Fluphenazine is a typical antipsychotic that is used for symptomatic management of psychosis in patients with schizophrenia. There is a long-acting fluphenazine decanoate formulation that is used primarily as maintenance therapy for chronic schizophrenia and related psychotic disorders in patients who do not tolerate oral formulations or in patients where medication compliance is a concern of the prescribing physician.
Although frequently prescribed off-label for psychosis or psychotic symptoms related to major neurocognitive disorder and related dementing illnesses, all antipsychotics (including fluphenazine) are not FDA-approved for these purposes. Their use should be avoided. Fluphenazine is not FDA-approved for augmentation of mood stabilization or treatment of concomitant psychotic symptoms in patients with bipolar disorder. Fluphenazine has also been used off-label for the management of chronic tic disorders as well as in Huntington disease for control of abnormal movements and chorea.
Like many of the other first-generation antipsychotics, fluphenazine has seen substantially decreased usage in developed countries after the advent of second-generation, atypical antipsychotics. This is due to improved side-effect profiles these newer agents possess, as well as, the increased efficacy these second-generation drugs have at targeting negative symptoms of schizophrenia (such as avolition or diminished emotional expressivity).
Fluphenazine acts primarily through antagonism of postsynaptic dopamine-2 receptors in mesolimbic, nigrostriatal, and tuberoinfundibular neural pathways. The blockage of postsynaptic dopamine-2 receptors in the mesolimbic pathway targets positive symptoms in schizophrenia, such as hallucinations, delusions, and disorganized speech. It is also known to have antagonistic properties at alpha-1 adrenergic receptors which contribute to its cardiac and orthostatic side effects (see below). Fluphenazine, like most other antipsychotic medications, has relatively strong antagonistic effects at both muscarinic-1 receptors and histamine-1 receptors.
Fluphenazine is part of a class of medications known as first-generation antipsychotics or conventional antipsychotics. It is considered a member of the phenothiazine-derived neuroleptic antipsychotics along with medications such as thioridazine and chlorpromazine. Of medications in this class, fluphenazine is considered to be high-potency.
Fluphenazine is available in multiple formulations, including oral tablets, intramuscular injection for acute symptoms, and long-acting intramuscular or subcutaneous injections. Oral dosing ranges from 1 mg to 40 mg and is available in 1-mg, 2.5-mg, 5-mg, or 10-mg tablets. Initial oral dosing is 0.5 mg to 10 mg per day with a maximum dosage of 40 mg per day. There are also liquid oral solutions available for patients that could not tolerate tablet formulations. Oral fluphenazine has a half-life of 14 to 16 hours. Intramuscular (IM) formulation for acute administration is typically given as 1.25 mg initial dose with options ranging from 2.5 mg to 10 mg per day. IM, short-acting formulations can be administered every 6 to 8 hours as needed for acute agitation in patients with psychosis. The half-life of the intramuscular formulation of fluphenazine is 6 to 10 days. The long-acting intramuscular or subcutaneous formulation is dosed initially 12.5 mg to 25 mg and is typically dosed every 28 days.
Fluphenazine has an adverse effect profile similar to other first-generation or typical antipsychotics. This is due to its dopamine receptor antagonism as well as its anticholinergic, antihistaminic, and alpha-adrenergic antagonistic properties. Common side effects include sedation, dry mouth, constipation, dry eyes, blurred vision, constipation, orthostasis, dizziness, hypotension, and urinary retention. Other possible side effects include rebound tachycardia, urinary retention, and weight gain. Due to dopaminergic antagonism, fluphenazine can cause extrapyramidal symptoms, including akathisia, parkinsonian features such as resting tremor and shuffling gait, acute dystonic reactions, oculogyric crises, opisthotonos, and tardive dyskinesia. Extrapyramidal side effects of fluphenazine and other antipsychotics can be managed with medications such as benztropine or sodium benzoate. Additionally, prolactin-induced side effects of galactorrhea, gynecomastia in men, sexual dysfunction, and in females amenorrhea or off-cycle bleeding can occur. Rare but serious side effects include neuroleptic malignant syndrome, liver function abnormalities and jaundice, seizures, and agranulocytosis. Like other antipsychotic medications, fluphenazine carries a black-box warning for increased risk of cerebrovascular events and death in elderly patients with psychosis related to the major neurocognitive disorder. Allergic reactions have been reported with the use of fluphenazine and other phenothiazine typical antipsychotics. Electrocardiogram abnormalities have also been reported with the use of fluphenazine and various other antipsychotics; QT-interval prolongation, as well as T-wave abnormalities, have been associated with fluphenazine use.
Fluphenazine is contraindicated for use in patients with the hepatobiliary disease or hepatic insufficiency as it can precipitate or worsen cholestatic jaundice.
This medication carries a black-box warning regarding its use in elderly patients with psychosis associated with the major neurocognitive disorder and other dementia-related illnesses for increased risk of cerebrovascular accidents and death in these populations. Meta-analyses have demonstrated an increased risk of 1.6 to 1.7 times of death in elderly patients with a major neurocognitive disorder associated psychosis prescribed antipsychotics versus placebo.
The risks and benefits of prescribing fluphenazine should be weighed against possible side effects guiding use. Caution should be used in patients with comorbid cardiac electrophysiological conditions due to possible alterations in cardiac conduction and electrocardiogram changes. Patients with impairments in gastrointestinal functioning, especially motility disorders, or urinary retention should be closely monitored for exacerbations in these conditions after starting fluphenazine; this is related to the drug’s anticholinergic properties. Caution should be exercised for the use of this drug in patients with coexisting ocular conditions such as narrow-angle glaucoma, motor disorders such as parkinsonism, renal insufficiency, or seizure disorders.
Patients taking any antipsychotic medication should be closely monitored for the appearance of side effects. Baseline electrocardiograms should be obtained in all patients with preexisting cardiac conduction abnormalities starting fluphenazine; close monitoring for electrocardiogram changes should be performed. Assessments for the appearance of extrapyramidal side effects should routinely be performed on patients taking fluphenazine; the Abnormal Involuntary Movement Scale is a well-studied, easy-to-administer assessment for the emergence of extrapyramidal effects. Complete blood counts and metabolic panels should be routinely obtained to monitor for changes in white blood cell counts, liver transaminases, and blood urea nitrogen and creatinine levels. Patients taking multiple medications should be monitored for interactions with fluphenazine; this medication is a major substrate of the CYP-2D6 system and is a weak inhibitor of CYP-2C9 and CYP-2E1 systems. Although serum levels of fluphenazine are not routinely ordered and dosing is typically based on clinical response, the therapeutic reference range is noted to be 1 nanogram to 10 nanograms per milliliter.