Chlorpromazine, Chlorpromazine Hydrochloride

Introduction
Chlorpromazine is a phenothiazine antipsychotic agent.
Uses
Psychotic Disorders
Chlorpromazine is used for the symptomatic management of psychotic disorders. Drug
therapy is integral to the management of acute psychotic episodes and accompanying
violent behavior in patients with schizophrenia and generally is required for long-term
stabilization to improve symptoms between episodes and to minimize the risk of
recurrent acute episodes. Antipsychotic agents are the principal class of drugs used for
the management of all phases of schizophrenia and generally are effective in all
subtypes of the disorder and subgroups of patients.Patient response and tolerance to
antipsychotic agents are variable, and patients who do not respond to or tolerate one
drug may be successfully treated with an agent from a different class or with a different
adverse effect profile. For additional information on the symptomatic management of
schizophrenia, see Uses: Psychoneurologic Disorders, in the Phenothiazines General
Statement 28:16.08.24.
Other Uses
Chlorpromazine is used for the prevention and treatment of nausea and vomiting; for
relief of restlessness and apprehension before surgery; for acute intermittent porphyria;
as an adjunct in the treatment of tetanus; for the symptomatic management of the manic
phase of bipolar disorder; and for relief of intractable hiccups.
Chlorpromazine is also used for the treatment of severe behavioral problems in children
marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to
immediate provocations), and for the short-term treatment of hyperactive children who
exhibit excessive motor activity with accompanying conduct disorders that are
manifested as impulsivity, difficulty sustaining attention, aggression, mood lability,
and/or poor frustration tolerance. However, the possible risks of tardive dyskinesia,
withdrawal dyskinesia, and other extrapyramidal reactions associated with the drug
should be considered. Some clinicians recommend routine administration of the
Abnormal Involuntary Movement Scale (AIMS) to all children receiving antipsychotic
agents for this indication.
Chlorpromazine may be effective in controlling anxiety, tension, and agitation which
occur in neuroses. Further studies are needed to establish the efficacy of the drug for
this use.
Dosage and Administration
Administration
Chlorpromazine is administered rectally. Chlorpromazine hydrochloride may be

administered orally, by deep IM or direct IV injection, or by IV infusion. Direct IV injection

is intended for use only during surgery to control nausea and vomiting and in the
adjunctive treatment of tetanus. IV infusion is only intended for use in the adjunctive
treatment of intractable hiccups in adults. Subcutaneous administration of the drug is
not recommended because of local irritation. Parenteral therapy should be reserved for
recumbent patients; however, if cautions are taken to avoid orthostatic hypotension (i.e.,
patient remains recumbent for at least 30 minutes after injection), acutely agitated
ambulatory patients may receive the drug IM.
For IM administration, injection should be made slowly, deep into a large muscle mass
such as the upper outer quadrant of the gluteus maximus; if irritation at the IM injection
site is a problem, the drug can be diluted with 0.9% sodium chloride injection or 2%
procaine hydrochloride. For direct IV injection, chlorpromazine hydrochloride injection
should be diluted with 0.9% sodium chloride injection to a concentration not exceeding 1
mg/mL and administered at a rate of 1 mg/minute in adults and 0.5 mg/minute in
children. IV administration of undiluted chlorpromazine hydrochloride injection should be
avoided. For IV infusion, chlorpromazine hydrochloride injection should be added to
500-1000 mL of 0.9% sodium chloride injection and administered slowly.
When chlorpromazine hydrochloride oral concentrate solution is used, the dose should
be diluted (e.g., with tomato or fruit juice, milk, simple syrup, orange syrup, carbonated
beverages, coffee, tea, water) just before administration; semisolid foods (e.g., soups,
puddings) may also be used as a vehicle for oral administration.
Dosage
Dosage of chlorpromazine is expressed in terms of chlorpromazine and dosage of
chlorpromazine hydrochloride is expressed in terms of the hydrochloride salt.
Therapeutic potency relationships on a weight basis among all dosage forms have not
been clearly established clinically; however, the total daily dose for conventional oral
preparations (i.e., solutions, tablets) of the drug generally may be used as the total daily
dose for extended-release capsules. The manufacturers state that the 100- and 200-mg
chlorpromazine tablets are intended for use in patients with severe neuropsychiatric
conditions.
Dosage must be carefully adjusted according to individual requirements and response,
using the lowest possible effective dosage. Dosage should be increased more gradually
in debilitated, emaciated, or geriatric patients. Since geriatric patients may be more
susceptible to hypotension and neuromuscular reactions, these patients should be
observed closely; in general, dosages in the lower end of the range are sufficient for
most geriatric patients. Because of the risk of adverse reactions associated with
cumulative effects of phenothiazines, patients with a history of long-term therapy with
chlorpromazine and/or other antipsychotic agents should be evaluated periodically to
determine whether maintenance dosage should be decreased or drug therapy
discontinued. Chlorpromazine should generally not be used in children younger than 6
months of age unless the condition to be treated is potentially life-threatening; dosage in
this age group has not been established.
Psychotic Disorders and Excessive Anxiety, Tension, and Agitation
For the symptomatic management of psychotic disorders in non-hospitalized patients

