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Chlordiazepoxide, Chlordiazepoxide Hydrochloride

Introduction
Chlordiazepoxide is a benzodiazepine.
Uses
Alcohol Withdrawal, Anxiety Disorders, and Preoperative Anxiolysis
Chlordiazepoxide shares the actions of other benzodiazepines and is used for the
management of anxiety disorders or for short-term relief of symptoms of anxiety,
preoperatively to relieve anxiety and tension, and for the management of agitation
associated with acute alcohol withdrawal. Anxiety or tension associated with the stress
of everyday life usually does not require treatment with an anxiolytic. The efficacy of
chlordiazepoxide for long-term use (i.e., for longer than 4 months) has not been
established, and the need for continued therapy with the drug should be periodically
reassessed.
Chlordiazepoxide hydrochloride, as the fixed-combination with amitriptylline, also has
been used in the management of depression associated with severe anxiety.
Peptic Ulcer Disease, Irritable Bowel Syndrome, Acute Enterocolitis
Chlordiazepoxide hydrochloride, as the fixed-combination with clidinium bromide, has
been used as an adjunct in the treatment of peptic ulcer disease and in the treatment of
functional disturbances of GI motility such as irritable bowel syndrome and acute
enterocolitis. For further information on the treatment of these disorders, see Uses in
Clidinium 12:08.08.
Dosage and Administration
Administration
Chlordiazepoxide and its hydrochloride salt are usually administered orally in 3 or 4
doses daily. After dosage has been stabilized, most clinicians believe that the drug may
be administered in 1 or 2 doses daily. When oral therapy is not feasible or when a rapid
therapeutic effect is necessary, chlordiazepoxide hydrochloride may be administered
slowly IV in adults. In most cases, however, IM injection is the preferred route of
administration because beneficial effects are usually evident within 15-30 minutes.
Therapy with oral chlordiazepoxide hydrochloride should replace parenteral
administration as soon as possible.
For IV administration, 5 mL of 0.9% sodium chloride injection or sterile water for
injection is added to the ampul containing 100 mg of chlordiazepoxide hydrochloride
immediately prior to administration, and the ampul is agitated gently. The resultant
solution contains 20 mg of chlordiazepoxide hydrochloride per mL. Chlordiazepoxide
injection should be made slowly IV over a 1-minute period. Chlordiazepoxide
hydrochloride powder for injection that has been reconstituted with the diluent supplied
by the manufacturer for IM use should not be given IV because air bubbles form in the

solution when the commercially available diluent is added to the powder for injection.
For IM administration, chlordiazepoxide hydrochloride injection is prepared by adding 2
mL of the diluent supplied by the manufacturer to the ampul containing 100 mg of the
drug and agitating the ampul gently until the drug is dissolved; the diluent should be
added carefully to minimize air bubble formation. The resultant solution contains 50 mg
of chlordiazepoxide hydrochloride per mL. IM chlordiazepoxide injection should be
made slowly, preferably by deep injection into the upper outer quadrant of the gluteus
muscle. The IV preparation reconstituted with 0.9% sodium chloride injection or sterile
water for injection should not be given IM because it may cause pain at the site of
injection.
Dosage
On the basis of molecular weight, 89 mg of chlordiazepoxide is equivalent to 100 mg of
chlordiazepoxide hydrochloride; however, the manufacturer of chlordiazepoxide base
claims that chlordiazepoxide and its hydrochloride salt may be used interchangeably on
a milligram-for-milligram basis. The doses recommended by the manufacturer for IM
and IV administration are identical.
Dosage must be individualized, and the smallest effective dosage should be used
(especially in geriatric or debilitated patients and in those with liver disease or low serum
albumin) to avoid oversedation.
Since chlordiazepoxide and its metabolites have long elimination half-lives, time to
reach steady-state plasma concentrations should be considered when dosage
adjustments are made.
Although a cumulative dose of 300 mg may be administered IM or IV during a 6-hour
period, this dose should not be exceeded in any 24-hour period.
Commercially available preparations containing chlordiazepoxide or its hydrochloride
salt in fixed combination with an anticholinergic (clidinium) or an antidepressant
(amitriptyline) generally should not be used as initial therapy in patients who require
both drugs. Dosage should first be adjusted by administering each drug separately. If it
is determined that the optimum maintenance dosage corresponds to the ratio in a
commercial combination preparation, such a product may be used. When dosage
adjustment is necessary, the drugs should be administered separately.
In patients who have received prolonged (e.g., for several months) chlordiazepoxide
hydrochloride therapy, abrupt discontinuance of the drug should be avoided since
manifestations of withdrawal can be precipitated; if the drug is to be discontinued in
such patients, it is recommended that dosage be gradually tapered.
Adult Dosage
Anxiety Disorders
For the management of mild to moderate anxiety, the usual adult oral dosage of
chlordiazepoxide hydrochloride is 5-10 mg 3 or 4 times daily. For severe anxiety, 20-25
mg may be given orally 3 or 4 times daily. Chlordiazepoxide hydrochloride also may be
administered IM or IV for the management of acute or severe anxiety at dosages of

50-100 mg initially, followed by 25-50 mg 3 or 4 times daily as needed.


