Perphenazine

Pronunciation

(per FEN a zeen)

Generic Available

Yes

Canadian Brand Names

Apo-Perphenazine®

Use

Treatment of schizophrenia; nausea and vomiting

Use - Unlabeled/Investigational

Ethanol withdrawal; dementia in elderly; Tourette's syndrome; Huntington's chorea; spasmodic torticollis; Reye's syndrome; psychosis

Pregnancy Risk Factor

Lactation

Enters breast milk/not recommended (AAP rates "of concern")

Contraindications

Hypersensitivity to perphenazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression; subcortical brain damage; bone marrow suppression; blood dyscrasias; coma

Warnings/Precautions

May cause hypotension. May be sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; predisposition to seizures; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (ie, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction - life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose).

Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is moderate-high relative to other neuroleptics). Older patients are at increased risk for developing tardive dyskinesia. May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy.

Adverse Reactions

Frequency not defined.

Cardiovascular: Hyper-/hypotension, orthostatic hypotension, tachycardia, bradycardia, dizziness, cardiac arrest

Central nervous system: Extrapyramidal symptoms (pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia), dizziness, cerebral edema, seizure, headache, drowsiness, paradoxical excitement, restlessness, hyperactivity, insomnia, neuroleptic malignant syndrome (NMS), impairment of temperature regulation

Dermatologic: Rash, discoloration of skin (blue-gray), photosensitivity

Endocrine & metabolic: Hypoglycemia, hyperglycemia, galactorrhea, lactation, breast enlargement, gynecomastia, menstrual irregularity, amenorrhea, SIADH, libido (changes in)

Gastrointestinal: Constipation, weight gain, vomiting, stomach pain, nausea, xerostomia, salivation, diarrhea, anorexia, ileus

Genitourinary: Difficulty in urination, ejaculatory disturbances, incontinence, polyuria, ejaculating dysfunction, priapism

Hematologic: Agranulocytosis, leukopenia, eosinophilia, hemolytic anemia, thrombocytopenic purpura, pancytopenia

Hepatic: Cholestatic jaundice, hepatotoxicity

Neuromuscular & skeletal: Tremor

Ocular: Pigmentary retinopathy, blurred vision, cornea and lens changes

Respiratory: Nasal congestion

Miscellaneous: Diaphoresis

Overdosage/Toxicology

Symptoms of overdose include deep sleep, dystonia, agitation, coma, abnormal involuntary muscle movements, hypotension, and arrhythmias (QTc prolongation, AV block, torsade de pointes, ventricular tachycardia/fibrillation). Children may have convulsive seizures.

Treatment is symptom-directed and supportive. Induction of emesis is not recommended. Peritoneal dialysis and hemodialysis are of no value. Gastric lavage and administration of activated charcoal together with a laxative should be considered. Cardiac function should be monitored for at least 5 days. Norepinephrine may be used to treat hypotension, but epinephrine should not be used.

Drug Interactions

Substrate of CYP1A2 (minor), 2C8/9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2D6 (weak)

Aluminum salts: May decrease the absorption of phenothiazines; monitor

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms; avoid concurrent use

Anticholinergics: May inhibit the therapeutic response to phenothiazines and excess anticholinergic effects may occur; includes benztropine, trihexyphenidyl, biperiden, and drugs with significant anticholinergic activity (TCAs, antihistamines, disopyramide)

Antihypertensives: Concurrent use of phenothiazines with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Bromocriptine: Phenothiazines inhibit the ability of bromocriptine to lower serum prolactin concentrations

CNS depressants: Sedative effects may be additive with phenothiazines; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

CYP2D6 inhibitors: May increase the levels/effects of perphenazine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Epinephrine: Chlorpromazine (and possibly other low potency antipsychotics) may diminish the pressor effects of epinephrine

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by phenothiazines

Levodopa: Phenothiazines may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Lithium: Phenothiazines may produce neurotoxicity with lithium; this is a rare effect

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Phenytoin: May reduce serum levels of phenothiazines; phenothiazines may increase phenytoin serum levels

Propranolol: Serum concentrations of phenothiazines may be increased; propranolol also increases phenothiazine concentrations

Polypeptide antibiotics: Rare cases of respiratory paralysis have been reported with concurrent use of phenothiazines

QTc-prolonging agents: Effects on QTc interval may be additive with phenothiazines, increasing the risk of malignant arrhythmias; includes type Ia antiarrhythmics, TCAs, and some quinolone antibiotics (sparfloxacin, moxifloxacin, and gatifloxacin)

Sulfadoxine-pyrimethamine: May increase phenothiazine concentrations

Tricyclic antidepressants: Concurrent use may produce increased toxicity or altered therapeutic response

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

Valproic acid: Serum levels may be increased by phenothiazines

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).

Stability

Store at 2°C to 25°C (36°F to 77°F). Protect from light.

