Continuing Education Activity

Fluphenazine is a typical antipsychotic used for the symptomatic management of psychosis in patients with schizophrenia. There is a long-acting fluphenazine decanoate formulation 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 provider. It is a first-generation antipsychotic. This activity outlines the indications, mechanism of action, dosing, significant adverse effects, contraindications, monitoring, and toxicity of fluphenazine, so providers can direct patient therapy to optimize outcomes in patient management.

Objectives:

• Describe the mechanism of action of fluphenazine.
• Identify the indications, both approved and off-label, for fluphenazine.
• Outline the adverse event profile and necessary monitoring for therapy with fluphenazine.
• Review interprofessional team strategies for improving care coordination and communication to advance fluphenazine therapy and improve outcomes.

Indications

Fluphenazine is a high-potency typical antipsychotic used for the symptomatic management of psychosis in patients with schizophrenia. There is a long-acting fluphenazine decanoate formulation 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] Fluphenaziine's clinical effectiveness is approximately equal to that of other lower-potency antipsychotics such as chlorpromazine.[4]

Although frequently prescribed off-label for psychosis or psychotic symptoms related to the major neurocognitive disorder and related dementing illnesses, all antipsychotics (including fluphenazine) are not FDA-approved for these purposes, and clinicians should avoid their use in such cases. Fluphenazine is not FDA-approved for augmentation of mood stabilization or treating concomitant psychotic symptoms in patients with bipolar disorder. Fluphenazine has also been used off-label to manage chronic tic disorders and Huntington disease to control abnormal movements and chorea.

Like many other first-generation antipsychotics, fluphenazine has seen substantially decreased usage in developed countries after the advent of second-generation, atypical antipsychotics. It was first used in 1959, but its use has fallen out of favor in recent years since newer drugs are equally effective.[5] 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).[5]

Mechanism of Action

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, contributing to its cardiac and orthostatic side effects (see below). Like most other antipsychotic medications, fluphenazine has relatively strong antagonistic effects at both muscarinic-1 receptors and histamine-1 receptors.[6][7]

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.[8]

Administration

Fluphenazine is available in multiple formulations, including oral tablets, intramuscular injections 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. There are also liquid oral solutions available for patients that are unable to tolerate tablet formulations.

Typical Psychosis Oral Dosing

• 2.5 to 10 mg per day divided every 6 to 8 hours. 
• Elderly patients should start at 1 to 2.5 mg per day (divided every 6 to 8 hours also)

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.

The maximum dosage of fluphenazine is 40 mg per day. There are no pediatric indications for this drug.

Adverse Effects

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, 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.[9]

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 the 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.[10][11][12]

Contraindications

Fluphenazine is contraindicated for use in patients with hepatobiliary disease or hepatic insufficiency as it can precipitate or worsen cholestatic jaundice.

The drug should be discontinued if ANC is less than 1000, and discontinuation should be considered if there is an unexplained decrease in the patient's WBC count.

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 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.

In pregnancy, clinicians should consider avoiding this medication during the first trimester, and caution is advised in the third trimester. There is no human safety data on fluphenazine in lactation and breastfeeding, so it is best to seek alternative therapy.[13]

Monitoring

Patients taking any antipsychotic medication require close monitoring 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 is necessary. Assessments for the appearance of extrapyramidal side effects should be routine for patients taking fluphenazine; the Abnormal Involuntary Movement Scale is a well-studied, easy-to-administer assessment for the emergence of extrapyramidal effects.

Clinicians should routinely obtain complete blood counts and metabolic panels to monitor for changes in white blood cell counts, liver transaminases, and blood urea nitrogen and creatinine levels. Patients taking multiple medications also require monitoring for fluphenazine interactions; 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 a routine part of therapy and dosing typically depends on clinical response, the therapeutic reference range is 1 nanogram to 10 nanograms per milliliter.

Monitoring a patient is also essential when discontinuing fluphenazine, which should be done gradually. Evidence exists that discontinuing antipsychotics can actually result in psychosis.[5]

Toxicity

In instances of fluphenazine overdose, there is no specific antidote for toxicity; treatment is symptomatic, usually based on the presenting anticholinergic effects.

Enhancing Healthcare Team Outcomes

Fluphenazine therapy is optimally managed by an interprofessional healthcare team comprised of physicians (MDs, DOs; including specialists), mid-level practitioners (NPs and PAs), nurses, and pharmacists. The drug is generally prescribed by a primary care provider, psychiatric nurse, or psychiatrist.

It is essential to monitor patients receiving fluphenazine therapy because the drug is notorious for causing extrapyramidal side effects and adverse cardiac events. An ECG is a requirement before starting the medication to ensure that the patient does not have QT abnormalities. The Abnormal Involuntary Movement Scale is a well-studied, easy-to-administer assessment for the emergence of extrapyramidal effects. Nursing staff can provide valuable feedback in this area and serve as the primary contact point for the patient with the team, coordinating all team members. Complete blood counts and metabolic panels are also necessary to monitor changes in white blood cell counts, liver transaminases, and blood urea nitrogen and creatinine levels. Additionally, the pharmacist must keep track of patient medications to verify dosing, avoid potential drug-drug interactions, counsel the patient regarding possible adverse events, and tell the patient how to dose their medication optimally. This interprofessional team approach with open information sharing can drive better patient outcomes with fewer adverse events. [Level 5]