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Pronunciation: per-FEN-a-zeen
Class: Antipsychotic, Phenothiazine derivative

Trade Names

- Tablets, oral 2 mg
- Tablets, oral 4 mg
- Tablets, oral 8 mg
- Tablets, oral 16 mg

Apo-Perphenazine (Canada)


Effects apparently caused by postsynaptic dopamine receptor blockade in CNS.

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T max is approximately 1 to 3 h (parent), 2 to 4 h (metabolite). Steady state is 72 h. C max is 984 pg/mL (parent compound) and 509 pg/mL (7-hydroxyperphenazine). C min is 442 pg/mL (parent compound) and 350 pg/mL (7-hydroxyperphenazine).


Readily crosses placenta, distributes into breast milk.


Extensively metabolized in liver to a number of metabolites mediated by CYP2D6 and is subject to genetic polymorphism.


Excreted in urine (70%), mainly as metabolites, and feces (5%). Terminal half-life is 9.9 to 18.8 h (metabolite). Plasma half-life is 9 to 12 h (perphenazine).

Special Populations


Plasma concentrations per daily ingested dose increase with increasing age.

Indications and Usage

Treatment of schizophrenia; control of severe nausea/vomiting in adults.


Comatose or greatly obtunded patients; allergy to any component of the product or to any phenothiazine; patients receiving large amounts of other CNS depressants; bone marrow depression or blood dyscrasias; liver damage; subcortical brain damage with or without hypothalamic damage.

Dosage and Administration

Adults and Children 12 y and older Nonhospitalized patients

PO 4 to 8 mg 3 times daily; reduce as soon as possible to minimum effective dosage.

Hospitalized patients

PO 8 to 16 mg 2 to 4 times daily; avoid dosages greater than 64 mg/day.


PO 8 to 16 mg/day in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable.


PO Initiation of lower dosages is recommended. Optimal clinical effect or benefit may require lower doses for a longer duration.

General Advice

  • Administer without regard to meals. Administer with food if GI upset occurs.
  • Because extrapyramidal symptoms increase in frequency and severity with increased dosage, it is important to use the lowest effective dosage. Reserve prolonged administration of dosages above 24 mg/day for hospitalized patients or patients under continued observation; an antiparkinson agent (eg, trihexyphenidyl, benztropine) is valuable in controlling drug-induced extrapyramidal symptoms.


Store between 68° and 77°F.

Drug Interactions

Anorexiants (eg, dextroamphetamine)

The effects of both agents may be reduced or reversed. If an interaction is suspected, consider discontinuing one of the drugs.

Anticholinergics (eg, atropine)

May reduce therapeutic effects of perphenazine and worsen anticholinergic effects. Coadministration may worsen schizophrenic symptoms and lead to tardive dyskinesia. Use with caution and closely monitor the patient.

Anticonvulsants (eg, carbamazepine)

Perphenazine can lower the convulsive threshold. Increased dosages of anticonvulsant agents may be needed in patients receiving perphenazine.


Cabergoline pharmacologic effects may be reduced. Coadministration is not recommended.

CNS depressants (eg, alcohol, antihistamines, barbiturates, narcotic analgesics/opiates)

Depressant effects may be additive and may precipitate dystonic reactions. Coadminister with caution. Avoid concurrent use of alcohol. Perphenazine is contraindicated in patients receiving large doses of CNS depressants.


If hypotension occurs in patients experiencing NMS, do not administer epinephrine because its action is blocked and partially reversed by perphenazine. In addition, coadministration can cause hypotension and tachycardia. If marked hypotension occurs, an alpha-adrenergic sympathomimetic amine may be needed to reverse the effects of this interaction.


Hypotensive action may be inhibited. The effects of this interaction may depend on the perphenazine dose. If coadministration cannot be avoided, larger dosages of guanethidine may be needed. Monitor BP and adjust the guanethidine dose as needed.


The pharmacologic effects of levodopa may be decreased. If coadministration cannot be avoided, monitor the clinical response to levodopa and adjust the dose as needed.


The pharmacologic effects of perphenazine may be decreased. The risk of severe neurotoxicity may be increased. Monitor the clinical status of the patient and adjust the dose of (or discontinue) either drug.


The risk of extrapyramidal reactions may be increased. Coadministration is contraindicated.


Perphenazine may decrease the pharmacologic effects of pergolide. Coadministration is not recommended.

SSRIs (eg, fluoxetine, paroxetine, sertraline)

Perphenazine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Closely monitor the clinical response and adjust the perphenazine dose as needed.


The pharmacologic effects of tamoxifen may be reduced. The risk of breast cancer recurrence may be increased. Avoid coadministration.


The risk of seizures may be increased. Avoid coadministration.


Trazodone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. If an interaction is suspected, decrease the dosage of trazodone.

Tricyclic antidepressants (eg, imipramine, nortriptyline)

Perphenazine and tricyclic antidepressant plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Closely monitor the clinical response and adjust therapy as needed.

Laboratory Test Interactions

False-positive pregnancy test results may occur. Increases in protein-bound iodine have been reported.

Adverse Reactions


Bradycardia; cardiac arrest; change in pulse rate; circulatory collapse; ECG changes; hypertension; hypotension; postural hypotension; shock-like condition; tachycardia.


Abnormality of CSF proteins; bizarre dreams; catatonic-like state; cerebral edema; dizziness; drowsiness; exacerbation of psychotic symptoms; extrapyramidal symptoms, including aching and numbness of the limbs, akathisia, ataxia, dyskinesia, dysphagia, dystonia, hyperreflexia, motor restlessness, opisthotonus, parkinsonism, retrocollis, slurred speech, tonic spasm of the masticatory muscles, tight feeling in the throat, torticollis, and trismus; faintness; hyperactivity; hyperreflexia; insomnia; lethargy; NMS; nocturnal confusion; paradoxical excitement; paranoid reactions; restlessness; sedation; seizures; tardive dyskinesia.