Preoperative Anxiolysis
To relieve anxiety and tension preoperatively in adults, the manufacturer recommends
that 5-10 mg of chlordiazepoxide hydrochloride be given orally 3 or 4 times daily for
several days preceding surgery or 50-100 mg of chlordiazepoxide hydrochloride be
given IM 1 hour prior to surgery.
Acute Alcohol Withdrawal
For the management of agitation associated with acute alcohol withdrawal, the initial IM
or IV dose is 50-100 mg; this dose may be repeated in 2-4 hours if needed.
If given orally for the management of agitation associated with acute alcohol withdrawal,
the initial dose is 50-100 mg; doses are repeated until agitation is controlled.
The manufacturers state that in acute alcohol withdrawal, dosage should not exceed
300 mg daily; however, some clinicians have used chlordiazepoxide hydrochloride
dosages of 600-800 mg daily to control symptoms without adverse effects. After
agitation is controlled, the drug should be withdrawn slowly.
Peptic Ulcer Disease, Irritable Bowel Syndrome, Acute Enterocolitis
When chlordiazepoxide hydrochloride is used in fixed combination with clidinium
bromide, the usual adult maintenance dosage of chlordiazepoxide hydrochloride is 5 or
10 mg 3 or 4 times daily, administered before meals and at bedtime.
Pediatric Dosage
Because of the unpredictable response of children to CNS drugs, chlordiazepoxide
therapy should be initiated with the lowest dosage and increased as required.
Alcohol Withdrawal, Anxiety Disorders, and Preoperative Anxiolysis
The usual oral dosage of chlordiazepoxide hydrochloride in children older than 6 years
of age is 5 mg 2-4 times daily; the initial dosage should not exceed 10 mg daily. If
necessary, dosage for children may be increased to 10 mg 2 or 3 times daily.
Alternatively, some clinicians have recommended a pediatric oral dosage of 0.5 mg/kg
daily or 15 mg/m2 daily, given in 3 or 4 divided doses.
The usual initial dosage of IM or IV chlordiazepoxide hydrochloride in children 12-18
years of age is 25-50 mg.
Dosage in Geriatric or Debilitated Patients
Geriatric or debilitated patients may receive 5 mg of chlordiazepoxide hydrochloride
orally 2-4 times daily; the initial dose should not exceed 10 mg daily. When
chlordiazepoxide hydrochloride is used in fixed combination with clidinium bromide, the
recommended initial geriatric dosage of chlordiazepoxide hydrochloride is 10 mg daily,
which may be increased gradually as needed and tolerated. (See Cautions: Geriatric
Precautions.)
The usual initial dosage of IM or IV chlordiazepoxide hydrochloride in geriatric or
debilitated patients is 25-50 mg.

Cautions
Precautions
Chlordiazepoxide shares the toxic potentials of the benzodiazepines, and the usual
precautions of benzodiazepine administration should be observed. (See Cautions in the
Benzodiazepines General Statement 28:24.08.) The precautions and contraindications
associated with antimuscarinics or tricyclic antidepressants also should be considered
when commercially available preparations containing chlordiazepoxide or its
hydrochloride salt in fixed combination with clidinium or amitriptyline are used. (See
Cautions in the Antimuscarinics/Antispasmodics General Statement 12:08.08 and also
see Cautions in the Tricyclic Antidepressants General Statement 28:16.04.28.)
Parenterally administered chlordiazepoxide hydrochloride may cause hypotension
and/or respiratory depression, particularly if the drug is administered too rapidly IV. The
drug should be administered slowly IV over a 1-minute period in adults, and facilities
and equipment for respiratory or cardiovascular assistance should be readily available.
According to the manufacturer of chlordiazepoxide hydrochloride injection, the patient
should be observed, preferably in bed, for up to 3 hours following parenteral
administration of the drug.
Pediatric Precautions
Safety and efficacy of orally administered chlordiazepoxide or chlordiazepoxide
hydrochloride in children younger than 6 years of age and safety and efficacy of
parenteral chlordiazepoxide hydrochloride in children younger than 12 years of age
have not been established.
Safety and efficacy of the fixed-combination preparation containing chlordiazepoxide
hydrochloride and clidinium bromide in pediatric patients have not been established.
Geriatric Precautions
Although safety and efficacy of chlordiazepoxide in geriatric patients have not been
studied specifically to date, one manufacturer states that geriatric adults may be
especially prone to adverse effects such as drowsiness, ataxia, and confusion when
receiving chlordiazepoxide hydrochloride in fixed combination with clidinium bromide.
These adverse effects usually can be prevented by proper dosage adjustment.
Therefore, it is recommended that the initial dosage of this combination in geriatric
patients be selected carefully and gradually increased if needed and tolerated.
However, these adverse effects occasionally have been observed in geriatric patients
receiving the lower range of the usual dosage of this combination.
Chemistry and Stability
Chemistry
Chlordiazepoxide is a benzodiazepine. Chlordiazepoxide occurs as a yellow, practically
odorless, crystalline powder and has solubilities of less than 0.1 mg/mL in water and
approximately 20 mg/mL in alcohol at 25C. Chlordiazepoxide hydrochloride occurs as a
white or practically white, odorless, crystalline powder and is soluble in water and in
alcohol and slightly soluble in propylene glycol. Chlordiazepoxide has a pKa of 4.8. The