with relatively mild symptomatology and for the management of excessive anxiety,
tension, and agitation, the usual initial adult oral dosage of chlorpromazine is 30-75 mg
daily given in 2-4 divided doses. For non-hospitalized patients with moderate to severe
symptomatology, the usual initial adult oral dosage is 25 mg 3 times daily. After 1 or 2
days, dosage may be gradually increased twice weekly by 20-50 mg until symptoms are
controlled. Although symptomatic relief may be seen in many patients during the first
week of therapy, optimum therapeutic response may not occur for weeks or even
months in some severely disturbed or symptomatic patients. Once an optimum dosage
is achieved, this dosage should be continued for 2 weeks and then gradually reduced to
the lowest possible effective dosage. In adult patients with excessive anxiety, tension,
and agitation, the usual oral dosage during prolonged maintenance therapy is 200 mg
daily; however, oral dosages up to 800 mg daily may be required in some patients (e.g.,
discharged psychiatric patients). For prompt control of severe symptoms in
non-hospitalized patients or in patients with anxiety, tension, and agitation, an IM dose
of 25 mg may be given initially; this dose may be repeated in 1 hour, if necessary. After
the patient's symptoms are controlled, oral therapy should replace parenteral therapy at
a dosage of 25-50 mg 3 times daily.
For the symptomatic management of psychotic disorders in hospitalized patients who
are acutely agitated, manic, or disturbed, the usual initial adult IM dose of
chlorpromazine is 25 mg. Additional IM doses of 25-50 mg may be given in 1 hour, if
necessary. Subsequent IM dosage should be gradually increased over several days to a
maximum of 400 mg every 4-6 hours until symptoms are controlled. Usually, patients
become quiet and cooperative within 24-48 hours after initiation of therapy; oral therapy
should replace parenteral therapy and dosage should be increased until the patient is
calm. Oral dosages of 500 mg daily are generally sufficient in most patients. Although
oral dosages greater than 2 g daily may be required in some patients, there is usually
little therapeutic gain achieved by exceeding dosages of 1 g daily for extended periods.
For hospitalized patients who are less acutely agitated, the usual initial adult oral
dosage of chlorpromazine is 25 mg 3 times daily. Subsequent dosage should be
gradually increased until optimum therapeutic response is obtained, but should usually
not exceed 400 mg daily.
The usual initial oral dosage of chlorpromazine for the management of psychotic
disorders and behavioral problems in children 6 months of age or older is 0.55 mg/kg
every 4-6 hours as necessary. The usual initial rectal dosage for the management of
psychotic disorders and behavioral problems in these children is 1.1 mg/kg every 6-8
hours as necessary. The usual initial IM dosage of chlorpromazine for the management
of psychotic disorders and behavioral problems in these children is 0.55 mg/kg every
6-8 hours as necessary. Subsequent dosage may be gradually increased as necessary.
Higher dosages (50-100 mg daily) may be necessary in children with severe behavior
disorders or psychotic conditions; older children may require 200 mg daily. There is little
evidence that improvement in behavior in severely disturbed mentally retarded children
is further enhanced at oral dosages greater than 500 mg daily. Maximum IM dosage of
chlorpromazine in children younger than 5 years of age and in those weighing less than
22.7 kg is 40 mg daily; maximum IM dosage in children 5-12 years of age and weighing
22.7-45.5 kg should not exceed 75 mg daily, except in unmanageable patients.
Nausea and Vomiting

