CHLORDIAZEPOXIDE
.
Librium, the original chlordiazepoxide HCl and prototype for the benzodiazepine
compounds, was synthesized and developed at Hoffmann-La Roche Inc. It is a
versatile therapeutic agent of proven value for the relief of anxiety. Librium
is among the safer of the effective psychopharmacologic compounds available, as
demonstrated by extensive clinical evidence.
Librium is available as capsules containing 10 mg or 25 mg chlordiazepoxide HCl. The molecular weight is 336.22.
ACTIONS/CLINICAL PHARMACOLOGY:
Librium (chlordiazepoxide HCl) has antianxiety, sedative, appetite-stimulating
and weak analgesic actions. The precise mechanism of action is not known. The
drug blocks EEG arousal from stimulation of the brain stem reticular formation.
It takes several hours for peak blood levels to be reached and the half-life of
the drug is between 24 and 48 hours. After the drug is discontinued plasma
levels decline slowly over a period of several days. Chlordiazepoxide is
excreted in the urine, with 1% to 2% unchanged and 3% to 6% as a conjugate.
Animal Pharmacology: The drug has been studied extensively in many species of
animals and these studies are suggestive of action on the limbic system of the
brain, which recent evidence indicates is involved in emotional responses.
Hostile monkeys were made tame by oral drug doses which did not cause sedation.
Chlordiazepoxide HCl revealed a "taming" action with the elimination of fear and
aggression. The taming effect of chlordiazepoxide HCl was further demonstrated
in rats made vicious by lesions in the septal area of the brain. The drug dosage
which effectively blocked the vicious reaction was well below the dose which
caused sedation in these animals.
The LD50 of parenterally administered chlordiazepoxide HCl was determined in
mice (72 hours) and rats (5 days), and calculated according to the method of
Miller and Tainter, with the following results: mice, IV, 123 (+/-) 12 mg/kg;
mice, IM, 366 (+/-) 7 mg/kg; rats, IV, 120 (+/-) 7 mg/kg; rats, IM, > 160 mg/kg.
Effects On Reproduction: Reproduction studies in rats fed 10, 20 and 80 mg/kg
daily and bred through one or two matings showed no congenital anomalies, nor
were there adverse effects on lactation of the dams or growth of the newborn.
However, in another study at 100 mg/kg daily there was noted a significant
decrease in the fertilization rate and a marked decrease in the viability and
body weight of offspring which may be attributable to sedative activity, thus
resulting in lack of interest in mating and lessened maternal nursing and care
of the young. One neonate in each of the first and second matings in the rat
reproduction study at the 100 mg/kg dose exhibited major skeletal defects.
Further studies are in progress to determine the significance of these findings.
INDICATIONS AND USAGE:
Librium is indicated for the management of anxiety disorders or for the short-
term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and
preoperative apprehension and anxiety. Anxiety or tension associated with the
stress of everyday life usually does not require treatment with an anxiolytic.
The effectiveness of Librium in long-term use, that is, more than 4 months, has
not been assessed by systematic clinical studies. The physician should
periodically reassess the usefulness of the drug for the individual patient.
CONTRAINDICATIONS:
Librium is contraindicated in patients with known hypersensitivity to the drug.
WARNINGS:
Chlordiazepoxide HCl may impair the mental and/or physical abilities required
for the performance of potentially hazardous tasks such as driving a vehicle or
operating machinery. Similarly, it may impair mental alertness in children. The
concomitant use of alcohol or other central nervous system depressants may have
an additive effect. PATIENTS SHOULD BE WARNED ACCORDINGLY.
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.
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
PHYSICIANS ABOUT THE DESIRABILITY OF DISCONTINUING THE DRUG.
Withdrawal symptoms of the barbiturate type have occurred after the
discontinuation of benzodiazepines. (See DRUG ABUSE AND DEPENDENCE section.)
PRECAUTIONS:
In elderly and debilitated patients, it is recommended that the dosage be
limited to the smallest effective amount to preclude the development of ataxia
or oversedation (10 mg or less per day initially, to be increased gradually as
needed and tolerated). In general, the concomitant administration of Librium and
other psychotropic agents is not recommended. If such combination therapy seems
indicated, careful consideration should be given to the pharmacology of the
agents to be employed--particularly when the known potentiating compounds such
as the MAO inhibitors and phenothiazines are to be used. The usual precautions
in treating patients with impaired renal or hepatic function should be observed.
Paradoxical reactions, eg, excitement, stimulation and acute rage, have been
reported in psychiatric patients and in hyperactive aggressive pediatric
patients, and should be watched for during Librium therapy. The usual
precautions are indicated when Librium is used in the treatment of anxiety
states where there is any evidence of impending depression; it should be borne
in mind that suicidal tendencies may be present and protective measures may be
necessary. Although clinical studies have not established a cause and effect
relationship, physicians should be aware that variable effects on blood
coagulation have been reported very rarely in patients receiving oral
anticoagulants and Librium. In view of isolated reports associating
chlordiazepoxide with exacerbation of porphyria, caution should be exercised in
prescribing chlordiazepoxide to patients suffering from this disease.
