Indications

Trifluoperazine is indicated in:

1. Anxiety states: it controls excessive anxiety, tension and agitation seen in neuroses or associated with somatic conditions.

2. The treatment or prevention of nausea and vomiting of various causes.

3. The management of psychotic disorders, such as acute or chronic catatonic, hebephrenic and paranoid schizophrenia; psychosis due to organic brain damage, toxic psychosis, and the manic phase of manic-depressive illness.

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Contraindications

Comatose or greatly depressed states due to central nervous system depressants; blood dyscrasias, bone marrow depression; liver damage.

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Warnings

Patients who have demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) with a phenothiazine should not be re-exposed to any phenothiazine, including trifluoperazine, unless, in the judgement of the physician, the potential benefits of treatment outweigh the possible hazard.

Trifluoperazine may impair mental and/or physical abilities, especially during the first few days of therapy. Therefore, patients should be cautioned about activities requiring alertness (e.g., operating vehicles or machinery).

If agents such as sedatives, narcotics, anesthetics, tranquilizers or alcohol are used either simultaneously or successively with trifluoperazine, the possibility of an undesirable additive depressant effect should be considered.

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Precautions

Clinical experience has demonstrated that trifluoperazine has a wide margin of safety. However, rare cases of blood dyscrasias (agranulocytosis, anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia) and jaundice of the cholestatic type have been reported in patients receiving high doses of trifluoperazine.

Geriatrics and Debilitated Patients:
Care should be exercised in treating elderly or debilitated patients as some appear prone to neurological adverse reactions.

Phenothiazines can produce alpha-adrenergic blockade. Because hypotension has occurred, large doses should be avoided in patients with impaired cardiovascular systems. If hypotension occurs, place patient in head-low position with legs raised. If a vasoconstrictor is required, norepinephrine or phenylephrine is suitable. Other pressor agents, including epinephrine, should not be used as they may cause a paradoxical further lowering of blood pressure (see Overdose).

Trifluoperazine therapy may produce an increase in mental and physical activity. In certain instances, this effect may not be desirable. For example, some patients with angina pectoris have complained of increased pain while taking trifluoperazine; therefore, if trifluoperazine is used in angina patients, such patients should be observed carefully and if an unfavorable response is noted, the drug should be withdrawn.

As with all drugs which exert an anticholinergic effect or cause mydriasis, trifluoperazine should be used with caution in patients with glaucoma.

Certain phenothiazines have been reported to produce retinopathy, especially with long-term treatment at high dosage. Should ophthalmoscopic examination or visual field studies demonstrate retinal changes in patients on trifluoperazine, the drug should be discontinued.

Skin pigmentation and ocular changes have been reported in a few hospitalized mental patients taking substantial doses of some phenothiazine derivatives for prolonged periods. Present evidence suggests that these changes may be reversible.

The antiemetic action of trifluoperazine may mask signs and symptoms of toxicity or overdosage of other drugs or may obscure the diagnosis of conditions such as intestinal obstruction, brain tumor and Reye's syndrome.

With prolonged administration at high dosages, the possibility of cumulative effects, with sudden onset of severe central nervous system or vasomotor symptoms, should be kept in mind. To lessen the likelihood of adverse reactions related to drug accumulation, patients on long-term therapy, particularly on high doses, should be evaluated periodically to decide whether the maintenance dosage could be lowered or drug therapy discontinued.

Although phenothiazines cause neither psychic nor physical dependence, sudden discontinuance in long-term psychiatric patients may cause temporary symptoms, e.g. nausea and vomiting, dizziness, tremulousness.

Phenothiazines have been found to be mutagenic with in vivo administration to rodents and in vitro administration to human cells and bacteria. No clinical relevance has been established.

Drug Interactions:
Phenothiazines may diminish the effect of oral anticoagulants.

Concomitant administration of propranolol with phenothiazines results in increased plasma levels of both drugs.

Phenothiazines may lower the convulsive threshold; dosage adjustment of anticonvulsants may be necessary. Potentiation of anticonvulsant effects does not occur. However, it has been reported that phenothiazines may interfere with the metabolism of phenytoin and thus precipitate phenytoin toxicity.