For the prevention and treatment of nausea and vomiting in patients who can tolerate
oral administration of the drug, the usual initial adult oral dosage of chlorpromazine is
10-25 mg every 4-6 hours as necessary; dosage may be increased if necessary. The
usual adult rectal dosage for the prevention and control of nausea and vomiting is 100
mg every 6-8 hours as necessary; in some patients, 50 mg every 6-8 hours will be
adequate. The usual initial adult IM dose of chlorpromazine for the control of nausea
and vomiting is 25 mg. If hypotension does not occur, additional IM doses of 25-50 mg
may be administered as necessary every 3-4 hours until symptoms subside; oral
therapy should then replace parenteral therapy if necessary.
For the prevention and treatment of nausea and vomiting in children 6 months of age or
older, the usual oral dosage of chlorpromazine is 0.55 mg/kg every 4-6 hours. The usual
rectal dosage for the prevention and control of nausea and vomiting in these children is
1.1 mg/kg every 6-8 hours as necessary. The usual initial IM dosage of chlorpromazine
for the control of nausea and vomiting in these children is 0.55 mg/kg every 6-8 hours
as necessary. Subsequent dosage should be carefully adjusted according to the
severity of symptoms and the patient's response. Maximum IM dosage of
chlorpromazine in children younger than 5 years of age and in those weighing less than
22.7 kg is 40 mg daily; maximum IM dosage in children 5-12 years of age and weighing
22.7-45.5 kg should not exceed 75 mg daily, except in severe cases.
Intermittent Porphyria
For acute intermittent porphyria, the usual adult oral dosage of chlorpromazine is 25-50
mg 3 or 4 times daily. The usual adult IM dosage of chlorpromazine for acute
intermittent porphyria is 25 mg 3 or 4 times daily. Oral therapy should replace parenteral
therapy as soon as the patient can tolerate oral administration of the drug. Therapy can
usually be discontinued after several weeks; however, maintenance therapy may be
required in some patients.
Intractable Hiccups
For relief of intractable hiccups, the usual adult oral dosage of chlorpromazine is 25-50
mg 3 or 4 times daily. If symptoms persist for 2-3 days, 25-50 mg may be given IM. If
hiccups continue, 25-50 mg of the drug may be administered by slow IV infusion (see
Dosage and Administration: Administration) with the patient in a supine position. Blood
pressure should be closely monitored during IV administration of chlorpromazine.
Tetanus
For adjunctive treatment of tetanus, the usual initial adult IM dosage of chlorpromazine
is 25-50 mg 3 or 4 times daily, usually in conjunction with barbiturates. The usual adult
direct IV dose of the drug is 25-50 mg. (See Dosage and Administration:
Administration.) The usual IM or direct IV dosage of chlorpromazine for adjunctive
treatment of tetanus in children 6 months of age or older is 0.55 mg/kg every 6-8 hours.
Maximum parenteral dosage of chlorpromazine in children weighing less than 22.7 kg is
40 mg daily; maximum parenteral dosage in children weighing 22.7-45.5 kg should not
exceed 75 mg daily, except in severe cases.
Surgery
For relief of restlessness and apprehension before surgery, the usual adult oral dose of
chlorpromazine is 25-50 mg given 2-3 hours before surgery. The usual adult IM dose is

