify
the effects of alcohol. Do not drink alcohol while taking this
medication.
If Zepran® is taken with certain other drugs, the effects of
either could be increased, decreased, or altered. It is
especially important to check with your doctor before combining
Zepran® with the following:
Antidepressant drugs known as MAO inhibitors (Nardil, Parnate)
and other antidepressants such as Elavil and Prozac
Barbiturates such as Nembutal and Seconal
Narcotic pain relievers such as Demerol and Percodan
Major tranquilizers such as Mellaril and Thorazine
Overdose:
Any medication taken in excess can have serious consequences. If
you suspect an overdose, seek medical treatment immediately.
Symptoms of Zepran® overdose may include:
Coma, low blood pressure, sedation
What are the
possible side effects of clorazepate (Zepran® SD, Zepran® Tab)?
Get emergency
medical help if you have any of these signs of an allergic
reaction: hives; difficulty breathing; swelling of your
face, lips, tongue, or throat.
Call your
doctor at once if you have any of these serious side effects:
-
confusion,
unusual thoughts or behavior;
-
depressed
mood, thoughts of suicide or hurting yourself;
-
muscle
twitching, tremor; or
-
problems
with urination.
Less serious
side effects may include:
-
drowsiness, tiredness;
-
amnesia
or...
What are the
precautions when taking clorazepate dipotassium (Zepran®)?
Before taking
this medication, tell your doctor or pharmacist if you are
allergic to it; or if you have any other allergies. This product
may contain inactive ingredients, which can cause allergic
reactions or other problems. Talk to your pharmacist for more
details.
Before using
this medication, tell your doctor or pharmacist your medical
history, especially of: liver disease, kidney disease,
lung/breathing problems (e.g., COPD, sleep apnea), drug or
alcohol abuse.
This drug may make you dizzy or drowsy or cause blurred vision.
Do not drive, use machinery, or do any activity that requires
alertness or clear vision until you are sure you can perform
such activities safely. Avoid alcoholic beverages.
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 ZEPRAN® 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.
Usage in
Pregnancy
An increased
risk of congenital malformations associated with the use of
minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate)
during the first trimester of pregnancy has been suggested in
several studies. Clorazepate dipotassium, a benzodiazepine
derivative, has not been studied adequately to determine whether
it, too, may be associated with an increased risk of fetal
abnormality. Because use of these drugs is rarely a matter of
urgency, their use during this period 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. Patients should 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.
To provide
information regarding the effects of in utero exposure to ZEPRAN®,
physicians are advised to recommend that pregnant patients
taking ZEPRAN® enroll in the North American Antiepileptic Drug (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 the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
Usage during
Lactation
ZEPRAN®
tablets should not be given to nursing mothers since it has been
reported that nordiazepam is excreted in human breast milk.
PRECAUTIONS
In those
patients in which a degree of depression accompanies the
anxiety, suicidal tendencies may be present and protective
measures may be required. The least amount of drug that is
feasible should be available to the patient.
Patients
taking ZEPRAN® tablets for prolonged periods should have blood
counts and liver function tests periodically. The usual
precautions in treating patients with impaired renal or hepatic
function should also be observed.
In elderly or
debilitated patients, the initial dose should be small, and
increments should be made gradually, in accordance with the
response of the patient, to preclude ataxia or excessive
sedation.
Information
for Patients
To assure the
safe and effective use of benzodiazepines, patients should be
informed that, since benzodiazepines may produce psychological
and physical dependence, it is essential that they consult with
their physician before either increasing the dose or abruptly
discontinuing this drug.
Patients,
their caregivers, and families should be counseled that AEDs,
including ZEPRAN®, may increase the risk of suicidal thoughts
and behavior and should be advised of the need to be alert for
the emergence or worsening of symptoms of depression, any
unusual changes in mood or behavior, or the emergence of
suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to
healthcare providers.
Patients
should be encouraged to enroll in the 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 Usage in Pregnancy).
Prescribers or other health professionals should inform
patients, their families, and their caregivers about the
benefits and risks associated with treatment with clorazepate
dipotassium and should counsel them in its appropriate use. A
patient Medication Guide is available for ZEPRAN®. The
prescriber or health professional should instruct patients,
their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents
of the Medication Guide and to obtain answers to any questions
they may have.