diluent supplied by the manufacturer to prepare chlordiazepoxide hydrochloride injection


contains benzyl alcohol as a preservative and its pH is adjusted to approximately
2.5-3.5 with maleic acid and sodium hydroxide. After reconstitution of 100 mg of
chlordiazepoxide hydrochloride with 2 mL of the commercially available diluent or with 5
mL of sterile water for injection or 0.9% sodium chloride injection, the pH of the injection
is about 3.
Stability
Chlordiazepoxide hydrochloride is unstable in water, 0.9% sodium chloride, and the
commercially available diluent. The injection should be prepared immediately before
use, and any unused portion should be discarded. The diluent is reportedly stable for at
least 48 hours at a temperature not exceeding 25C; however, the diluent should be
stored at 2-8C since hydrolysis of polysorbate 80 may cause opalescence of the
diluent. The diluent should not be used if it is hazy or opalescent. Chlordiazepoxide
tablets and chlordiazepoxide hydrochloride capsules and powder for injection must be
protected from light.
Chlordiazepoxide hydrochloride injection has been reported to be incompatible with
various drugs, but the compatibility may depend on several factors (e.g., concentration
of the drugs, resulting pH, temperature). Specialized references should be consulted for
more specific compatibility information.
For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions,
chronic toxicity, acute toxicity, drug interactions, laboratory test interferences, and
dosage and administration of chlordiazepoxide, see the Benzodiazepines General
Statement 28:24.08.
Preparations
Single-entity preparations of chlordiazepoxide and its hydrochloride salt and
preparations containing the drug in combination with amitriptyline hydrochloride are
subject to control under the Federal Controlled Substances Act of 1970 as schedule IV
(C-IV) drugs.
Chlordiazepoxide and Amitriptyline Hydrochloride
Oral
Tablets, film5 mg Chlordiazepoxide and Chlordiazepoxide and
coated
Amitriptyline Hydrochloride Amitriptyline Hydrochloride
12.5 mg (of amitriptyline) Tablets, ((C-IV)) Mylan
Limbitrol , ((C-IV);
with povidone) Valeant
10 mg Chlordiazepoxide and Chlordiazepoxide and
Amitriptyline Hydrochloride Amitriptyline Hydrochloride
25 mg (of amitriptyline)
Tablets, ((C-IV)) Mylan

Limbitrol DS, ((C-IV); with


povidone) Valeant

Chlordiazepoxide Hydrochloride
Oral
Capsules

5 mg

Chlordiazepoxide Hydrochloride
Capsules, ((C-IV)) Barr
Watson
Librium , ((C-IV);
with parabens)
Valeant

10 mg

Chlordiazepoxide Hydrochloride
Capsules, ((C-IV)) Barr
Watson
Librium , ((C-IV);
with parabens)
Valeant

25 mg

Chlordiazepoxide Hydrochloride
Capsules, ((C-IV)) Barr
Watson
Librium , ((C-IV);
with parabens)
Valeant

Parenteral
For injection

100 mg

Librium , ((C-IV); with 2 mL


diluent containing benzyl
alcohol 1.5% propylene glycol)
Valeant

Chlordiazepoxide Hydrochloride and Clidinium Bromide


Oral
Capsules

5 mg Chlordiazepoxide
Chlordiazepoxide Hydrochloride
Hydrochloride and Clidinium and Clidinium Bromide Capsules

Bromide 2.5 mg

, Amide United Research


Librax , (with
parabens) Valeant

References
Location In Book:
AHFS DRUG INFORMATION (2004)
28:00 Central Nervous System Agents
28:24 Anxiolytics, Sedatives, and Hypnotics
28:24.08 Benzodiazepines
Chlordiazepoxide, Chlordiazepoxide Hydrochloride