Fluphenazine is a typical antipsychotic 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 of concern.[1][2][3]

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 and clinicians should avoid their use. 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 reduction in use is due to the improved side-effect profiles of these newer agents, as well as the increased efficacy that these second-generation drugs have in targeting negative symptoms of schizophrenia (such as avolition or diminished emotional expressivity).[4]

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.[5][6]

Fluphenazine is part of a class of drugs 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 the drugs in this class, fluphenazine rates as 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 a 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 typical dosing is every 28 days.

Fluphenazine has an adverse effect profile similar to other first-generation or typical antipsychotics, which 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 are manageable 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 major neurocognitive disorder. There are reports of allergic reactions with the use of fluphenazine and other phenothiazine typical antipsychotics. Reports also exist of electrocardiogram abnormalities with the use of fluphenazine and various other antipsychotics; QT-interval prolongation, as well as T-wave abnormalities, have been associated with fluphenazine use.[7][8][9]

Fluphenazine is contraindicated for use in patients with 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 major neurocognitive disorder and other dementia-related illnesses for increased risk of cerebrovascular accidents and death in these populations. Meta-analyses have revealed 1.6 to 1.7 times increased risk of death in elderly patients with a major neurocognitive disorder and associated psychosis who were prescribed antipsychotics versus placebo.

The risks and benefits of prescribing fluphenazine should be weighed against possible side effects guiding use. Caution is necessary for 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. Clinicians should exercise caution using this drug in patients with coexisting ocular conditions such as narrow-angle glaucoma, motor disorders such as parkinsonism, renal insufficiency, or seizure disorders.