VA Class:CN701

AHFS Class:

• Phenothiazines 28:16.08.24

Generic Name(s):

• Perphenazine

• Perphenazine and Amitriptyline Hydrochloride

Perphenazine is a phenothiazine antipsychotic agent. The drug is considered a conventional or first-generation antipsychotic agent.

Psychotic Disorders

Perphenazine is used for the symptomatic management of psychotic disorders (e.g., schizophrenia).

Schizophrenia

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to improve symptoms between episodes and to minimize the risk of recurrent acute episodes. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia and generally are effective in all subtypes of the disorder and subgroups of patients. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile. For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Severe Nausea and Vomiting

Perphenazine is used for the control of severe nausea and vomiting in adults. Safe use of perphenazine for the prevention and treatment of nausea and vomiting of pregnancy has not been established, and the manufacturers recommend that the drug be used during pregnancy only when the potential benefits justify the possible risks to the fetus. (See Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.)

Administration

Perphenazine is administered orally. Perphenazine oral solution is intended for use only in hospitalized patients. When the oral concentrate solution is used, the dose should be diluted (e.g., with water, Seven-Up^®, sodium chloride solution, or milk, or with pineapple, apricot, prune, orange, tomato, V-8^®, or grapefruit juice) just before administration. (See Chemistry and Stability: Stability.) For optimum palatability, the manufacturer suggests that at least 60 mL of diluent be used for each 16 mg (5 mL) of concentrate administered.

Dosage

Dosage of perphenazine must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. Dosage should be increased more gradually in debilitated or geriatric patients. Because of the risk of adverse reactions associated with cumulative effects of phenothiazines, patients with a history of long-term therapy with perphenazine and/or other antipsychotic agents should be evaluated periodically to determine whether maintenance dosage could be decreased or drug therapy discontinued.

Prolonged administration of perphenazine dosages exceeding 24 mg daily should be limited to hospitalized patients or patients under continued observation for early detection and management of adverse reactions.100 An antiparkinsonian agent, such as trihexyphenidyl or benztropine, is valuable in controlling drug-induced extrapyramidal reactions.100

Schizophrenia

For the symptomatic management of schizophrenia in moderately disturbed outpatients, the usual initial oral dosage of perphenazine in adults and children older than 12 years of age is 4-8 mg 3 times daily. Subsequent dosage of perphenazine should be reduced to the lowest possible effective dosage as soon as possible. For the symptomatic management of schizophrenia in hospitalized adults and children older than 12 years of age, the usual initial oral dosage of perphenazine is 8-16 mg 2-4 times daily. Oral dosage of perphenazine in adults should not exceed 64 mg daily. Dosage for children younger than 12 years of age has not been established.

Severe Nausea and Vomiting

For the control of severe nausea and vomiting in adults, the usual initial oral dosage of perphenazine is 8-16 mg daily in divided doses. Occasionally, dosages up to 24 mg daily may be required in some patients, but subsequent dosage should be reduced as soon as possible.

Dosage in Geriatric Patients

Although geriatric dosages of perphenazine preparations have not been established, plasma concentrations of perphenazine per daily ingested dose appear to increase with increasing patient age.100 In general, dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosage range, and reflect the greater frequency of decreased hepatic function and concomitant disease or drug therapy observed in geriatric individuals.100 Geriatric patients are particularly sensitive to certain adverse effects of perphenazine (e.g., sedation, orthostatic hypotension), which potentially may result in injuries (e.g., falls, hip fractures).100 Perphenazine may be administered before bedtime as needed.100 Administration of lower dosages for longer periods of time may be required to achieve optimal therapeutic results in this patient population.100 For information on the use of antipsychotic agents for dementia-associated psychosis, see Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses and see Cautions: Geriatric Precautions, in the Phenothiazines General Statement 28:16.08.24.

Perphenazine shares the toxic potentials of other phenothiazines, and the usual precautions of phenothiazine therapy should be observed. (See Cautions in the Phenothiazines General Statement 28:16.08.24.) When preparations containing perphenazine in combination with other drugs are administered, the cautions applicable to each ingredient should be considered.

Geriatric patients with dementia-related psychosis treated with either conventional (first-generation) or atypical (second-generation) antipsychotic agents are at an increased risk of mortality.101,102,103,104 (See Dosage in Geriatric Patients under Dosage and Administration: Dosage.) For additional information on the use of antipsychotic agents for dementia-associated psychosis and other behavioral disturbances, see Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses and see Cautions: Geriatric Precautions, in the Phenothiazines General Statement 28:16.08.24.

Some commercially available formulations of perphenazine contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Care should be taken to avoid contact with perphenazine oral solution or injection, since contact dermatitis has occurred rarely.

Safety and efficacy of perphenazine in children younger than 12 years of age have not been established.

Pharmacology

The principal pharmacologic effects of perphenazine are similar to those of chlorpromazine. Perphenazine has moderate anticholinergic effects, weak to moderate sedative effects, and strong extrapyramidal effects. Perphenazine has strong antiemetic activity.

Chemistry and Stability

Chemistry

Perphenazine is a phenothiazine antipsychotic agent. The drug is a propylpiperazine derivative of phenothiazine. Perphenazine occurs as a white to creamy white, odorless powder with a bitter taste and is practically insoluble in water and freely soluble in alcohol. The commercially available injection has a pH of 4.2-5.6 and contains disodium citrate and sodium bisulfite. The commercially available oral concentrate solution has a pH of 4.5-4.9.

Stability

Commercially available preparations of perphenazine should be stored in tight, light-resistant containers. Perphenazine tablets and oral concentrate solution should be stored at 2-25 and 2-30°C, respectively; freezing of the oral concentrate solution should be avoided.

Additional Information

For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of perphenazine, see the Phenothiazines General Statement 28:16.08.24.

Only references cited for selected revisions after 1984 are available electronically.

100. Schering Corporation. Trilafon^® (perphenazine) tablets and injection prescribing information. Kenilworth, NJ; 2001 Jul.

101. Food and Drug Administration. FDA Alert: Information for healthcare professionals: antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website. [Web]

102. Food and Drug Administration. FDA News: FDA requests boxed warnings on older class of antipsychotic drugs. Rockville, MD; 2008 Jun 16. From the FDA website. [Web]

103. Schneeweiss S, Setoguchi S, Brookhart A et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ . 2007; 176:627-32. [PubMedCentral][PubMed 17325327]

104. Gill SS, Bronskill SE, Normand SL et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med . 2007; 146:775-86. [PubMed 17548409]