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Perphenazine

Class: Phenothiazines
VA Class: CN701
Chemical Name: 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-1-yl]ethanol
Molecular Formula: C21H26CIN3OS
CAS Number: 58-39-9
Brands: Trilafon

Perphenazine is also contained as an ingredient in the following combinations:
Perphenazine and Amitriptyline Hydrochloride

Medically reviewed by Drugs.com. Last updated on March 11, 2021.

Warning

    Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

  • Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.

  • Antipsychotic agents, including perphenazine, are not approved for the treatment of dementia-related psychosis.

Introduction

Propylpiperazine-derivative phenothiazine; conventional (prototypical, first-generation) antipsychotic agent.

Uses for Perphenazine

Psychotic Disorders

Symptomatic management of psychotic disorders (i.e., schizophrenia).

Management of acute depressive episodes (in fixed combination with amitriptyline hydrochloride) in patients with schizophrenia.

Anxiety and Depressive Disorders

Management of moderate to severe anxiety and/or agitation (in fixed combination with amitriptyline hydrochloride) in patients with depressed mood.

Management of severe anxiety and/or agitation (in fixed combination with amitriptyline hydrochloride) in patients with depression.

Management of depression and anxiety (in fixed combination with amitriptyline hydrochloride) in association with chronic physical disease.

Nausea and Vomiting

Management of severe nausea and vomiting in adults.

Mental Retardation

Efficacy not established for the management of behavioral complications in patients with mental retardation.

Perphenazine Dosage and Administration

General

  • Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.

  • For symptomatic relief of psychotic disorders, initial therapeutic response to antipsychotic therapy usually occurs within 2–4 weeks and optimum therapeutic response occurs within 6 months or longer.

  • Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued. (See Tardive Dyskinesia under Cautions.)

  • Fixed-ratio combination preparations generally should not be used as initial therapy. First administer each drug separately. If the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, a fixed-combination preparation may be used. If dosage adjustment is necessary, administer the drugs separately. Fixed-ratio combination preparations do not permit individual titration of dosages.

  • Therapeutic response with combination therapy usually evident within days or weeks; may take longer in some patients.

Administration

Oral Administration

Administered orally. Has been given parenterally† as perphenazine, perphenazine decanoate, and perphenazine enanthate, but a parenteral dosage form of the drug is no longer commercially available in the US.

Dosage

Available as perphenazine (alone and in fixed combination with amitriptyline hydrochloride); dosage expressed in terms of base.

Pediatric Patients

Psychotic Disorders
Monotherapy in Outpatients
Oral

Children ≥12 years of age: Initially, 4–8 mg 3 times daily. Carefully adjust subsequent dosage according to the patient’s tolerance and therapeutic response. During maintenance therapy, keep dosage at the lowest effective level.

Prolonged administration of dosages >24 mg daily should be limited to hospitalized patients or patients under continuous observation.

Monotherapy in Hospitalized Patients
Oral

Children ≥12 years of age: Initially, 8–16 mg 2–4 times daily. Carefully adjust subsequent dosage according to the patient’s tolerance and therapeutic response. During maintenance therapy, keep dosage at the lowest effective level.

Prolonged administration of dosages >24 mg daily should be limited to hospitalized patients or patients under continuous observation.

Perphenazine/Amitriptyline Combination Therapy
Oral

Adolescents: Initially, 4 mg (in fixed combination with 10 mg amitriptyline hydrochloride) 3 or 4 times daily; adjust as required. (See Pediatric Use under Cautions.)

Maximum daily dosages of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.

Adults

Psychotic Disorders
Monotherapy in Outpatients
Oral

Initially, 4–8 mg 3 times daily. Carefully adjust subsequent dosage according to the patient’s tolerance and therapeutic response. During maintenance therapy, keep dosage at the lowest effective level.

Prolonged administration of dosages >24 mg daily should be limited to hospitalized patients or patients under continuous observation.

Monotherapy in Hospitalized Patients
Oral

Initially, 8–16 mg 2–4 times daily. Carefully adjust subsequent dosage according to the patient’s tolerance and therapeutic response. During maintenance therapy, keep dosage at the lowest effective level.