Geriatric
Use
Clinical
studies of ZEPRAN® were not adequate to determine whether
subjects aged 65 and over respond differently than younger
subjects. Elderly or debilitated patients may be especially
sensitive to the effects of all benzodiazepines, including
ZEPRAN®. In general, elderly or debilitated patients should be
started on lower doses of ZEPRAN® and observed closely,
reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and concomitant disease or other drug therapy.
Dose adjustments should also be made slowly, and with more
caution in this patient population (see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
ADVERSE
REACTIONS
The side
effect most frequently reported was drowsiness. Less commonly
reported (in descending order of occurrence) were: dizziness,
various gastrointestinal complaints, nervousness, blurred
vision, dry mouth, headache, and mental confusion. Other side
effects included insomnia, transient skin rashes, fatigue,
ataxia, genitourinary complaints, irritability, diplopia,
depression, tremor, and slurred speech.
There have
been reports of abnormal liver and kidney function tests and of
decrease in hematocrit.
Decrease in
systolic blood pressure has been observed.
To report
SUSPECTED ADVERSE REACTIONS, contact Taj Pharma India. at
1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE AND
ADMINISTRATION
For the
symptomatic relief of anxiety
ZEPRAN® T-TAB
tablets are administered orally in divided doses. The usual
daily dose is 30 mg. The dose should be adjusted gradually
within the range of 15 to 60 mg daily in accordance with the
response of the patient. In elderly or debilitated patients it
is advisable to initiate treatment at a daily dose of 7.5 to 15
mg.
ZEPRAN®
tablets may also be administered in a single dose daily at
bedtime; the recommended initial dose is 15 mg. After the
initial dose, the response of the patient may require adjustment
of subsequent dosage. Lower doses may be indicated in the
elderly patient. Drowsiness may occur at the initiation of
treatment and with dosage increment.
For the
symptomatic relief of acute alcohol withdrawal
The following
dosage schedule is recommended:
|
1st 24 hours (Day 1)
|
30 mg
initially; followed by
30 to 60 mg in divided doses |
|
2nd 24 hours (Day 2)
|
45 to
90 mg in divided doses |
|
3rd 24 hours (Day 3)
|
22.5
to 45 mg in divided doses |
|
Day 4 |
15 to
30 mg in divided doses |
Thereafter,
gradually reduce the daily dose to 7.5 to 15 mg. Discontinue
drug therapy as soon as patient's condition is stable.
The maximum
recommended total daily dose is 90 mg. Avoid excessive
reductions in the total amount of drug administered on
successive days.
As an Adjunct
to Antiepileptic Drugs
In order to
minimize drowsiness, the recommended initial dosages and dosage
increments should not be exceeded.
Adults
The maximum
recommended initial dose in patients over 12 years old is 7.5 mg
three times a day. Dosage should be increased by no more than
7.5 mg every week and should not exceed 90 mg/day.
Children (9-12
years)
The maximum
recommended initial dose is 7.5 mg two times a day. Dosage
should be increased by no more than 7.5 mg every week and should
not exceed 60 mg/day.
DRUG
INTERACTIONS
If ZEPRAN® is
to be combined with other drugs acting on the central nervous
system, careful consideration should be given to the
pharmacology of the agents to be employed. Animal experience
indicates that clorazepate dipotassium prolongs the sleeping
time after hexobarbital or after ethyl alcohol, increases the
inhibitory effects of chlorpromazine, but does not exhibit
monoamine oxidase inhibition. Clinical studies have shown
increased sedation with concurrent hypnotic medications. The
actions of the benzodiazepines may be potentiated by
barbiturates, narcotics, phenothiazines, monoamine oxidase
inhibitors or other antidepressants.
If ZEPRAN®
tablets are used to treat anxiety associated with somatic
disease states, careful attention must be paid to possible drug
interaction with concomitant medication.
In
bioavailability studies with normal subjects, the concurrent
administration of antacids at therapeutic levels did not
significantly influence the bioavailability of ZEPRAN® tablets.
OVERDOSAGE
Overdosage is
usually manifested by varying degrees of CNS depression ranging
from slight sedation to coma. As in the management of overdosage
with any drug, it should be borne in mind that multiple agents
may have been taken.
The treatment
of overdosage should consist of the general measures employed in
the management of overdosage of any CNS depressant. Gastric
evacuation either by the induction of emesis, lavage, or both,
should be performed immediately. General supportive care,
including frequent monitoring of the vital signs and close
observation of the patient, is indicated. Hypotension, though
rarely reported, may occur with large overdoses. In such cases
the use of agents such as norepinephrine bitartrate injection,
USP or metaraminol bitartrate injection, USP should be
considered.