Mechanism of Action

Perphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones

Pharmacodynamics/Kinetics

Absorption: Oral: Well absorbed

Distribution: Crosses placenta

Metabolism: Extensively hepatic to metabolites via sulfoxidation, hydroxylation, dealkylation, and glucuronidation

Half-life elimination: Perphenazine: 9-12 hours; 7-hydroxyperphenazine: 11.3 hours

Time to peak, serum: Perphenazine: 1-3 hours; 7-hydroxyperphenazine: 2-4 hours

Excretion: Urine and feces

Dosage

Oral:

Children:

Schizophrenia/psychoses:

1-6 years: 4-6 mg/day in divided doses

6-12 years: 6 mg/day in divided doses

>12 years: 4-16 mg 2-4 times/day

Adults:

Schizophrenia/psychoses: 4-16 mg 2-4 times/day not to exceed 64 mg/day

Nausea/vomiting: 8-16 mg/day in divided doses up to 24 mg/day

Elderly: Behavioral symptoms associated with dementia: Initial: 2-4 mg 1-2 times/day; increase at 4- to 7-day intervals by 2-4 mg/day. Increase dose intervals (bid, tid, etc) as necessary to control behavior response or side effects. Maximum daily dose: 32 mg; gradual increase (titration) and bedtime administration may prevent some side effects or decrease their severity.

Hemodialysis: Not dialyzable (0% to 5%)

Dosing adjustment in hepatic impairment: Dosage reductions should be considered in patients with liver disease although no specific guidelines are available

Monitoring Parameters

Vital signs; lipid profile, fasting blood glucose/Hgb A1c; BMI; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS)

Reference Range

2-6 nmol/L

Patient Education

Use exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results; do not discontinue without consulting prescriber. Do not take within 2 hours of any antacid. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid skin contact with medication; may cause contact dermatitis (wash immediately with warm, soapy water). You may experience excess drowsiness, restlessness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); dry mouth, nausea, vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); urinary retention (void before taking medication); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); or decreased perspiration (avoid strenuous exercise in hot environments). Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); chest pain, palpitations, rapid heartbeat, severe dizziness; unresolved urinary retention or changes in urinary pattern; menstrual pattern, change in libido, or ejaculatory difficulty; vision changes; skin rash or yellowing of skin; respiratory difficulty; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations

Coadministration of two or more antipsychotics does not improve clinical response and may increase the potential for adverse effects.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment:

Significant hypotension may occur, especially when the drug is administered parenterally; orthostatic hypotension is due to alpha-receptor blockade, the elderly are at greater risk for orthostatic hypotension.

Tardive dyskinesia: Prevalence rate may be 40% in elderly; development of the syndrome and the irreversible nature are proportional to duration and total cumulative dose over time. Extrapyramidal reactions are more common in elderly with up to 50% developing these reactions after 60 years of age. Drug-induced Parkinson's syndrome occurs often; akathisia is the most common extrapyramidal reaction in elderly.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called "epinephrine reversal" phenomenon. This has never been observed when epinephrine is given by infiltration as part of the anesthesia procedure.

Dosage Forms

Tablet: 2 mg, 4 mg, 8 mg, 16 mg

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

Azaz-Livshits TL, Symmer LI, and Fraenkel YM, "Atypical Neuroleptic Malignant Syndrome Presenting as Rhabdomyolysis, Altered Consciousness, and Leukocytosis," J Pharm Technol , 1995, 11:173-5.

Hansen LB and Larsen NE, "Metabolic Interaction Between Perphenazine and Disulfiram," Lancet , 1982, 2(8313):1472.

Harper G, Dawes M, Azlin C, et al, "Small Bowel Obstruction in a Child on an Antipsychotic," J Child Adolesc Psychopharm , 1995, 5:81-4.

Peabody CA, Warner MD, Whiteford HA, et al, "Neuroleptics and the Elderly," J Am Geriatr Soc , 1987, 35(3):233-8.

Risse SC and Barnes R, "Pharmacologic Treatment of Agitation Associated With Dementia," J Am Geriatr Soc , 1986, 34(5):368-76.

Saltz BL, Woerner MG, Kane JM, et al, "Prospective Study of Tardive Dyskinesia Incidence in the Elderly," JAMA , 1991, 266(17):2402-6.

Seifert RD, "Therapeutic Drug Monitoring: Psychotropic Drugs," J Pharm Pract , 1984, 6:403-16.

International Brand Names

Apo-Perphenazine® (CA); Conazine® (TH); Decentan® (AT, DE, ES); Decentan Depot® [inj.] (DE); Fentazin® (GB); Leptopsique® (MX); Peratsin® (FI); Perfenazin® (CZ); Pernamed® (TH); Pernazine® (TH); Perphenazin-neuraxpharm® (DE); Perzine-P® (TH); Porazine® (TH); Trilafon® (BE, CH, DK, ID, IT, LU, NL, NO, PL, SE, ZA); Trilafon dekanoat® (DK, NO, SE); Trilafon enantat® (SE); Trilafon prolongatum® (SE); Trilifan Retard® [inj.] (FR)

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