Brand name: Formerly available as Prolixin
Drug class: Phenothiazines
VA class: CN701
CAS number: 5002-47-1

Medically reviewed by Drugs.com on Nov 6, 2023. Written by ASHP.

Introduction

Propylpiperazine-derivative phenothiazine; conventional (prototypical, first-generation) antipsychotic agent.

Uses for fluPHENAZine

Psychotic Disorders

Symptomatic management of psychotic disorders (i.e., schizophrenia).

The long-acting decanoate ester is used mainly for maintenance therapy in patients with chronic schizophrenic disorder who cannot be relied on to take oral antipsychotic drugs; do not use for acute management of severely agitated patients.

fluPHENAZine Dosage and Administration

General

• Use shorter-acting fluphenazine hydrochloride formulations in patients with acute schizophrenic reactions so that dosage can be readily adjusted according to patient’s tolerance and therapeutic response.

Administration

Administer fluphenazine hydrochloride orally or IM.

Administer fluphenazine decanoate IM or sub-Q. If used outside of psychiatric institutions, administer under direction of clinician experienced in use of psychotropic drugs, particularly phenothiazine derivatives.

Avoid skin contact with elixir, oral concentrate solution, or injection since contact dermatitis rarely occurs.

Oral Administration

Fluphenazine hydrochloride: Administer orally every 6–8 hours initially; maintenance therapy can often be administered as a single daily dose.

When oral concentrate solution is used, dilute dose with at least 60 mL of suitable diluent (e.g., water; uncaffeinated soft drinks [e.g., Seven-Up]; carbonated orange beverage; sodium chloride; milk; V-8; or pineapple, apricot, prune, orange, tomato, or grapefruit juice) just before administration. (See Compatibility under Stability.)

IM or Sub-Q Administration

Fluphenazine hydrochloride: Administer IM every 6–8 hours.

Fluphenazine decanoate: Administer IM or sub-Q using a dry syringe and needle of at least 21 gauge; use of a wet needle or syringe may cause solution to become cloudy.

Dosage

Available as fluphenazine hydrochloride or fluphenazine decanoate; dosage expressed in terms of the salt.

Carefully adjust dosage according to individual requirements and response, using lowest possible effective dosage.

Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage may be decreased or drug therapy discontinued. (See Tardive Dyskinesia under Cautions.)

Conversion from oral fluphenazine hydrochloride to long-acting decanoate injection may be indicated for psychotic patients stabilized on a fixed daily oral dosage. In patients without a history of therapy with phenothiazines, administer shorter-acting form for several weeks prior to instituting therapy with fluphenazine decanoate in order to determine patient’s approximate dosage requirements and susceptibility to adverse effects.

Precise formula for converting therapy from fluphenazine hydrochloride to fluphenazine decanoate not established. An approximate conversion ratio of 12.5 mg every 3 weeks of fluphenazine decanoate for every 10 mg daily of fluphenazine hydrochloride has been used.

Adults

Psychotic Disorders

Oral

Fluphenazine hydrochloride: Initially, 2.5–10 mg daily given in divided doses every 6–8 hours. Dosage may be gradually increased, if necessary, until desired clinical effects are obtained.

Optimum therapeutic effect often occurs with oral fluphenazine hydrochloride dosages <20 mg daily. Dosages up to 40 mg may be required in severely disturbed patients, but safety of prolonged administration of such dosages not established. Use dosages >20 mg daily with caution.

After maximum response attained, reduce fluphenazine hydrochloride dosage gradually to maintenance dosage of 1–5 mg daily, often as a single dose. To avoid recurrence of psychotic symptoms, continued therapy is required following optimum therapeutic response.

IM

Fluphenazine hydrochloride: Generally, IM dose is approximately one-third to one-half the oral dose.

Usual initial fluphenazine hydrochloride dose is 1.25 mg. Depending on severity and duration of symptoms, initial total IM dosage may range from 2.5–10 mg daily given in divided doses every 6–8 hours; may gradually increase dosage if necessary, until symptoms are controlled.

Use fluphenazine hydrochloride dosages >10 mg daily with caution.

After symptoms are controlled, oral therapy generally should replace parenteral therapy.

IM or Sub-Q

Fluphenazine decanoate: In patients with chronic schizophrenic disorder, usual initial dose is 12.5–25 mg.

Carefully adjust subsequent fluphenazine decanoate dose and dosage interval according to patient tolerance and response; if doses >50 mg are deemed necessary, increase the next and succeeding doses cautiously in increments of 12.5 mg, but do not exceed 100 mg.

When administered as maintenance therapy, a single fluphenazine decanoate injection may be effective in controlling schizophrenic symptoms for up to 4 weeks or longer; response may persist for up to 6 weeks in some patients.