Pediatric Use: Because pf the varied response of pediatric patients to CNS-
acting drugs, therapy should be initiated with the lowest dose and increased as
required (see DOSAGE AND ADMINISTRATION). Since clinical experience with Librium
in pediatric patients under 6 years of age is limited, use in this age group is
not recommended. Hyperactive aggressive pediatric patients should be monitored
for paradoxical reactions to Librium (see PRECAUTIONS).
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 advisable that they consult
with their physician before either increasing the dose or abruptly discontinuing
this drug.
DRUG INTERACTIONS:
SEE WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS:
The necessity of discontinuing therapy because of undesirable effects has been
rare. Drowsiness, ataxia and confusion have been reported in some patients--
particularly the elderly and debilitated. While these effects can be avoided in
almost all instances by proper dosage adjustment, they have occasionally been
observed at the lower dosage ranges. In a few instances syncope has been
reported.
Other adverse reactions reported during therapy include isolated instances of
skin eruptions, edema, minor menstrual irregularities, nausea and constipation,
extrapyramidal symptoms, as well as increased and decreased libido. Such side
effects have been infrequent and are generally controlled with reduction of
dosage. Changes in EEG patterns (low-voltage fast activity) have been observed
in patients during and after Librium treatment.
Blood dyscrasias (including agranulocytosis), jaundice and hepatic dysfunction
have occasionally been reported during therapy. When Librium treatment is
protracted, periodic blood counts and liver function tests are advisable.
DRUG ABUSE AND DEPENDENCE:
Chlordiazepoxide hydrochloride capsules are classified by the Drug Enforcement
Administration as a Schedule IV controlled substance.
Withdrawal symptoms, similar in character to those noted with barbiturates and
alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and
sweating), have occurred following abrupt discontinuance of chlordiazepoxide.
The more severe withdrawal symptoms have usually been limited to those patients
who had 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. Addiction-prone individuals (such as drug addicts or
alcoholics) should be under careful surveillance when receiving chlordiazepoxide
or other psychotropic agents because of the predisposition of such patients to
habituation and dependence.
OVERDOSAGE:
Manifestations of Librium overdosage include somnolence, confusion, coma and
diminished reflexes. Respiration, pulse and blood pressure should be monitored,
as in all cases of drug overdosage, although, in general, these effects have
been minimal following Librium overdosage. General supportive measures should be
employed, along with immediate gastric lavage. Intravenous fluids should be
administered and an adequate airway maintained. Hypotension may be combated by
the use of Levophed(R) (norepinephrine) or Aramine (metaraminol). Dialysis is of
limited value. There have been occasional reports of excitation in patients
following chlordiazepoxide HCl overdosage; if this occurs barbiturates should
not be used. As with the management of intentional overdosage with any drug, it
should be borne in mind that multiple agents may have been ingested.
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./
DOSAGE AND ADMINISTRATION:
Because of the wide range of clinical indications for Librium, the optimum
dosage varies with the diagnosis and response of the individual patient. The
dosage, therefore, should be individualized for maximum beneficial effects.
ADULTS USUAL DAILY DOSE
Relief Of Mild And 5 mg or 10 mg, 3
Moderate Anxiety Dis- or 4 times daily
Orders And Symptoms
Of Anxiety
Relief Of Severe 20 mg or 25 mg, 3
Anxiety Disorders or 4 times daily
And Symptoms Of
Anxiety
Geriatric Patients, 5 mg, 2 to 4 times daily
or in the presence
of debilitating disease
Preoperative Apprehension And Anxiety:
On days preceding surgery, 5 to 10 mg orally, 3 or 4 times daily. If used as
preoperative medication, 50 to 100 mg IM* 1 hour prior to surgery.
PEDIATRIC PATIENTS USUAL DAILY DOSE
Because of the 5 mg, 2 to 4 times
varied response of daily (may be in-
pediatric patients to creased in some
CNS-act-ing drugs, therapy pediatric patients to 10 mg,
should be initiated 2 to 3 times daily)
with the lowest dose
and increased as required.
Since clinical experience
in pediatric patients under
6 years of age is limited,
the use of the drug
in this age group is
not recommended.
For the relief of withdrawal symptoms of acute alcoholism, the parenteral form*
is usually used initially. If the drug is administered orally, the suggested
initial dose is 50 to 100 mg, to be followed by repeated doses as needed until
agitation is controlled--up to 300 mg per day. Dosage should then be reduced to
maintenance levels.
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* See package insert for Injectable Librium (chlordiazepoxide HCl).
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