Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Chlorpromazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING ).
The extrapyramidal symptoms which can occur secondary to chlorpromazine may be confused with the central nervous system signs of an undiagnosed primary disease responsible for the vomiting, e.g., Reye’s syndrome or other encephalopathy.
The use of chlorpromazine and other potential hepatotoxins should be avoided in children and adolescents whose signs and symptoms suggest Reye’s syndrome.
Tardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs.
Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.
Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and therapy may possibly mask the underlying disease process.
The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.
Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.
In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.
The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered.
However, some patients may require treatment despite the presence of the syndrome.
For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on PRECAUTIONS and ADVERSE REACTIONS .
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs.
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available.
There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored, since recurrences of NMS have been reported.
An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and FBS) has occurred in a few patients treated with lithium plus an antipsychotic.
In some instances, the syndrome was followed by irreversible brain damage.
Because of a possible causal relationship between these events and the concomitant administration of lithium and antipsychotics, patients receiving such combined therapy should be monitored closely for early evidence of neurologic toxicity and treatment discontinued promptly if such signs appear.
This encephalopathic syndrome may be similar to or the same as neuroleptic malignant syndrome (NMS).
Patients with bone marrow depression or who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) with a phenothiazine, should not receive any phenothiazine, including chlorpromazine, unless in the judgment of the physician the potential benefits of treatment outweigh the possible hazard.
Chlorpromazine may impair mental and/or physical abilities, especially during the first few days of therapy.
Therefore, caution patients about activities requiring alertness (e.g., operating vehicles or machinery).
The use of alcohol with this drug should be avoided due to possible additive effects and hypotension.
Chlorpromazine may counteract the antihypertensive effect of guanethidine and related compounds.
Falls Chlorpromazine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.
For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Usage in Pregnancy: Safety for the use of chlorpromazine during pregnancy has not been established.
Therefore, it is not recommended that the drug be given to pregnant patients except when, in the judgment of the physician, it is essential.
The potential benefits should clearly outweigh possible hazards.
There are reported instances of prolonged jaundice, extrapyramidal signs, hyperreflexia or hyporeflexia in newborn infants whose mothers received phenothiazines.
Reproductive studies in rodents have demonstrated potential for embryotoxicity, increased neonatal mortality and nursing transfer of the drug.
Tests in the offspring of the drug–treated rodents demonstrate decreased performance.
The possibility of permanent neurological damage cannot be excluded.
Non-teratogenic Effects: Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.
There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates.
These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Chlorpromazine Hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: There is evidence that chlorpromazine is excreted in the breast milk of nursing mothers.
Because of the potential for serious adverse reactions in nursing infants from chlorpromazine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
(See also ADVERSE REACTIONS .) Symptoms Primarily symptoms of central nervous system depression to the point of somnolence or coma.
Hypotension and extrapyramidal symptoms.
Other possible manifestations include agitation and restlessness, convulsions, fever, autonomic reactions such as dry mouth and ileus.
EKG changes and cardiac arrhythmias.
Treatment It is important to determine other medications taken by the patient since multiple drug therapy is common in overdosage situations.
Treatment is essentially symptomatic and supportive.
Early gastric lavage is helpful.
Keep patient under observation and maintain an open airway, since involvement of the extrapyramidal mechanism may produce dysphagia and respiratory difficulty in severe overdosage.
Do not attempt to induce emesis because a dystonic reaction of the head or neck may develop that could result in aspiration of vomitus.
Extrapyramidal symptoms may be treated with anti-parkinsonism drugs, barbiturates, or diphenhydramine hydrochloride.
See prescribing information for these products.
Care should be taken to avoid increasing respiratory depression.
If administration of a stimulant is desirable, amphetamine, dextroamphetamine, or caffeine with sodium benzoate is recommended.
Stimulants that may cause convulsions (e.g., picrotoxin or pentylenetetrazol) should be avoided.
If hypotension occurs, the standard measures for managing circulatory shock should be initiated.
If it is desirable to administer a vasoconstrictor, norepinephrine and phenylephrine are most suitable.
Other pressor agents, including epinephrine, are not recommended because phenothiazine derivatives may reverse the usual elevating action of these agents and cause a further lowering of blood pressure.
Limited experience indicates that phenothiazines are not dialyzable.
Chlorpromazine hydrochloride, a dimethylamine derivative of phenothiazine, has a chemical formula of 2-chloro-10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride.
It is available in tablets for oral administration.
It has the following structural formula: Chlorpromazine hydrochloride occurs as white or slightly creamy white, odorless, crystalline powder which darkens on prolonged exposure to light.
Each tablet for oral administration contains 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg of chlorpromazine HCl, USP.
Inactive ingredients: acacia, black iron oxide, calcium sulfate, carnauba wax, D&C Yellow #10 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, anhydrous lactose, magnesium stearate, methylparaben, pharmaceutical glaze, povidone, propylparaben, sodium benzoate, sucrose and titanium dioxide.
: Chlorpromazine Hydrochloride Tablets, USP, 10 mg are round, butterscotch colored, sugar coated tablets, imprinted on one side with “832” above “10” and no print on the reverse side.
They are available as follows: NDC 51079-518-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
Chlorpromazine Hydrochloride Tablets, USP, 25 mg are round, butterscotch colored, sugar coated tablets, imprinted on one side with “832” above “25” and no print on the reverse side.