12.5-25 mg given 1-2 hours before surgery. For relief of restlessness and apprehension
before surgery in children 6 months of age or older, the usual oral or IM dose of
chlorpromazine is 0.55 mg/kg administered 2-3 or 1-2 hours before surgery,
respectively.
To control acute nausea and vomiting during surgery, the usual adult IM dose of
chlorpromazine is 12.5 mg; this dose may be repeated in 30 minutes, if necessary and if
hypotension does not occur. Alternatively during surgery in adults, fractional 2-mg doses
may be given IV at 2-minute intervals up to a maximum total dose of 25 mg. To control
acute nausea and vomiting during surgery in children 6 months of age or older, the
usual IM dose of chlorpromazine is 0.275 mg/kg; this dose may be repeated in 30
minutes, if necessary and if hypotension does not occur. Alternatively during surgery in
these children, fractional 1-mg doses may be given IV at 2-minute intervals up to a total
dose of 0.275 mg/kg; if after 30 minutes it is necessary to readminister the drug and if
hypotension does not occur, the fractional IV dosage regimen may be repeated.
Following surgery, the usual adult oral dosage of chlorpromazine is 10-25 mg every 4-6
hours as necessary. The usual adult IM dose of chlorpromazine following surgery is
12.5-25 mg; this dose may be repeated in 1 hour, if necessary and if hypotension does
not occur. Following surgery in children 6 months of age or older, the usual initial oral or
IM dose of chlorpromazine is 0.55 mg/kg. The initial oral dose may be repeated every
4-6 hours as needed; the initial IM dose may be repeated in 1 hour, if necessary and if
hypotension does not occur.
Cautions
Chlorpromazine shares the toxic potentials of other phenothiazines, and the usual
precautions of phenothiazine therapy should be observed. (See Cautions in the
Phenothiazines General Statement 28:16.08.24.)
Care should be taken to avoid skin contact with chlorpromazine hydrochloride oral
solutions or injection, since contact dermatitis has occurred rarely.
Because a rubbery, orange substance was noticed in the stool of a patient who ingested
chlorpromazine oral solution immediately after ingesting carbamazepine oral
suspension and subsequent testing has shown that mixing chlorpromazine oral solution
with carbamazepine oral suspension results in a rubbery, orange precipitate, it has been
recommended that chlorpromazine oral solution not be administered simultaneously
with carbamazepine oral suspension. It is not known whether the development of this
precipitate results in decreased bioavailability of either chlorpromazine or
carbamazepine.
Some commercially available formulations of chlorpromazine contain sulfites that may
cause allergic-type reactions, including anaphylaxis and life-threatening or less severe
asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite
sensitivity in the general population is unknown but probably low; such sensitivity
appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Safety and efficacy of chlorpromazine in children younger than 6 months of age have

not been established; the manufacturer recommends that the drug should generally not
be used in these children unless the condition to be treated is potentially
life-threatening. Chlorpromazine should not be used in conditions for which pediatric
dosage has not been established.
Pharmacology
The principal pharmacologic effects of chlorpromazine are similar to those of other
propylamino derivatives of phenothiazine. Chlorpromazine has strong anticholinergic
and sedative effects and moderate extrapyramidal effects. Chlorpromazine has strong
antiemetic and adrenergic blocking activity and weak ganglionic blocking, antihistaminic,
and antiserotonergic activity.
Pharmacokinetics
Absorption
Chlorpromazine hydrochloride is rapidly absorbed from the GI tract and from parenteral
sites of injection; however, following oral administration, the drug undergoes
considerable metabolism during absorption (in the GI mucosa) and first pass through
the liver. Although not clearly established in humans, chlorpromazine and its
metabolites undergo enterohepatic circulation in animals. (See Pharmacokinetics:
Elimination.)
Considerable interindividual variations in peak plasma concentrations have been
reported with the same oral dose of chlorpromazine. The variability is thought to result
from wide interindividual variation in bioavailability, apparently because of genetic
differences in the rate of first-pass metabolism. As a result of first-pass metabolism, less
chlorpromazine reaches systemic circulation as unchanged drug, and peak plasma
chlorpromazine concentrations are much lower following oral administration than
following IM administration.
Following oral administration of chlorpromazine hydrochloride in a tablet formulation, the
onset of pharmacologic action occurs within 30-60 minutes; the duration of action is 4-6
hours. The onset of pharmacologic action following oral administration of
chlorpromazine hydrochloride in an extended-release formulation is approximately
30-60 minutes; the duration of action is 10-12 hours. The onset of pharmacologic action
following rectal administration of chlorpromazine is generally slower than that following
oral administration of chlorpromazine hydrochloride; rectally administered
chlorpromazine has a duration of action of 3-4 hours.
The therapeutic range for plasma chlorpromazine concentrations and the relationship of
plasma concentration to clinical response and toxicity have not been clearly established.
Distribution
Chlorpromazine is widely distributed into most body tissues and fluids. Chlorpromazine
crosses the blood-brain barrier, and concentrations of the drug in the brain are higher
than those in plasma.
Chlorpromazine is 92-97% bound to plasma proteins, principally albumin, at plasma

