VA Class:CN701

AHFS Class:

• Phenothiazines 28:16.08.24

Generic Name(s):

• fluPHENAZine Decanoate

• fluPHENAZine Hydrochloride

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

Psychotic Disorders

Fluphenazine is used orally and parenterally for the symptomatic management of psychotic disorders (i.e., 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, see Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

The long-acting decanoate ester of fluphenazine is used mainly for maintenance therapy in patients with chronic schizophrenic disorder who cannot be relied on to take oral antipsychotic drugs. The principal disadvantage of therapy with the decanoate ester is the inability to terminate the drug's action when severe adverse effects occur. Although fluphenazine hydrochloride injection may be used for acute management of severely agitated patients, the decanoate should not be used.

Administration

Fluphenazine hydrochloride is administered orally or by IM injection. Fluphenazine decanoate is administered by IM or subcutaneous injection, using a dry syringe and needle of at least 21-gau use of a wet needle or syringe may cause the solution to become cloudy. When fluphenazine hydrochloride oral concentrate solution is used, the dose should be diluted (e.g., with water; Seven-Up^®; carbonated orange bevera sodium chloride solution; milk; V-8^®; or pineapple, apricot, prune, orange, tomato, or grapefruit juice) just before administration. (See Chemistry and Stability: Stability.)

Dosage

There is a range of optimum individual dosage requirements of fluphenazine and dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. Dosage should be increased more gradually in debilitated, emaciated, 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 fluphenazine and/or other antipsychotic agents should be evaluated periodically to determine whether maintenance dosage could be decreased or drug therapy discontinued. Fluphenazine therapy is best instituted with a low initial dosage, which may be gradually increased, if necessary, until the desired clinical effects are obtained.

Psychotic Disorders

For the symptomatic management of psychotic disorders in adults, the usual initial oral dosage of fluphenazine hydrochloride is 2.5-10 mg daily given in divided doses every 6-8 hours. Optimum therapeutic effect often occurs with oral dosages under 20 mg daily. Dosages up to 40 mg daily may be required in some severely disturbed patients; however, the safety of prolonged administration of such dosages has not been established, and oral dosages greater than 20 mg daily should be used with caution. After the maximum response is attained, dosage should be reduced gradually to oral maintenance dosages of 1-5 mg daily, often given as a single dose. To avoid recurrence of psychotic symptoms, continued therapy with fluphenazine is required following optimum therapeutic response. Dosage during prolonged maintenance therapy should be kept at the lowest possible effective dosage and subsequently adjusted according to the patient's tolerance and therapeutic response. For the symptomatic management of psychotic disorders in geriatric patients, the usual initial oral dosage of fluphenazine hydrochloride is 1-2.5 mg daily.

In general, the IM dose of fluphenazine hydrochloride has been found to be approximately one-third to one-half the oral dose. For the symptomatic management of psychotic disorders in adults, the usual initial IM dose of fluphenazine hydrochloride is 1.25 mg. Depending on the severity and duration of symptoms, initial total IM dosage of fluphenazine hydrochloride may range from 2.5-10 mg daily given in divided doses every 6-8 hours; dosage may then be gradually increased, if necessary, until symptoms are controlled. IM dosages of fluphenazine hydrochloride exceeding 10 mg daily should be used with caution. After the patient's symptoms are controlled, oral therapy should generally replace parenteral therapy, often with single daily doses.

Conversion of therapy from oral fluphenazine hydrochloride dosage forms (e.g., tablets, elixir) to the long-acting decanoate parenteral dosage form may be indicated for psychotic patients who have been stabilized on a fixed daily oral dosage of fluphenazine hydrochloride; however, because of their prolonged elimination, the principal disadvantage of therapy with fluphenazine decanoate is the inability to terminate their action when severe adverse effects occur. Therefore, in patients without a history of therapy with phenothiazines, it is recommended that a shorter-acting form of fluphenazine (e.g., fluphenazine hydrochloride) be administered for several weeks prior to instituting therapy with fluphenazine decanoate in order to determine the patient's approximate dosage requirements and susceptibility to adverse effects. Shorter-acting phenothiazines should also be used in patients with acute schizophrenic reactions so that dosage can readily be adjusted according to the patient's tolerance and therapeutic response. A precise formula for converting therapy from fluphenazine hydrochloride to fluphenazine decanoate has not been established. However, data from a controlled, multicenter study in patients receiving oral fluphenazine hydrochloride dosages of 5-60 mg daily showed that approximately 20 mg of fluphenazine hydrochloride daily was equivalent to 25 mg of fluphenazine decanoate every 3 weeks. This represents an approximate conversion ratio of 12.5 mg of fluphenazine decanoate every 3 weeks for every 10 mg of fluphenazine hydrochloride daily.

For the management of patients requiring prolonged parenteral antipsychotic therapy, such as those with chronic schizophrenic disorder, the usual initial adult IM or subcutaneous dose of fluphenazine decanoate is 12.5-25 mg. Subsequent dose and dosage interval should be carefully adjusted according to the patient's tolerance and therapeutic response. When administered as maintenance therapy, a single injection of fluphenazine decanoate may be effective in controlling schizophrenic symptoms for up to 4 weeks or longer; the response to a single dose has been shown to persist for up to 6 weeks in a few patients on maintenance therapy.

Fluphenazine 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.) Like other propylpiperazine derivatives of phenothiazine, fluphenazine has a tendency to produce extrapyramidal reactions, particularly during early treatment with fluphenazine decanoate. Extrapyramidal reactions usually appear 2-3 days following administration of a long-acting fluphenazine ester and persist for approximately 5 days. The incidence of extrapyramidal reactions is greatest following the first dose of the ester and may be minimized by using small doses initially and increasing dosage very gradually. Although fluphenazine decanoate has been reported to have a lesser tendency to produce extrapyramidal reactions than fluphenazine enanthate, this has not been established.