Prolonged administration of dosages >24 mg daily should be limited to hospitalized patients or patients under continuous observation.

Avoid dosages >64 mg daily.

Perphenazine/Amitriptyline Combination Therapy
Oral

Initially, 2 tablets of 4 mg (in fixed combination with 25 mg amitriptyline hydrochloride) 3 times daily. If needed, a fourth dose may be given at bedtime.

Carefully adjust subsequent dosage according to the patient’s tolerance and therapeutic response. During maintenance therapy, keep dosage at the lowest effective level. Perphenazine maintenance dosages usually range from 4–16 mg and amitriptyline hydrochloride maintenance dosages usually range from 50–100 mg daily.

Maximum daily dosages of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.

Anxiety and Depressive Disorders
Perphenazine/Amitriptyline Combination Therapy
Oral

Initially, 2 mg (in fixed combination with 25 mg amitriptyline hydrochloride) or 4 mg (in fixed combination with 25 mg amitriptyline hydrochloride) 3 or 4 times daily. Alternatively, 4 mg (in fixed combination with 50 mg amitriptyline hydrochloride) twice daily.

Carefully adjust subsequent dosage according to the patient’s tolerance and therapeutic response. During maintenance therapy, keep dosage at the lowest effective level. Perphenazine maintenance dosages usually range from 4–16 mg and amitriptyline hydrochloride maintenance dosages usually range from 50–100 mg daily.

Maximum daily dosages of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.

Nausea and Vomiting
Oral

Initially, 8–16 mg in divided doses. Some patients may require dosages ≤24 mg daily; early dosage reduction desirable.

Prolonged administration of dosages >24 mg daily should be used only in hospitalized patients or patients under continuous observation.

Prescribing Limits

Pediatric Patients

Psychotic Disorders
Perphenazine/Amitriptyline Combination Therapy
Oral

Adolescents: Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.

Adults

Psychotic Disorders
Monotherapy
Oral

Prolonged administration of dosages >24 mg daily limited to hospitalized patients or patients under continuous observation.

Maximum 64 mg daily in hospitalized patients.

Perphenazine/Amitriptyline Combination Therapy
Oral

Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.

Anxiety and Depressive Disorders
Perphenazine/Amitriptyline Combination Therapy
Oral

Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.

Special Populations

Geriatric Patients

No specific dosage recommendations for geriatric patients, but generally select dosage at the lower end of recommended range; increase dosage more gradually and monitor closely. May administer before bedtime. (See Geriatric Use under Cautions.)

Lower dosages for longer duration may be necessary for optimal therapeutic response.

Psychotic Disorders

When used in fixed combination with amitriptyline hydrochloride, an oral dosage of 4 mg of perphenazine and 10 mg of amitriptyline hydrochloride 3 or 4 times daily is recommended initially. Subsequent dosage adjustments may be made as necessary.

Cautions for Perphenazine

Contraindications

  • Comatose or greatly obtunded states or in the presence of large amounts of CNS depressants (e.g., alcohol, antihistamines, barbiturates, opiates). (See Specific Drugs and Laboratory Tests under Interactions.)

  • Bone marrow depression, blood dyscrasias, or liver damage.

  • Suspected or established subcortical brain damage, with or without hypothalamic damage.

  • Known hypersensitivity to perphenazine, any component in the formulations, or other phenothiazine derivatives.

Warnings/Precautions

Warnings

Shares the toxic potentials of other phenothiazines; observe the usual precautions of phenothiazine therapy.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.

Antipsychotic agents, including perphenazine, are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with use of antipsychotic agents, including perphenazine.

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.

APA recommends assessing patients receiving conventional antipsychotic agents for abnormal involuntary movements every 6 months; for patients at increased risk for tardive dyskinesia, assess every 3 months. Consider discontinuance of perphenazine if signs and symptoms of tardive dyskinesia appear. However, some patients may require treatment despite the presence of the syndrome.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including perphenazine.

Immediately discontinue therapy and initiate supportive and symptomatic treatment if NMS occurs. Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.

