Adult: Dosage is individualised and adjusted according to severity, patient response and tolerability; use the lowest possible effective dose. In moderately disturbed non-hospitalised patients: Initially, 4-8 mg tid; reduce to the minimum effective dose as soon as possible. Max: 24 mg daily. In hospitalised patients: Initially, 8-16 mg 2-4 times daily. Max: 64 mg daily. Elderly: Initiate at the lower end of the dosing range.
Oral Severe nausea and vomiting
Adult: 8-16 mg daily in divided doses, occasionally, up to 24 mg daily may be given as necessary. Reduce to the minimum effective dose as soon as possible. Elderly: Initiate at the lower end of the dosing range.
Special Patient Group
CYP2D6 poor metabolisers
Perphenazine is mainly metabolised by CYP2D6 isoenzyme into several metabolites. Individuals with little or no CYP2D6 activity, also known as CYP2D6 poor metabolisers, are reported to be approx 7-10% in Caucasians and a low percentage in Asians. CYP2D6 poor metabolisers may metabolise perphenazine more slowly and experience higher plasma concentrations resulting in an increased risk of enhanced adverse effects as compared to normal/extensive metabolisers.
Administration
Should be taken with food.
Contraindications
Comatose or greatly obtunded patients, suspected or established subcortical brain damage (with or without hypothalamic damage), bone marrow depression, blood dyscrasias. Liver damage. Patients taking large doses of CNS depressants.
Special Precautions
Patient with CV disease, respiratory disease (e.g. asthma, emphysema), seizure disorder, psychic depression; cerebrovascular disease, hypovolaemia, paralytic ileus, decreased gastrointestinal motility, benign prostatic hyperplasia; pre-existing low WBC count, history of drug-induced leucopenia or neutropenia; at risk of aspiration pneumonia (e.g. Alzheimer’s disease). CYP2D6 poor metabolisers. Patients undergoing surgery; subjected to dehydration, strenuous exercise, extreme heat or phosphorus insecticide exposure. Not approved for the treatment of dementia-related psychosis. Avoid abrupt withdrawal. Renal and hepatic impairment. Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Extrapyramidal symptoms (e.g. tardive dyskinesia, pseudoparkinsonism, dystonia, akathisia), anticholinergic effects (e.g. blurred vision, xerostomia, constipation, urinary retention), oesophageal dysmotility and aspiration, postural hypotension, motor and sensory instability causing falls; liver damage (prolonged use), elevated prolactin levels, photosensitivity, ocular effects (e.g. pigmentary retinopathy, lenticular and corneal deposits), impaired core body temperature regulation. Cardiac disorders: Bradycardia, tachycardia. Eye disorders: Glaucoma, mydriasis. Gastrointestinal disorders: Salivation, nausea, vomiting, diarrhoea, faecal impaction, dysphagia. General disorders and administration site conditions: Ataxia. Hepatobiliary disorders: Jaundice. Immune system disorders: Hypersensitivity reactions (e.g. angioneurotic or laryngeal oedema, anaphylactoid reactions, exfoliative or contact dermatitis, asthma). Metabolism and nutrition disorders: Anorexia, hyperglycaemia. Nervous system disorders: Dizziness, drowsiness, agitation, hyperreflexia, cerebral oedema, convulsive seizures. Renal and urinary disorders: Urinary incontinence, bladder paralysis, polyuria, glycosuria. Reproductive system and breast disorders: Galactorrhoea, gynaecomastia, menstrual cycle disturbance, amenorrhoea, changes in libido, inhibition of ejaculation. Respiratory, thoracic and mediastinal disorders: Nasal congestion. Skin and subcutaneous tissue disorders: Skin pigmentation, perspiration. Vascular disorders: Pallor, hypertension or hypotension. Potentially Fatal: Neuroleptic malignant syndrome, adynamic ileus, circulatory collapse, arrhythmias, cardiac arrest, blood dyscrasias (e.g. leucopenia, neutropenia, agranulocytosis).