They are available as follows: NDC 51079-519-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
Chlorpromazine Hydrochloride Tablets, USP, 50 mg are round, butterscotch colored, sugar coated tablets, imprinted on one side with “832” above “50” and no print on the reverse side.
They are available as follows: NDC 51079-130-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
THESE TABLET STRENGTHS LISTED BELOW ARE FOR USE ONLY IN SEVERE NEUROPSYCHIATRIC CONDITIONS.
Chlorpromazine Hydrochloride Tablets, USP, 100 mg are round, butterscotch colored, sugar coated tablets, imprinted on one side with “832” above “100” and no print on the reverse side.
They are available as follows: NDC 51079-516-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
Chlorpromazine Hydrochloride Tablets, USP, 200 mg are round, butterscotch colored, sugar coated tablets, imprinted on one side with “832” above “200” and no print on the reverse side.
They are available as follows: NDC 51079-517-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from light and moisture.
INDICATIONS AND USAGE
For the management of manifestations of psychotic disorders.
For the treatment of schizophrenia.
To control nausea and vomiting.
For relief of restlessness and apprehension before surgery.
For acute intermittent porphyria.
As an adjunct in the treatment of tetanus.
To control the manifestations of the manic type of manic-depressive illness.
For relief of intractable hiccups.
For the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability and poor frustration tolerance.
WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.
Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
Chlorpromazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS ).
DOSAGE AND ADMINISTRATION
–ADULTS Adjust dosage to individual and the severity of his condition, recognizing that the milligram for milligram potency relationship among all dosage forms has not been precisely established clinically.
It is important to increase dosage until symptoms are controlled.
Dosage should be increased more gradually in debilitated or emaciated patients.
In continued therapy, gradually reduce dosage to the lowest effective maintenance level, after symptoms have been controlled for a reasonable period.
The 100 mg and 200 mg tablets are for use in severe neuropsychiatric conditions.
Elderly Patients – In general, dosages in the lower range are sufficient for most elderly patients.
Since they appear to be more susceptible to hypotension and neuromuscular reactions, such patients should be observed closely.
Dosage should be tailored to the individual, response carefully monitored, and dosage adjusted accordingly.
Dosage should be increased more gradually in elderly patients.
Psychotic Disorders – Increase dosage gradually until symptoms are controlled.
Maximum improvement may not be seen for weeks or even months.
Continue optimum dosage for 2 weeks; then gradually reduce dosage to the lowest effective maintenance level.
Daily dosage of 200 mg is not unusual.
Some patients require higher dosages (e.g., 800 mg daily is not uncommon in discharged mental patients).
Hospitalized Patients: Acute Schizophrenic or Manic States – It is recommended that initial treatment be with chlorpromazine HCI injection until patient is controlled.
Usually patient becomes quiet and co-operative within 24 to 48 hours and oral doses may be substituted and increased until the patient is calm.
500 mg a day is generally sufficient.
While gradual increases to 2,000 mg a day or more may be necessary, there is usually little therapeutic gain to be achieved by exceeding 1,000 mg a day for extended periods.
In general, dosage levels should be lower in the elderly, the emaciated and the debilitated.
Less Acutely Disturbed – 25 mg t.i.d.
Increase gradually until effective dose is reached – usually 400 mg daily.
Outpatients – 10 mg t.i.d.
or q.i.d., or 25 mg b.i.d.
More Severe Cases – 25 mg t.i.d.
After 1 or 2 days, daily dosage may be increased by 20 to 50 mg at semi-weekly intervals until patient becomes calm and cooperative.
Prompt Control of Severe Symptoms – Initial treatment should be with intramuscular chlorpromazine.
Subsequent doses should be oral, 25 to 50 mg t.i.d.
Nausea and Vomiting – 10 to 25 mg q4 to 6h, p.r.n., increased, if necessary.
Presurgical Apprehension – 25 to 50 mg, 2 to 3 hours before the operation.
Intractable Hiccups – 25 to 50 mg t.i.d.
If symptoms persist for 2 to 3 days, parenteral therapy is indicated.
Acute Intermittent Porphyria – 25 to 50 mg t.i.d.
Can usually be discontinued after several weeks, but maintenance therapy may be necessary for some patients.
– PEDIATRIC PATIENTS (6 months to 12 years of age) Chlorpromazine should generally not be used in pediatric patients under 6 months of age except where potentially lifesaving.
It should not be used in conditions for which specific pediatric dosages have not been established.
Severe Behavioral Problems Outpatients – Select route of administration according to severity of patient’s condition and increase dosage gradually as required.
Oral: ¼ mg/lb body weight q4 to 6h, p.r.n.
(e.g., for 40 lb child – 10 mg q4 to 6h).
Hospitalized Patients – As with outpatients, start with low doses and increase dosage gradually.
In severe behavior disorders higher dosages (50 to 100 mg daily and in older children, 200 mg daily or more) may be necessary.
There is little evidence that behavior improvement in severely disturbed mentally retarded patients is further enhanced by doses beyond 500 mg per day.
Nausea and Vomiting – Dosage and frequency of administration should be adjusted according to the severity of the symptoms and response of the patient.
The duration of activity following intramuscular administration may last up to 12 hours.
Subsequent doses may be given by the same route if necessary.
Oral: ¼ mg/lb body weight (e.g., 40 lb child – 10 mg q4 to 6h).
Presurgical Apprehension –¼ mg/lb body weight orally 2 to 3 hours before operation.