Cardiovascular Effects

Possible hypotension (including orthostatic hypotension). Patients with pheochromocytoma or mitral insufficiency may be especially prone to hypotensive effects. Rebound hypertension may occur in pheochromocytoma patients. If severe hypotension occurs, may use norepinephrine or phenylephrine to treat; epinephrine or dopamine should not be used. (See Specific Drugs and Laboratory Tests under Interactions.)

Seizures

May lower seizure threshold. Use with caution in patients experiencing alcohol withdrawal, patients with seizure disorders, and in those receiving anticonvulsant agents. (See Specific Drugs and Laboratory Tests under Interactions.)

CNS Depression

May impair mental and/or physical abilities, especially during the first few days of therapy; use caution with activities requiring alertness (e.g., operating vehicles or machinery).

Because of CNS depressant effects, use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).

Sensitivity Reactions

Possible sensitivity reactions (e.g., anaphylactoid reactions, cholestatic jaundice, blood dyscrasias, skin reactions). Use generally not recommended in patients who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to a phenothiazine, unless potential benefits outweigh the possible risks.

Photosensitivity may occur; avoid excessive exposure to sun during therapy.

Contact dermatitis reported.

General Precautions

Hematologic Effects

Leukopenia and neutropenia temporally related to antipsychotic agents reported during clinical trial and/or postmarketing experience. Agranulocytosis also reported with antipsychotic agents, including perphenazine.

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia. Monitor CBC frequently during the first few months of therapy in patients with such risk factors. Discontinue perphenazine at the first sign of a decline in WBC count in the absence of other causative factors.

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur. Discontinue perphenazine if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.

Hepatic Effects

Cholestatic jaundice or liver damage reported.

Periodically monitor liver function tests during therapy; if abnormal results occur, discontinue therapy.

Prolactin Secretion

Elevated prolactin concentrations reported; elevation persists during chronic administration.

Clinical importance unknown; consider that approximately one-third of human breast cancers are prolactin dependent when prescribed in patients with previously detected breast cancer.

Galactorrhea, amenorrhea, gynecomastia, and impotence reported.

Ocular Effects

Consider possibility of pigmentary retinopathy and lenticular and corneal deposits in patients receiving prolonged therapy.

Regulation of Body Temperature

Phenothiazines depress the hypothalamic mechanism for body temperature regulation; possible hyperthermia or hypothermia when exposed to temperature extremes.

Use with caution in patients exposed to extreme heat or cold.

Suicide

Attendant risk with depression; closely supervise high-risk patients. Prescribe in the smallest quantity consistent with good patient management to reduce risk.

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, mydriasis, constipation, obstipation, nausea, adynamic ileus, atonic colon, urinary retention, decreased perspiration, and impotence).

Use in Fixed Combination

When used in fixed combination with amitriptyline hydrochloride, consider the cautions, precautions, and contraindications associated with amitriptyline hydrochloride.

Other Precautions

Periodically monitor renal function tests during long-term use; if BUN becomes abnormal, discontinue therapy.

Antiemetic effects may mask signs of overdosage of other drugs (e.g., antineoplastic agents) or obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).

Specific Populations

Pregnancy

Category C.

Safety of use during pregnancy not established.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

Use during pregnancy only when potential benefits justify possible risks to the mother and fetus.

Lactation

Distributed into milk. Caution if used in nursing women; carefully assess potential benefits and risks.

Pediatric Use

Use of perphenazine not recommended in children <12 years of age.

Safety and efficacy of the perphenazine-amitriptyline hydrochloride fixed combination not established in pediatric patients.

Geriatric Use

Use with caution. (See Geriatric Patients under Dosage and Administration.)

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents. Possible increased risk for falls and consequent hip fractures.

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Hepatic Impairment

Contraindicated in patients with liver damage.

Renal Impairment

Use with caution. Monitor renal function periodically; if BUN becomes abnormal, discontinue therapy.

Common Adverse Effects

Extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia, tardive dyskinesia), drowsiness, muscular weakness, dry mouth, blurred vision, weight gain, skin reactions, amenorrhea, galactorrhea.

Interactions for Perphenazine

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma perphenazine concentrations) with concomitant use of CYP2D6 inhibitors; use with caution.