Prescribing Limits

Adults

Psychotic Disorders

Oral

Fluphenazine hydrochloride: Safety of prolonged administration of dosages up to 40 mg daily not established. Use dosages >20 mg daily with caution.

IM

Fluphenazine hydrochloride: Use dosages >10 mg daily with caution.

IM or Sub-Q

Fluphenazine decanoate: Do not exceed 100 mg.

Special Populations

Geriatric Patients

Fluphenazine hydrochloride: Initially, 1–2.5 mg orally daily; adjust subsequent dosage based on patient response. Increase dosage more gradually in debilitated, emaciated, or geriatric patients.

Cautions for fluPHENAZine

Contraindications

• Suspected or established subcortical brain damage.

• Comatose or severely depressed states.

• Blood dyscrasia or liver damage.

• Concomitant therapy with large doses of hypnotics.

• Known hypersensitivity to fluphenazine or other phenothiazine derivatives (unless potential benefits outweigh possible risks).

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.

Antipsychotic agents, including fluphenazine, are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with use of antipsychotic agents, including fluphenazine.

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.

APA recommends assessing patients receiving conventional antipsychotic agents for abnormal involuntary movements every 6 months; for patients at increased risk for tardive dyskinesia, assess every 3 months. Consider discontinuance of fluphenazine if signs and symptoms of tardive dyskinesia appear. However, some patients may require treatment despite the presence of the syndrome.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including fluphenazine.

Immediately discontinue therapy and initiate supportive and symptomatic treatment if NMS occurs. Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.

Sensitivity Reactions

Hypersensitivity

Skin disorders (e.g., pruritus, erythema, urticaria, seborrhea, photosensitivity, eczema, exfoliative dermatitis) reported with phenothiazine derivatives. Contact dermatitis reported rarely.

Consider possibility of anaphylactoid reactions.

Cross-sensitivity

Possible cross-sensitivity with other phenothiazines; use with caution in patients who have developed cholestatic jaundice, dermatoses, or other allergic reactions to phenothiazine derivatives.

General Precautions

Use phenothiazines with caution in debilitated patients, patients with renal or hepatic disease, patients with glaucoma or prostatic hypertrophy, and patients exposed to organophosphate insecticides.

Use phenothiazines with caution in patients with hypocalcemia, since susceptibility to dystonic reactions may be increased.

Hematologic Effects

Leukopenia and neutropenia temporally related to antipsychotic agents, including fluphenazine, reported during clinical trial and/or postmarketing experience. Agranulocytosis (including fatal cases) also reported with antipsychotic agents.

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia. Monitor CBC frequently during the first few months of therapy in patients with such risk factors. Discontinue fluphenazine at the first sign of a decline in WBC count in the absence of other causative factors.

Carefully monitor patients with clinically important neutropenia for fever or other signs and symptoms of infection and treat promptly if they occur. In patients with severe neutropenia (ANC <1000/mm³), discontinue fluphenazine and monitor WBC until recovery occurs.

Other blood dyscrasias, including thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia, reported with phenothiazine derivatives. Perform hematologic evaluations periodically.

Abrupt Withdrawal

Gastritis, nausea, vomiting, dizziness, and tremulousness reported after abrupt discontinuance of high-dose therapy; minimize symptoms by continuing concomitant antiparkinsonian agents for several weeks after phenothiazine is withdrawn.

Cardiovascular Effects

Hypotension occurs rarely. Patients with pheochromocytoma, cerebral or vascular insufficiency, or severe cardiac reserve deficiency (e.g., mitral insufficiency), or psychotic patients receiving large doses of phenothiazines who are undergoing surgery may be especially prone to hypotensive effects; closely monitor such patients during therapy.

Hypertension and fluctuations in BP may occur.

Nervous System Effects

Possible risk of seizures; phenothiazines may lower seizure threshold. Use with caution in patients with a history of seizures or EEG abnormalities or in those receiving anticonvulsant agents. Maintain adequate anticonvulsant therapy.

Drowsiness or lethargy possible; may necessitate dosage reduction.

Because of CNS depressant effects of phenothiazines, use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).

Neurologic reactions from phenothiazine therapy may be similar to CNS manifestations accompanying certain disorders (e.g., Reye’s syndrome, encephalopathy, meningitis, tetanus); diagnosis of these disorders may be obscured or disease-associated manifestations may be incorrectly diagnosed as drug induced.

Antiemetic effect of phenothiazines may mask signs of overdosage of toxic drugs (e.g., antineoplastic agents) or may obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).

Phenothiazines depress hypothalamic mechanism for body temperature regulation; use caution in patients exposed to extreme heat or cold.

Extrapyramidal symptoms occur frequently and are usually reversible; persistent reactions can usually be controlled by concomitant therapy with an antiparkinsonian drug and subsequent dosage reduction.

