Perphenazine

PERPHENAZINE- perphenazine tablet
GOLDEN STATE MEDICAL SUPPLY, INC.

WARNING

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Perphenazine tablets, USP are not approved for the treatment of patients with dementia-related psychosis ( see WARNINGS).

DESCRIPTION

Perphenazine (4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol), a piperazinyl phenothiazine, having the molecular formula, C 21 H 26 CIN 3 OS. It is available as oral tablets containing 2 mg, 4 mg, 8 mg, and 16 mg of perphenazine. Its structural formula is:

figure
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Perphenazine is a white or yellowish-white crystalline powder. It is practically insoluble in water; freely soluble in alcohol and in chloroform; soluble in acetone.

Each film-coated perphenazine tablet intended for oral administration contains 2 mg, 4 mg, 8 mg and 16 mg of perphenazine. In addition, each tablet contains the following inactive ingredients: corn starch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Additionally, each film-coated perphenazine tablet contains opadry II white 03B28796 which contains hypromellose, polyethylene glycol and titanium dioxide.

CLINICAL PHARMACOLOGY

Perphenazine has actions at all levels of the central nervous system, particularly the hypothalamus. However, the site and mechanism of action of therapeutic effect are not known.

Pharmacokinetics

Following oral administration of perphenazine tablets, mean peak plasma perphenazine concentrations were observed between 1 to 3 hours. The plasma elimination half-life of perphenazine was independent of dose and ranged between 9 and 12 hours. In a study in which normal volunteers (n=12) received perphenazine 4 mg q8h for 5 days, steady-state concentrations of perphenazine were reached within 72 hours. Mean (%CV) C max and C min values for perphenazine and 7-hydroxyperphenazine at steady-state are listed below:

Parameter
Perphenazine
7 Hydroxyperphenazine
C m a x (pg/mL)
984 (43)
509 (25)
C m i n (pg/mL)
442 (76)
350 (56)

Peak 7-hydroxyperphenazine concentrations were observed between 2 to 4 hours with a terminal phase half-life ranging between 9.9 to 18.8 hours. Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation. The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquine which is mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism – i.e., 7% to 10% of Caucasians and a low percentage of Asians have little or no activity and are called “poor metabolizers.” Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or “extensive” metabolizers.

INDICATIONS AND USAGE

Perphenazine tablets, USP are indicated for use in the treatment of schizophrenia and for the control of severe nausea and vomiting in adults.

Perphenazine tablets, USP have not been shown effective for the management of behavioral complications in patients with mental retardation.

CONTRAINDICATIONS

Perphenazine products are contraindicated in comatose or greatly obtunded patients and in patients receiving large doses of central nervous system depressants (barbiturates, alcohol, narcotics, analgesics, or antihistamines); in the presence of existing blood dyscrasias, bone marrow depression, or liver damage; and in patients who have shown hypersensitivity to perphenazine products, their components, or related compounds.

Perphenazine products are also contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures in excess of 104°F may occur in such patients, sometimes not until 14 to 16 hours after drug administration. Total body ice-packing is recommended for such a reaction; antipyretics may also be useful.

WARNINGS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Perphenazine tablets, USP are not approved for the treatment of patients with dementia-related psychosis ( see BOXED WARNING).

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Older patients are at increased risk for development of tardive dyskinesia. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, especially in the elderly, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to Information for Patients and ADVERSE REACTIONS.)

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