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Alcohol

Potential additive CNS effects; concomitant use with alcohol potentiates hypotension observed with perphenazine

Advise patients to avoid alcohol

Anticholinergic agents

Additive anticholinergic effects

Use with caution

Anticonvulsants

Perphenazine may lower seizure threshold

Dosage adjustments of anticonvulsants may be necessary

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Possible increased plasma concentrations of perphenazine

Observe patients closely for adverse effects

Dosage reduction of SSRI or perphenazine may be necessary

Antidepressants, tricyclic (TCAs)

Possible increased plasma concentrations of perphenazine

Observe patients closely for adverse effects

Dosage reduction of TCA or perphenazine may be necessary

CNS depressants (e.g., analgesics, antihistamines, barbiturates, general anesthetics, opiates)

Possible additive effects or potentiated action of other CNS depressants

Use concomitantly with caution; dosage reduction of the added CNS depressant may be necessary

Epinephrine or dopamine

Possible further lowering of BP

Do not use epinephrine or dopamine for phenothiazine-induced hypotension (see Cardiovascular Effects under Cautions)

Lithium

An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations present

Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appear

Test for phenylketonuria (PKU)

Potential false-positive test results may occur during phenothiazine use

Perphenazine Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration ; appears to undergo substantial first-pass metabolism. Peak plasma concentrations generally attained within 1–3 hours.

Distribution

Extent

Not fully characterized. Phenothiazines are widely distributed into most body tissues and fluids.

Crosses the placenta. Distributed into breast milk.

Plasma Protein Binding

Phenothiazines are highly bound to plasma proteins.

Elimination

Metabolism

Extensively metabolized in the liver by sulfoxidation, hydroxylation, dealkylation and glucuronidation. Poor metabolizers of CYP2D6 metabolize the drug more slowly than normal metabolizers.

Elimination Route

Phenothiazines and their metabolites are excreted in urine and feces.

Unlikely to be removed by hemodialysis and peritoneal dialysis.

Half-life

9–12 hours following oral administration.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C (may be exposed to 15-30°C).

Fixed-combination (with Amitriptyline Hydrochloride) Tablets

Tight, light-resistant containers at 20–25°C.

Actions

  • Precise mechanism(s) of antipsychotic action not determined, but may be principally related to antidopaminergic effects.

  • Exhibits moderate anticholinergic effects, weak to moderate sedative effects, and strong extrapyramidal effects; possesses strong antiemetic activity.

Advice to Patients

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. Patients and caregivers also should be informed that perphenazine is not approved for treating geriatric patients with dementia-related psychosis.

  • Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.

  • Risk of drowsiness and impairment of mental and physical abilities required for driving a car or operating heavy machinery.

  • Importance of avoiding alcohol during perphenazine therapy.

  • Importance of informing patients in whom chronic perphenazine use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.

  • Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, seizures).

  • Importance of avoiding exposure to temperature extremes.

  • Risk of leukopenia/neutropenia. Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during perphenazine therapy.

  • Importance of informing clinician if sore throat or other signs of infection occur.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions). Importance of advising patients not to stop taking perphenazine if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Perphenazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2 mg*

Perphenazine Tablets

4 mg*

Perphenazine Tablets

8 mg*

Perphenazine Tablets

16 mg*

Perphenazine Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Perphenazine and Amitriptyline Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg Perphenazine and Amitriptyline Hydrochloride 10 mg*

Perphenazine and Amitriptyline Hydrochloride Tablets

2 mg Perphenazine and Amitriptyline Hydrochloride 25 mg*

Perphenazine and Amitriptyline Hydrochloride Tablets

4 mg Perphenazine and Amitriptyline Hydrochloride 10 mg*

Perphenazine and Amitriptyline Hydrochloride Tablets

4 mg Perphenazine and Amitriptyline Hydrochloride 25 mg*

Perphenazine and Amitriptyline Hydrochloride Tablets

4 mg Perphenazine and Amitriptyline Hydrochloride 50 mg*

Perphenazine and Amitriptyline Hydrochloride Tablets

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 21, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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