trifluoperazine (Rx)

Frequency Not Defined

EPS (60%; muscle stiffness, dystonia, parkinsonism, tardive dyskinesia, akathisia)

NMS (infrequent but serious)

Sedation

Anticholinergic effects

Weight gain

Oligomenorrhea/amenorrhea

Erectile dysfunction

Insomnia

Restlessness

Anxiety

Euphoria

Agitation

Depression

Weakness

Headache

Cerebral edema

Poikilothermia

Orthostatic hypotension

Tachycardia

Dizziness

Lens opacities (prolonged use)Anorexia

Dyspepsia

Constipation

Ileus

Blood dyscrasia

ECG changes

Photosensitivity

Pruritis

Diarrhea

Galactorrhea

Ejaculatory d/o

Seizure (rare)

Priapism (rare)

Cholestatic jaundice (rare)

Contraindications

Hypersensitivity to phenothiazines or excipients

Comatose or greatly depressed states due to central nervous system depressants, existing blood dyscrasias, bone marrow depression, and preexisting liver damage

Cautions

Thrombocytopenia and anemia reported in patients receiving therapy; agranulocytosis and pancytopenia also reported; warn patients to report sudden appearance of sore throat or other signs of infection; if white blood cell and differential counts indicate cellular depression, stop treatment and start antibiotic and other suitable therapy

Jaundice of cholestatic type of hepatitis or liver damage reported; if fever with grippe-like symptoms occurs, appropriate liver studies should be conducted; if tests indicate an abnormality, stop treatment

One result of therapy may be an increase in mental and physical activity; for example, a few patients with angina pectoris have complained of increased pain while taking the drug; patients with angina should be observed carefully and, if an unfavorable response noted, the drug should be withdrawn

Because hypotension has occurred, large doses and parenteral administration should be avoided in patients with impaired cardiovascular systems; to minimize occurrence of hypotension after injection, keep patient lying down and observe for at least 1/2 hour; if hypotension occurs from parenteral or oral dosing, place patient in head-low position with legs raised

If a vasoconstrictor is required, norepinephrine bitartrate and phenylephrine hydrochloride are suitable; other pressor agents, including epinephrine, should not be used as they may cause a paradoxical further lowering of blood pressure

Since certain phenothiazines reported to produce retinopathy, the drug should be discontinued if ophthalmoscopic examination or visual field studies should demonstrate retinal changes; an antiemetic action of this drug may mask signs and symptoms of toxicity or overdosage of other drugs and may obscure diagnosis and treatment of other 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

Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration; tissue culture experiments indicate that approximately 1/3 of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescribing of these drugs is contemplated in a patient with a previously detected breast cancer

Although disturbances such as galactorrhea, amenorrhea, gynecomastia and impotence reported, the clinical significance of elevated serum prolactin levels is unknown for most patients; an increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs

Neither clinical nor epidemiologic studies conducted to date, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time

Chromosomal aberrations in spermatocytes and abnormal sperm demonstrated in rodents treated with certain antipsychotics

Because phenothiazines may interfere with thermoregulatory mechanisms, use caution in persons who will be exposed to extreme heat

As with all drugs which exert an anticholinergic effect, and/or cause mydriasis, trifluoperazine should be used with caution in patients with glaucoma; phenothiazines may diminish effect of oral anticoagulants

Phenothiazines can produce alpha-adrenergic blockade; concomitant administration of propranolol with phenothiazines results in increased plasma levels of both drugs

Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concurrently; thiazide diuretics may accentuate orthostatic hypotension that may occur with phenothiazines

Phenothiazines may lower convulsive threshold; dosage adjustments of anticonvulsants may be necessary; potentiation of anticonvulsant effects does not occur; however, it has been reported that phenothiazines may interfere with metabolism of phenytoin and thus precipitate phenytoin toxicity; drugs which lower seizure threshold, including phenothiazine derivatives, should not be used with metrizamide

As with other phenothiazine derivatives, trifluoperazine hydrochloride 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 control of nausea and vomiting occurring either prior to myelography or post-procedure with metrizamide

To lessen likelihood of adverse reactions related to cumulative drug effects, patients with a history of long-term therapy with trifluoperazine hydrochloride and/or other antipsychotics should be evaluated periodically to decide whether maintenance dosage could be lowered, or drug therapy discontinued

The presence of phenothiazines may produce false-positive phenylketonuria (PKU) test results

Leukopenia, neutropenia, and agranulocytosis

• In clinical trial and post-marketing experience, events of leukopenia/neutropenia and agranulocytosis reported temporally related to antipsychotic agents
• Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia; patients with a preexisting low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during first few months of therapy and should discontinue therapy at first sign of a decline in WBC in the absence of other causative factors
• Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms occur
• Patients with severe neutropenia (absolute neutrophil count < 1000/mm ) should discontinue therapy and have their WBC followed until recovery

Tardive dyskinesia

• Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk; the decision to inform patients and/or their guardians must obviously take into account clinical circumstances and competency of patient to understand information provided
• 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 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 risk of developing the syndrome and likelihood that it will become irreversible are believed to increase as 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) signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process; the effect that symptomatic suppression has on long-term course of the syndrome is unknown
• Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize occurrence of tardive dyskinesia; chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs, and, 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 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, consider drug discontinuation; however, some patients may require treatment despite presence of syndrome

Neuroleptic malignant syndrome (NMS)

• A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) 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 clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection, etc) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS)
• Other important considerations in differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology; the management of NMS should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and 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; recurrences of NMS 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 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 who have demonstrated a hypersensitivity reaction (eg, blood dyscrasias, jaundice) with a phenothiazine should not be reexposed to any phenothiazine, including trifluoperazine hydrochloride unless in judgment of physician the potential benefits of treatment outweigh possible hazard
• This drug may impair mental and/or physical abilities, especially during first few days of therapy; therefore, caution patients about activities requiring alertness (eg, operating vehicles or machinery); if agents such as sedatives, narcotics, anesthetics, tranquilizers, or alcohol are used either simultaneously or successively with the drug, the possibility of an undesirable additive depressant effect should be considered

Pregnancy

Safety for use during pregnancy not established; not recommended that the drug be given to pregnant patients except when, in judgment of physician, it is essential; 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

Neonates exposed to antipsychotic drugs, during 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; this drug should be used during pregnancy only if potential benefit justifies potential risk to fetus

Animal data

• Reproductive studies in rats given over 600 times human dose showed increased incidence of malformations above controls and reduced litter size and weight linked to maternal toxicity; these effects were not observed at half this dosage; no adverse effect on fetal development was observed in rabbits given 700 times human dose nor in monkeys given 25 times human dose

Lactation

There is evidence that phenothiazines are excreted in breast milk of nursing mothers; because of potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account importance of drug to mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Piperazine phenothiazine agent; antagonist for the postsynaptic mesolimbic dopaminergic D2 receptors in the brain; decreases the release of hypothalamic and hypophyseal hormones

Pharmacokinetics

Half-Life elimination: 24 hr

Metabolism: Liver