DailyMed Label: Perphenazine

DailyMed Label: Perphenazine

2010

DailyMed Prescription

Perphenazine

Perphenazine

Contract Pharmacy Services-PA

NDC: 67046-540

NDC: 67046-540

NDC: 67046-541

NDC: 67046-541

Perphenazine (4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol), a piperazinyl phenothiazine, having the chemical 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. Inactive ingredients: lactose (monohydrate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, starch (corn), titanium dioxide, and polysorbate 80. Its structural formula is: Structural Formula

Perphenazine is indicated for use in the treatment of schizophrenia and for the control of severe nausea and vomiting in adults. Perphenazine has not been shown effective for the management of behavioral complications in patients with mental retardation.

Dosage must be individualized and adjusted according to the severity of the condition and the response obtained. As with all potent drugs, the best dose is the lowest dose that will produce the desired clinical effect. Since extrapyramidal symptoms increase in frequency and severity with increased dosage, it is important to employ the lowest effective dose. These symptoms have disappeared upon reduction of dosage, withdrawal of the drug, or administration of an antiparkinsonian agent. Prolonged administration of doses exceeding 24 mg daily should be reserved for hospitalized patients or patients under continued observation for early detection and management of adverse reactions. An antiparkinsonian agent, such as trihexyphenidyl hydrochloride or benztropine mesylate, is valuable in controlling drug-induced extrapyramidal symptoms. Suggested dosages for various conditions follow: 4 to 8 mg t.i.d. initially; reduce as soon as possible to minimum effective dosage. 8 to 16 mg b.i.d. to q.i.d.; avoid dosages in excess of 64 mg daily. 8 to 16 mg daily in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable. With increasing age, plasma concentrations of perphenazine per daily ingested dose increase. Geriatric dosages of perphenazine preparations have not been established, but initiation of lower dosages is recommended. Optimal clinical effect or benefit may require lower doses for a longer duration. Dosing of perphenazine may occur before bedtime, if required.

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 tablets, 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.

The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. This type of patient should not have access to large quantities of this drug. As with all phenothiazine compounds, perphenazine should not be used indiscriminately. Caution should be observed in giving it to patients who have previously exhibited severe adverse reactions to other phenothiazines. Some of the untoward actions of perphenazine tend to appear more frequently when high doses are used. However, as with other phenothiazine compounds, patients receiving perphenazine products in any dosage should be kept under close supervision. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. The antiemetic effect of perphenazine may obscure signs of toxicity due to overdosage of other drugs, or render more difficult the diagnosis of disorders such as brain tumors or intestinal obstruction. A significant, not otherwise explained, rise in body temperature may suggest individual intolerance to perphenazine, in which case it should be discontinued. Patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, reduced amounts of anesthetics or central nervous system depressants may be necessary. Since phenothiazines and central nervous system depressants (opiates, analgesics, antihistamines, barbiturates) can potentiate each other, less than the usual dosage of the added drug is recommended and caution is advised when they are administered concomitantly. Use with caution in patients who are receiving atropine or related drugs because of additive anticholinergic effects and also in patients who will be exposed to extreme heat or phosphorus insecticides. The use of alcohol should be avoided, since additive effects and hypotension may occur. Patients should be cautioned that their response to alcohol may be increased while they are being treated with perphenazine products. The risk of suicide and the danger of overdose may be increased in patients who use alcohol excessively due to its potentiation of the drug’s effect. Blood counts and hepatic and renal functions should be checked periodically. The appearance of signs of blood dyscrasias requires the discontinuance of the drug and institution of appropriate therapy. If abnormalities in hepatic tests occur, phenothiazine treatment should be discontinued. Renal function in patients on long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes abnormal, treatment with the drug should be discontinued. The use of phenothiazine derivatives in patients with diminished renal function should be undertaken with caution. Use with caution in patients suffering from respiratory impairment due to acute pulmonary infections, or in chronic respiratory disorders such as severe asthma or emphysema. In general, phenothiazines, including perphenazine, do not produce psychic dependence. Gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high-dose therapy. Reports suggest that these symptoms can be reduced by continuing concomitant antiparkinson agents for several weeks after the phenothiazine is withdrawn. The possibility of liver damage, corneal and lenticular deposits, and irreversible dyskinesias should be kept in mind when patients are on long-term therapy. Because photosensitivity has been reported, undue exposure to the sun should be avoided during phenothiazine treatment. Metabolism of a number of medications, including antipsychotics, antidepressants, ß-blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called “poor” metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects. In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events. The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g., fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Given the likelihood that a substantial proportion of patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. Clinical studies of perphenazine products did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease or other drug therapy. Geriatric patients are particularly sensitive to the side effects of antipsychotics, including perphenazine. These side effects include extrapyramidal symptoms (tardive dyskinesia, antipsychotic-induced parkinsonism, akathisia), anticholinergic effects, sedation and orthostatic hypotension (See WARNINGS ). Elderly patients taking psychotropic drugs may be at increased risk for falling and consequent hip fractures. Elderly patients should be started on lower doses and observed closely.

Not all of the following adverse reactions have been reported with this specific drug; however, pharmacological similarities among various phenothiazine derivatives require that each be considered. With the piperazine group (of which perphenazine is an example), the extrapyramidal symptoms are more common, and others (e.g., sedative effects, jaundice, and blood dyscrasias) are less frequently seen.

Metabolism of a number of medications, including antipsychotics, antidepressants, ß-blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called “poor” metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects. In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events. The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g., fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.

Perphenazine tablets, USP are round, unscored, film-coated white tablets available as: 4 mg: debossed GG 107 on one side and plain on the reverse side, supplied as: NDC 67046-540-30 blister of 30 tablets 8 mg: debossed GG 108 on one side and plain on the reverse side, supplied as: NDC 67046-541-30 blister of 30 tablets Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Dispense in a tight, light-resistant container.

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 max (pg/mL) 984 (43) 509 (25) C min (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.

4 mg