Eczema; erythema; exfoliative dermatitis; perspiration; photosensitivity; pigmentation of the skin; pruritus; urticaria.


Blurred vision; epithelial keratopathies; fine particulate matter in the lens and cornea sometimes progressing to star-shaped lenticular opacities; glaucoma; mydriasis; myosis; nasal congestion; parotid swelling; photophobia; pigmentary retinopathy.


Adynamic ileus; anorexia; constipation; diarrhea; dry mouth; fecal impaction; nausea; obstipation; polyphagia; salivation; vomiting.


Amenorrhea; bladder paralysis; changes in libido; galactorrhea; glycosuria; gynecomastia; inhibition of ejaculation; lactation; menstrual cycle disturbances; polyuria; SIADH; urinary frequency, incontinence, or retention.


Agranulocytosis; eosinophilia; hemolytic anemia; leukopenia; pancytopenia; thrombocytopenic purpura.


Biliary stasis; jaundice.


Hyperglycemia; hypoglycemia; increased appetite and weight; peripheral edema.


Muscle weakness.




Anaphylactoid reactions; angioneurotic edema; fever; laryngeal edema; pallor; SLE-like syndrome.



Increased mortality

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death. Over the course of a 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5% compared with 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Perphenazine is not approved for the treatment of patients with dementia-related psychosis.


Periodically reassess the need for continued treatment. Assess renal function, liver enzymes, and CBC with differential before starting therapy and then periodically thereafter during prolonged treatment. Patients with preexisting low WBC or a history of drug-induced leukopenia/neutropenia should have their CBC monitored frequently during the first few months of therapy. Carefully monitor patients with neutropenia for signs and symptoms of infection. Monitor patients for signs and symptoms of tardive dyskinesia. Carefully monitor patients who require reintroduction of treatment after NMS because recurrences have been reported.


Pregnancy category undetermined. Neonates exposed to antipsychotics during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.




Not recommended in children younger than 12 y.


More susceptible to effects; consider a lower dose.

Renal Function

Use with caution.

Special Risk Patients

Use caution in patients with alcohol withdrawal, chronic respiratory disorders (eg, asthma, emphysema), depression, respiratory impairment due to acute pulmonary infection, and seizure disorders.

Antiemetic effects

May obscure signs of toxicity due to overdosage of other drugs, or make the diagnosis of some disorders (eg, brain tumor, intestinal obstruction) more difficult.

Body temperature elevation

A significant, not otherwise explained body temperature elevation may suggest intolerance to perphenazine; in this case, discontinue the drug. Patients with suspected or established subcortical brain damage with or without hypothalamic damage may experience a hyperthermic reaction that may be delayed (14 to 16 h after administration); perphenazine use is contraindicated in these patients.

CNS effects

May impair mental or physical abilities, especially during first few days of therapy. May lower convulsive threshold; dosage adjustments of anticonvulsants may be necessary.

Hematologic effects

Leukopenia/neutropenia and agranulocytosis have been reported.


Patients treated with antipsychotic agents often have elevation in prolactin levels; however, there is no evidence of increased breast tumor risk.


Severe, acute hypotension has occurred and is more likely in patients with mitral insufficiency or pheochromocytoma.

Long-term use

The possibility of liver damage, corneal and lenticular deposits, and irreversible dyskinesias should be considered when patients are on long-term therapy.

Neuroleptic malignant syndrome

Potentially fatal NMS has occurred with agents of this class. Signs and symptoms are hyperpyrexia, muscle rigidity, altered mental status, irregular pulse, irregular BP, tachycardia, and diaphoresis.


Has been reported; patients should avoid unnecessary exposure to the sun.


Because of the possibility of suicide in depressed patients, avoid providing access to large quantities of this drug.


Observe patients for possible hypotensive phenomena.

Tardive dyskinesia

Syndrome of potentially irreversible involuntary body and facial movements may develop. Prevalence is highest in elderly patients, especially women. Use smallest effective doses for shortest possible time period.



Atrioventricular block, cardiac arrest, coma, hypotension, hypothermia, QRS or QTc prolongation, seizures, stupor, tachycardia, torsades de pointes, ventricular dysrhythmia.

Patient Information

  • Advise patients, families, or caregivers that dose will be adjusted periodically until max benefit has been obtained.
  • Advise patients, families, or caregivers not to change the dose or stop taking unless advised by their health care provider.
  • Instruct patients, families, or caregivers to immediately report fainting or loss of consciousness, palpitations, dizziness, high fever, muscle rigidity or unusual muscle movements, altered mental status, irregular pulse, sore throat or other signs of infection, bleeding or unusual bruising, or yellowing of the skin or eyes.
  • Advise patients on long-term therapy of the risk of tardive dyskinesia.
  • Advise patients, families, or caregivers to notify their health care provider of the following: excessive drowsiness, increased agitation or anxiety, involuntary body or facial movements.
  • Advise patients to avoid strenuous activity during periods of high temperature or humidity.
  • Instruct patients to avoid alcoholic beverages and other depressants while taking this medication.
  • Instruct patients to get up slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to their health care provider. Caution patients that hot tubs and hot showers or baths may worsen dizziness.
  • Advise patients to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Advise patients that perphenazine may cause drowsiness or impaired judgment or thinking skills and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Caution patients that medication may cause sensitivity to sunlight and to avoid unnecessary exposure to UV light (sunlight, tanning booths) and to use sunscreen and wear protective clothing when exposed to UV light until tolerance is determined.

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