chlorpromazine concentrations of 0.01-1 mcg/mL.

Chlorpromazine and its metabolites cross the placenta and are distributed into milk.
Elimination
Although the exact metabolic fate of chlorpromazine is not clearly established, the drug
is extensively metabolized, principally in the liver and kidneys. About 10-12 metabolites
which occur in humans in appreciable quantities have been identified. In addition to
hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the
N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is
also metabolized to an N-oxide. Two principal groups of metabolites have been found in
urine. The unconjugated fraction, which represents approximately 20% of
chlorpromazine and its metabolites excreted in urine, consists of unchanged drug,
demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites,
and chlorpromazine-N-oxide. The conjugated fraction, which represents approximately
80% of chlorpromazine and its metabolites excreted in urine, consists principally of
O-glucuronides, with small amounts of ethereal sulfates of the mono- and
dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major
metabolites found in urine are the monoglucuronide of N-dedimethylchlorpromazine and
7-hydroxychlorpromazine.
Following a single oral chlorpromazine dose of 120 mg/m2 to 4 healthy men, less than
1% of the dose was excreted in urine as unchanged drug within 72 hours, with most
urinary excretion of unchanged drug occurring within 6 hours. Following continuous oral
administration of chlorpromazine to a limited number of psychiatric patients in a dosage
ranging from 0.1-1.4 g daily, an average of 37% of the dose was excreted in urine,
principally as metabolites. In blacks, a relatively high percentage of chlorpromazine is
excreted in urine as unconjugated 7-hydroxychlorpromazine; however, in whites, this
may be an indication of existing or developing hyperpigmentation of the skin.
Chemistry and Stability
Chemistry

chlorpromazine

Chlorpromazine is a phenothiazine antipsychotic agent. The drug is a propylamino

derivative of phenothiazine and is structurally similar to promazine, but differs from