Patient Counseling Information
This drug may cause drowsiness and impair your mental or physical abilities; if affected, do not drive or operate machinery. Avoid prolonged exposure to sunlight.
Monitoring Parameters
Monitor mental status, vital signs, blood pressure, and CBC as clinically indicated; weight, height, BMI, waist circumference at baseline, every visit for the 1st 6 months then quarterly; electrolytes, hepatic and renal functions annually then as clinically indicated; fasting plasma glucose level/HbA1c at baseline then annually; lipid panel at baseline and as needed. Monitor for abnormal involuntary movements or parkinsonian signs, tardive dyskinesia, visual changes, and fall risk. Perform ophthalmic screening at the start then periodically throughout the treatment.
Overdosage
Symptoms: Stupor or coma, tachycardia, QRS or QTc interval prolongation, torsade de pointes, atrioventricular block, ventricular dysrhythmia, hypotension or cardiac arrest; hypothermia or severe hyperthermia may occur. Management: Symptomatic and supportive treatment. Perform gastric lavage and administer activated charcoal together with a laxative. Maintain an open airway and adequate fluid intake. May use norepinephrine to treat hypotension. Regulation of body temperature and close monitoring of cardiac function is advisable.
Drug Interactions
Drugs that inhibit CYP2D6 activity including TCAs and SSRIs (e.g. fluoxetine, sertraline, paroxetine) may increase the plasma levels of perphenazine. May block or partially reverse the action of epinephrine. May cause additive anticholinergic effect with atropine. Potentially Fatal: Additive effects (e.g. sedation, hypotension) when taken with large doses of CNS depressants (e.g. barbiturates, narcotics, analgesics, antihistamines).
Food Interaction
Additive CNS depressant effects and increased risk of hypotension with alcohol.
Lab Interference
May cause false-positive result in pregnancy tests.
Action
Description: Perphenazine is a phenothiazine antipsychotic with a piperazine side-chain. It blocks the dopaminergic receptors in the mesolimbocortical and nigrostriatal areas of the brain. Perphenazine has a strong antiemetic activity, and it has moderate anticholinergic, weak to moderate sedative, and strong extrapyramidal effects. Onset: Psychotic symptom control: 2-4 weeks. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: Approx 60-80%. Time to peak plasma concentration: 1-3 hours (perphenazine); 2-4 hours (7-hydroxyperphenazine). Distribution: Widely distributed. Crosses the placenta. Metabolism: Extensively metabolised in the liver via sulfoxidation, hydroxylation, dealkylation, and glucuronidation mainly by CYP2D6 isoenzyme to N-dealkylated perphenazine, perphenazine sulfoxide, and 7-hydroxyperphenazine (active). Undergoes some first-pass metabolism. Excretion: Via urine (approx 70%, mainly as metabolites); faeces (approx 5%). Elimination half-life: 9-12 hours (perphenazine); 10-19 hours (7-hydroxyperphenazine).
Chemical Structure
Perphenazine Source: National Center for Biotechnology Information. PubChem Database. Perphenazine, CID=4748, https://pubchem.ncbi.nlm.nih.gov/compound/Perphenazine (accessed on Jan. 22, 2020)
N05AB03 - perphenazine ; Belongs to the class of phenothiazine antipsychotics with piperazine structure. Used in the management of psychosis.
References
Annotation of FDA Label for Perphenazine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 17/09/2020.Anon. Perphenazine. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 26/08/2020.Anon. Perphenazine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 26/08/2020.Apo-Perphenazine Tablet (Pharmaforte [M] Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 17/09/2020.Buckingham R (ed). Perphenazine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 26/08/2020.Perphenazine Tablet (Cadila Healthcare Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 26/08/2020.Perphenazine Tablets, USP (Sandoz, Inc). U.S. FDA. https://www.fda.gov/. Accessed 26/08/2020.
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