Autonomic reactions (e.g., nausea, appetite loss, salivation, polyuria, perspiration, dry mouth, headache, constipation) may occur.

Hepatic Effects

Liver damage, manifested by cholestatic jaundice may occur, particularly during first months of therapy; discontinue immediately if liver damage occurs.

Consider possibility of liver damage in patients receiving prolonged therapy. Monitor hepatic function periodically.

Ocular Effects

Consider possibility of pigmentary retinopathy and lenticular and corneal deposits in patients receiving prolonged therapy. Periodic ophthalmic examinations recommended in patients receiving prolonged phenothiazine therapy with moderate to high dosages.

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence).

If contemplating fluphenazine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin dependent in vitro.

Pulmonary Effects

Clinicians should be alert to possible development of “silent pneumonias” in patients receiving phenothiazines, including fluphenazine.

Use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).

Specific Populations

Pregnancy

Category C.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

Use during pregnancy only if potential benefit justifies potential risk to the fetus.

Lactation

Phenothiazines are distributed into milk. Women receiving phenothiazines should not breast-feed.

Pediatric Use

Insufficient experience with fluphenazine hydrochloride to establish safety and efficacy.

Safety and efficacy of fluphenazine decanoate not established in children <12 years of age.

Geriatric Use

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents. (See Geriatric Patients under Dosage and Administration.)

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Hepatic Impairment

Use phenothiazines with caution in patients with hepatic disease. Monitor hepatic function periodically.

Renal Impairment

Use phenothiazines with caution in patients with renal disease. Monitor renal function periodically; if BUN becomes abnormal, discontinue therapy.

Common Adverse Effects

Extrapyramidal reactions (e.g., pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, hyperreflexia), drowsiness, lethargy, weight gain.

Drug Interactions

Specific Drugs and Laboratory Tests

fluPHENAZine Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract and from parenteral sites. Peak serum concentrations were attained within 1.5–2 or 0.5 hours after IM or oral administration, respectively, of fluphenazine hydrochloride.

Onset

Fluphenazine hydrochloride: Usually occurs within 1 hour following oral or IM administration.

Fluphenazine decanoate: Within 24–72 hours.

Duration

Fluphenazine hydrochloride: 6–8 hours following oral or IM administration.

Fluphenazine decanoate: Usually 1–6 weeks (average: 2 weeks).

Distribution

Extent

Not fully elucidated; reportedly crosses blood-brain barrier.

Phenothiazines cross the placenta and are distributed into milk.

Elimination

Metabolism

Metabolic fate not fully elucidated.

Elimination Route

Excreted in feces and urine as unchanged drug, fluphenazine sulfoxide, and 7-hydroxyfluphenazine following IM administration of fluphenazine decanoate in 1 patient studied; also excreted in urine as metabolite conjugates.

Half-life

Fluphenazine hydrochloride: 14.7–15.3 hours following IM or oral administration.

Fluphenazine decanoate: 6.8–9.6 days following IM administration.

Stability

Storage

Oral

Tablets

Tightly closed containers at 20–25°C. Protect from light.

Elixir

Tightly closed containers at 20–25°C, unless otherwise specified by manufacturer; avoid freezing. Protect from light.

Solution, Concentrate

Tightly closed containers at 20–25°C, unless otherwise specified by manufacturer; avoid freezing. Protect from light.

Parenteral

Injection

Fluphenazine decanoate: 20–25°C. Protect from light.

Fluphenazine hydrochloride: 20–25°C ; avoid freezing. Protect from light.

Compatibility

Oral

Do not mix oral concentrate solution with beverages containing caffeine (e.g., coffee, cola), tannic acid (e.g., tea), or pectinates (e.g., apple juice), since physical incompatibility may result. (See Oral Administration under Dosage and Administration.)

Parenteral

Drug Compatibility (for Fluphenazine Hydrochloride)

Actions

• Precise mechanism(s) of antipsychotic action not determined but may be principally related to antidopaminergic effects.

• Exhibits weak anticholinergic and sedative effects and strong extrapyramidal effects; has weak antiemetic activity.

Advice to Patients

• Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. Importance of informing patients and caregivers that fluphenazine is not approved for treating geriatric patients with dementia-related psychosis.

• Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.

• Risk of drowsiness and impairment of mental and physical abilities required for driving a car or operating heavy machinery.

• Importance of avoiding alcohol during fluphenazine therapy.

• Importance of informing patients in whom chronic fluphenazine use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.

• Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.

• Risk of leukopenia/neutropenia. Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during fluphenazine therapy.

• Importance of informing clinician if sore throat or other signs of infection occur.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, seizures).

• Importance of avoiding exposure to temperature extremes.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions). Importance of advising patients not to stop taking fluphenazine if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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