While reports
indicate that individuals have survived overdoses of clorazepate
dipotassium as high as 450 to 675 mg, these doses are not
necessarily an accurate indication of the amount of drug
absorbed since the time interval between ingestion and the
institution of treatment was not always known. Sedation in
varying degrees was the most common physiological manifestation
of clorazepate dipotassium overdosage. Deep coma when it
occurred was usually associated with the ingestion of other
drugs in addition to clorazepate dipotassium.
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.
ANIMAL
PHARMACOLOGY AND TOXICOLOGY
Studies in
rats and monkeys have shown a substantial difference between
doses producing tranquilizing, sedative and toxic effects. In
rats, conditioned avoidance response was inhibited at an oral
dose of 10 mg/kg; sedation was induced at 32 mg/kg; the LD50 was
1320 mg/kg. In monkeys aggressive behavior was reduced at an
oral dose of 0.25 mg/kg; sedation (ataxia) was induced at 7.5
mg/kg; the LD50 could not be determined because of the emetic
effect of large doses, but the LD50 exceeds 1600 mg/kg.
Twenty-four
dogs were given clorazepate dipotassium orally in a 22-month
toxicity study; doses up to 75 mg/kg were given. Drug-related
changes occurred in the liver; weight was increased and
cholestasis with minimal hepatocellular damage was found, but
lobular architecture remained well preserved.
Eighteen
rhesus monkeys were given oral doses of clorazepate dipotassium
from 3 to 36 mg/kg daily for 52 weeks. All treated animals
remained similar to control animals. Although total leucocyte
count remained within normal limits it tended to fall in the
female animals on the highest doses.
Examination of
all organs revealed no alterations attributable to clorazepate
dipotassium. There was no damage to liver function or structure.
Reproduction
Studies
Standard
fertility, reproduction, and teratology studies were conducted
in rats and rabbits. Oral doses in rats up to 150 mg/kg and in
rabbits up to 15 mg/kg produced no abnormalities in the fetuses.
ZEPRAN® did not alter the fertility indices or reproductive
capacity of adult animals. As expected, the sedative effect of
high doses interfered with care of the young by their mothers
(see Usage in Pregnancy).
MEDICATION
GUIDE
ZEPRAN®*
TABlets
(clorazepate dipotassium)
tablets
C-IV/DEA Schedule IV
Read this
Medication Guide before you start taking ZEPRAN® 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.
What is the most important information I should know about
ZEPRAN®
Do not stop
taking ZEPRAN® without first talking to your healthcare
provider.
Stopping
ZEPRAN® suddenly can cause serious problems.
ZEPRAN® can
cause serious side effects, including:
1. ZEPRAN®
can make you sleepy or dizzy and can slow your thinking and
motor skills
-
Do not
drive, operate heavy machinery, or do other dangerous
activities until you know how ZEPRAN® affects you.
-
Do not
drink alcohol or take other drugs that may make you sleepy
or dizzy while taking ZEPRAN® without first talking to your
healthcare provider. When taken with alcohol or drugs that
cause sleepiness or dizziness, ZEPRAN® may make your
sleepiness or dizziness much worse.
2. ZEPRAN®
can cause abuse and dependence.
-
Do not
stop taking ZEPRAN® all of a sudden. Stopping ZEPRAN®
suddenly can cause seizures that do not stop, hearing or
seeing things that are not there (hallucinations), shaking,
and stomach and muscle cramps.
-
Talk
to your doctor about slowly stopping ZEPRAN® to avoid
getting sick with withdrawal symptoms.
-
Physical dependence is not the same as drug addiction.
Your healthcare provider can tell you more about the
differences between physical dependence and drug
addiction.
ZEPRAN® is a
federally controlled substance (C-IV) because it can be abused
or lead to dependence. Keep ZEPRAN® in a safe place to prevent
misuse and abuse. Selling or giving away ZEPRAN® may harm
others, and is against the law. Tell your healthcare provider if
you have ever abused or been dependent on alcohol, prescription
medicines or street drugs.
3. ZEPRAN®
may harm your unborn or developing baby.
Medicines like
ZEPRAN® can cause birth defects. Talk with your healthcare
provider if you are pregnant or plan to become pregnant. Tell
your healthcare provider right away if you become pregnant while
taking ZEPRAN®. You and your healthcare provider should decide
if you will take ZEPRAN® while 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.