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.100,101,102,103 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 also see Cautions: Geriatric Precautions, in the Phenothiazines General Statement 28:16.08.24.

In general, fluphenazine produces a lower incidence of sedative and hypotensive effects than does chlorpromazine. Hypertension and fluctuations in blood pressure may occur in patients receiving fluphenazine. Although hypotension rarely occurs in patients receiving fluphenazine, patients with pheochromocytoma, cerebrovascular or renal insufficiency, or severe cardiac reserve deficiency (e.g., mitral insufficiency) appear to be especially prone to the hypotensive effects of phenothiazine therapy and these patients should be closely monitored while receiving the drug.

Other reported adverse effects of fluphenazine include nausea, polyuria, headache, glaucoma, urinary retention, fecal impaction, and peripheral edema. Mental depression appears to be common in patients receiving fluphenazine esters and patients should be carefully monitored for this adverse effect.

Care should be taken to avoid skin contact with fluphenazine hydrochloride elixir, oral concentrate solution, or injection and fluphenazine decanoate injection, since contact dermatitis has occurred rarely.

Safety and efficacy of fluphenazine decanoate in children younger than 12 years of age have not been established; the manufacturers state that the drug is contraindicated in this age group. There is insufficient experience with use of fluphenazine hydrochloride in children to establish its safety and efficacy.

For other precautions and contraindications associated with fluphenazine, see the Phenothiazines General Statement 28:16.08.24.

Pharmacology

The principal pharmacologic effects of fluphenazine are similar to those of chlorpromazine. Fluphenazine is more potent on a weight basis than chlorpromazine. Fluphenazine has weak anticholinergic and sedative effects and strong extrapyramidal effects. Fluphenazine has weak antiemetic activity.

Pharmacokinetics

Fluphenazine hydrochloride is rapidly absorbed from the GI tract and from parenteral sites. Following oral or IM administration of fluphenazine hydrochloride, the onset of action usually occurs within 1 hour; the duration of action is 6-8 hours. Following administration of a single dose of fluphenazine hydrochloride in one limited study, peak serum fluphenazine concentrations were reached within 1.5-2 or 0.5 hours following IM or oral administration, respectively.

Esterification of fluphenazine slows the rate of release of the drug from fatty tissues, thus prolonging the drug's duration of action; administration of the esters in a sesame oil vehicle further delays their rate of release. Following IM administration of fluphenazine decanoate in sesame oil, the onset of action occurs within 24-72 hours; the duration of action is usually 1-6 weeks, with an average of 2 weeks.

The distribution and metabolic fate of fluphenazine have not been fully elucidated. Fluphenazine reportedly crosses the blood-brain barrier; radioactivity was present in CSF following IM administration of radiolabeled fluphenazine decanoate in 2 individuals. In one limited study in which unchanged radiolabeled drug was measured, the plasma elimination half-life of fluphenazine was 14.7-15.3 hours or 6.8-9.6 days following IM or oral administration of the hydrochloride or IM administration of the decanoate, respectively. In one individual in this study, fluphenazine was excreted as unchanged drug, fluphenazine sulfoxide, and 7-hydroxyfluphenazine in feces and as these compounds and their conjugates in urine following IM administration of the decanoate.

Chemistry and Stability

Chemistry

Fluphenazine is a phenothiazine antipsychotic agent. The drug is a propylpiperazine derivative of phenothiazine and is structurally similar to perphenazine, but differs from perphenazine in the substitution of a trifluoromethyl group for chlorine at the 2 position of the phenothiazine nucleus. Fluphenazine is commercially available as the decanoic acid ester (decanoate) and hydrochloride salt. Each 12.5 mg of fluphenazine decanoate is approximately equivalent to 10.75 mg of fluphenazine hydrochloride.

Fluphenazine decanoate occurs as a pale yellow, viscous liquid or yellow, crystalline, oily solid, which has a characteristic odor and is insoluble in water, freely soluble in alcohol, and soluble in fixed oils (e.g., sesame oil). Fluphenazine decanoate injections are commercially available as sterile solutions of the drugs in sesame oil and contain benzyl alcohol as a preservative. Fluphenazine hydrochloride occurs as a white or almost white, crystalline powder, and is freely soluble in water and slightly soluble in alcohol. Commercially available fluphenazine hydrochloride injection is a colorless to light amber, sterile solution of the drug in water for injection. Sodium hydroxide and/or hydrochloric acid may be added during manufacture of fluphenazine hydrochloride injection to adjust the pH to 4.8-5.2; the preparation also contains sodium chloride for isotonicity and parabens as preservatives. Fluphenazine hydrochloride elixir and oral concentrate solution have pHs of 5.3-5.8 and 4-5, respectively.

Stability

Commercially available preparations of fluphenazine should be protected from light and stored at room temperature; oral preparations should be stored in tightly closed containers. Freezing of the oral solution and injections should be avoided. Slight yellowish discoloration of fluphenazine hydrochloride injection will not affect potency or efficacy, but the injection should not be used if markedly discolored or if a precipitate is present. Fluphenazine hydrochloride oral concentrate solution should not be mixed with beverages containing caffeine (e.g., coffee, cola), tannic acid (e.g., tea), or pectinates (e.g., apple juice), since physical incompatibility may result.

At the time of manufacture, air in the vials of the commercially available fluphenazine decanoate and fluphenazine hydrochloride injections is replaced with nitrogen to avoid oxidation and discoloration.

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 fluphenazine, see the Phenothiazines General Statement 28:16.08.24.

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

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

101. 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]

102. 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]

103. 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]