Drugs which lower the seizure threshold, including phenothiazine derivatives, should not be used with metrizamide. As with other phenothiazine derivatives, trifluoperazine should be discontinued at least 48 hours before myelography, should not be resumed for at least 24 hours post procedure, and should not be used for the control of nausea and vomiting occurring either prior to myelography or post procedure.

Pregnancy:
Animal reproduction studies and follow-up studies in 819 women in Canada and Great Britain, who had taken trifluoperazine during pregnancy, showed no causal relationship between the drug and congenital malformations.

It is generally recognized that caution should always be observed when prescribing for the pregnant patient, especially during the first trimester. Trifluoperazine should not be used during pregnancy unless the physician considers that the benefit outweighs the possible risk.

Lactation:
There is evidence that phenothiazines are excreted in the milk of nursing mothers.

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Adverse Effects

At therapeutic dosage levels, adverse reactions are infrequent, usually mild and transient, and unlikely to affect the course of treatment. Drowsiness, dizziness, skin reactions, dry mouth, stimulation, insomnia, fatigue, weakness, anorexia, amenorrhea, lactation and blurred vision may be seen occasionally. Extrapyramidal symptoms may occur but are rare at dosages of 6 mg or less. Tardive dyskinesia has been reported.

Extrapyramidal Symptoms:
These symptoms are seen in a significant number of hospitalized mental patients receiving higher dosages of trifluoperazine (10 mg to 40 mg or more daily). They may be characterized by motor restlessness, may be of the dystonic type, or may resemble parkinsonism. Depending on the severity of symptoms, dosage should be reduced or discontinued. If therapy is reinstituted, it should be a lower dosage. Should these symptoms occur in children or pregnant patients, the drug should be stopped and not reinstituted. The administration of an antiparkinsonian agent usually produces rapid reversal of symptoms. Injectable diphenhydramine may be useful. Suitable supportive measures such as maintaining a clear airway and adequate hydration should be employed.

Motor Restlessness:
Symptoms may include agitation or jitteriness and sometimes insomnia. These symptoms often disappear spontaneously. At times these symptoms may be similar to the original neurotic or psychotic symptoms. Dosage should not be increased until these side effects have subsided. If this condition becomes too troublesome, the symptoms can be controlled by dosage reduction or change of drug. Treatment with antiparkinsonian agents or benzodiazepines may be helpful.

Dystonias:
Symptoms may include spasm of the neck muscles, sometimes progressing to torticollis; extensor rigidity of back muscles; sometimes progressing to opisthotonos; carpopedal spasm, trismus, swallowing difficulty, oculogyric crises and protrusion of the tongue. The onset of the dystonias may be sudden. They may last several minutes, disappear and then recur. There is typically no loss of consciousness and definite prodromata are usually present. They usually subside within a few hours, and almost always within 24 to 48 hours after the drug has been discontinued.

Neuroleptic Malignant Syndrome:
As with other neuroleptic drugs, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure). Additional signs may include elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. NMS is potentially fatal and requires symptomatic treatment and immediate discontinuation of neuroleptic treatment.

Pseudo-parkinsonism:
Symptoms may include mask-like face, drooling, tremor, pillrolling motion, cogwhell rigidity and shuffling gait. Reassurance and sedation are important. In most cases these symptoms are readily reversible when an antiparkinsonian agent is administered concomitantly. (Note: antiparkinsonian agents should be used only when required. Levodopa has not been found effective in pseudo-parkinsonism). Occasionally it is necessary to lower the dosage or to discontinue the drug temporarily.

Tardive Dyskinesia:
In rare instances, this syndrome may occur on long-term therapy with phenothiazines, including trifluoperazine, or may appear after drug treatment has been discontinued. The risk appears to be greater in elderly patients, especially females, on high-dose therapy. The syndrome is characterized by rhythmical involuntary movements of the tongue and facial muscles (e.g., protrusion of the tongue, puffing of cheeks, puckering of mouth, chewing movements) and sometimes of the extremities. The symptoms may persist for many months or even years, and while they gradually disappear in some patients, they appear to be irreversible in others.

There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. If there is a reinstitution of treatment, or an increase in the dosage of the drug, or a switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome and if the medication is stopped at that time, the syndrome may not develop.

ECG Changes:
ECG changes, particularly nonspecific, usually reversible Q and T wave distortions, have been observed in some patients receiving phenothiazine tranquilizers. This relationship to myocardial damage has not been confirmed.