-
If you
become pregnant while taking ZEPRAN®, 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.
-
ZEPRAN®
can pass into breast milk. Talk to your healthcare provider
about the best way to feed your baby if you take ZEPRAN®.
You and your healthcare provider should decide if you will
take ZEPRAN® or breast feed. You should not do both.
4. Like other
antiepileptic drugs, ZEPRAN® may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call your
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
-
attempts
to commit suicide
-
new or
worse depression
-
new or
worse anxiety
-
feeling
agitated or restless
-
panic
attacks
-
trouble
sleeping (insomnia)
-
new or
worse irritability
-
acting
aggressive, being angry, or violent
-
acting on
dangerous impulses
-
an extreme
increase in activity and talking (mania)
-
other
unusual changes in behavior or mood
How can I
watch for early symptoms of suicidal thoughts and actions?
-
Pay
attention to any changes, especially sudden changes, in
mood, behaviors, thoughts, or feelings.
-
Keep all
follow-up visits with your healthcare provider as scheduled.
Call your
healthcare provider between visits as needed, especially if you
are worried about symptoms.
Do not stop
ZEPRAN® without first talking to a healthcare provider.
Stopping
ZEPRAN® suddenly can cause serious problems.
Stopping a
seizure medicine suddenly in a patient who has epilepsy can
cause seizures that will not stop (status epilepticus).
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.
What is ZEPRAN®?
ZEPRAN® is a
prescription medicine used:
-
to treat
anxiety disorders
-
with other
medicines to treat partial seizures
-
to treat
the symptoms of sudden alcohol withdrawal
Who should not take ZEPRAN®?
Do not take
ZEPRAN® if you:
-
are
allergic to clorazepate dipotassium or any of the
ingredients in ZEPRAN®. See the end of this Medication Guide
for a complete list of ingredients in ZEPRAN®.
-
have an
eye disease called acute narrow angle glaucoma.
What should I tell my healthcare provider before taking ZEPRAN®?
Before you
take ZEPRAN®, tell your healthcare provider if you:
-
have liver
or kidney problems
-
have or
have had depression, mood problems, or suicidal thoughts or
behavior
-
have a
history of abnormal thinking and behavior (psychotic
reactions)
-
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 ZEPRAN® with certain other medicines
can cause side effects or affect 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 ZEPRAN®?
-
Take
ZEPRAN® exactly as prescribed. Your healthcare provider will
tell you how much ZEPRAN® to take.
-
Your
healthcare provider may change your dose. Do not change your
dose of ZEPRAN® without talking to your healthcare provider.
-
Do not
stop taking ZEPRAN® without first talking to your healthcare
provider. Stopping ZEPRAN® suddenly can cause serious
problems.
If you take
too much ZEPRAN®, call your healthcare provider or local Poison
Control Center right away.
What are the possible side effects of ZEPRAN®?
See "What is
the most important information I should know about ZEPRAN®?"
The most
common side effects of ZEPRAN® include:
-
drowsiness
-
dizziness
-
upset
stomach
-
blurred
vision
-
dry mouth
-
confusion
These are not
all the possible side effects of ZEPRAN®. For more information
ask your healthcare provider or pharmacist.
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 ZEPRAN®?
-
Store
ZEPRAN® between 68°F to 77°F (20°C to 25°C).
-
Keep
ZEPRAN® in a tightly closed container.
-
Keep
ZEPRAN® out of the light.
-
Keep
ZEPRAN® tablets dry.
Keep ZEPRAN®
and all medicines away from children.
General Information about ZEPRAN®
Medicines are
sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use ZEPRAN® for a condition for which
it was not prescribed. Do not give ZEPRAN® 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
ZEPRAN®. If you would like more information, talk with your
healthcare provider. You can ask your pharmacist or healthcare
provider for information about ZEPRAN® that is written for
health professionals.
What are the ingredients in ZEPRAN®?
Active
ingredient: clorazepate dipotassium
Inactive
ingredients: colloidal silicon dioxide, magnesium oxide,
magnesium stearate, microcrystalline cellulose, potassium
carbonate, potassium chloride and talc.
In addition:
-
the 3.75
mg tablets contain FD&C Blue No. 2
-
the 7.5 mg
tablets contain FD&C Yellow No. 6
-
the 15 mg
tablets contain FD&C Red No. 3
This
Medication Guide has been approved by the U.S. Food and Drug
Administration.
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