promazine in the substitution of a chlorine atom for hydrogen at the 2 position of the
phenothiazine nucleus. Chlorpromazine is commercially available as the base and as
the hydrochloride salt. Each 111 mg of chlorpromazine hydrochloride is approximately
equivalent to 100 mg of chlorpromazine base.
Chlorpromazine occurs as a white, crystalline solid that has an amine odor and is
practically insoluble in water and freely soluble in alcohol. Chlorpromazine hydrochloride
occurs as a white or slightly creamy white, odorless, very bitter tasting, crystalline
powder and has approximate solubilities of 1 g/mL in water and 667 mg/mL in alcohol at
25C.
Chlorpromazine hydrochloride injection is a sterile solution of the drug in water for
injection. The commercially available injection has a pH of 3-5 and may contain benzyl
alcohol as a preservative, a sulfite(s), and other excipients.
Stability
Chlorpromazine and its hydrochloride salt darken on prolonged exposure to light.
Commercially available preparations of chlorpromazine and its hydrochloride salt should
be protected from light. Chlorpromazine hydrochloride oral solutions, tablets,
extended-release capsules, and injection should be stored at a temperature less than
40C, preferably between 15-30C; freezing of the oral solutions and injection should be
avoided. Oral preparations of chlorpromazine hydrochloride should be stored in tightly
closed containers. Chlorpromazine suppositories should be stored in well-closed
containers between 15-30C. Slight yellowish discoloration of the oral solutions or
injection will not affect potency or efficacy, but they should not be used if markedly
discolored or if a precipitate is present. Chlorpromazine hydrochloride oral concentrate
solution should be dispensed in amber glass bottles. At the time of manufacture, air in
the containers of the commercially available chlorpromazine hydrochloride injection is
replaced with nitrogen to avoid oxidation. Oxidation of chlorpromazine hydrochloride
occurs readily in alkaline media.
Testing has shown that mixing chlorpromazine oral solution with carbamazepine oral
suspension results in a rubbery, orange precipitate. (See Cautions.) It is not known
whether the development of this precipitate results in decreased bioavailability of either
chlorpromazine or carbamazepine. Therefore, it is recommended that chlorpromazine
oral solution not be administered simultaneously with carbamazepine oral suspension.
Chlorpromazine hydrochloride injection is physically and/or chemically incompatible with
some drugs, but the compatibility depends on several factors (e.g., concentrations of the
drugs, specific diluents used, resulting pH, temperature). Specialized references should
be consulted for specific compatibility information.
For further information on chemistry and stability, pharmacology, pharmacokinetics,
uses, cautions, acute toxicity, drug interactions, laboratory test interferences, and
dosage and administration of chlorpromazine, see the Phenothiazines General
Statement 28:16.08.24.
Preparations

Chlorpromazine
Rectal
Suppositories

25 mg

100 mg

Thorazine, GlaxoSmithKline
(also promoted by Scios)
Thorazine , GlaxoSmithKline
(also promoted by Scios)

Chlorpromazine Hydrochloride
Oral
Capsules, extended- 30 mg
release

Thorazine Spansule, (with

benzyl alcohol and povidone)
GlaxoSmithKline (also promoted
by Scios)

75 mg

Thorazine Spansule, (with

benzyl alcohol and povidone)
GlaxoSmithKline (also promoted
by Scios)

150 mg

Thorazine Spansule,
(with benzyl alcohol and
povidone) GlaxoSmithKline (also
promoted by Scios)

Solution

10 mg/5 mL

Thorazine Syrup,
GlaxoSmithKline (also promoted
by Scios)

Solution,
concentrate

30 mg/mL

Chlorpromazine Hydrochloride
Intensol , (with alcohol
0.068%) Roxane

100 mg/mL

Chlorpromazine Hydrochloride
Concentrate, Alpharma
Chlorpromazine Hydrochloride
Intensol , (with alcohol

0.068%) Roxane

Tablets

10 mg

Thorazine , (with parabens)

GlaxoSmithKline (also promoted
by Scios)

25 mg

Thorazine , (with parabens)

GlaxoSmithKline (also promoted
by Scios)

50 mg

Thorazine , (with parabens)

GlaxoSmithKline (also promoted
by Scios)

100 mg

Thorazine , (with parabens)

GlaxoSmithKline (also promoted
by Scios)

200 mg

Thorazine , (with parabens)

GlaxoSmithKline (also promoted
by Scios)

Parenteral
Injection

25 mg/mL

Thorazine , (with sulfites in

ampuls or with benzyl alcohol
2% and sulfites in multipledose vials) GlaxoSmithKline
(also promoted by Scios)

Location In Book:
AHFS DRUG INFORMATION (2004)
28:00 Central Nervous System Agents
28:16 Psychotherapeutic Agents
28:16.08 Antipsychotics
28:16.08.24 Phenothiazines
Chlorpromazine, Chlorpromazine Hydrochloride