Fluphenazine25 mg/ml

Fluphenazine is a long-acting (depot) injectable formulation of the first-generation (typical) antipsychotic fluphenazine, esterified with decanoic acid to allow slow release from an intramuscular or subcutaneous depot.

Established / FDA-approved use

• Maintenance treatment of schizophrenia in patients who require prolonged parenteral neuroleptic therapy, particularly patients with chronic psychotic symptoms who benefit from a long-acting formulation because of adherence difficulties with daily oral therapy.

Important scope limitations (per approved labeling)

• Fluphenazine has not been shown to be effective for managing behavioral complications in patients with intellectual disability.
• It is not approved for treating dementia-related psychosis in elderly patients (see Precautions and Warnings for the boxed mortality warning).

Because of its delayed onset (effects generally begin 24–72 hours after injection) and long duration of action, Fluphenazine is generally not used to treat acute psychotic agitation; patients are usually stabilised first on a shorter-acting form of fluphenazine before being converted to the decanoate depot.

Each mL of Fluphenazine Decanoate injection typically contains fluphenazine decanoate 25 mg in a sesame oil vehicle, with benzyl alcohol as a preservative. Strength and pack size may vary by manufacturer/brand; always check the product label of the dispensed brand.

Fluphenazine is the decanoate ester of fluphenazine, a trifluoromethyl phenothiazine derivative belonging to the first-generation ("typical") antipsychotic class. Esterification of the fluphenazine molecule with decanoic acid, and formulation in an oily vehicle, markedly slows release and absorption after intramuscular or subcutaneous injection, converting a drug that would otherwise need daily oral dosing into a depot product that is typically injected once every 2 to 4 weeks (up to 100 mg per dose, per approved labeling).

Fluphenazine is used for long-term maintenance therapy of schizophrenia, particularly in patients for whom adherence to daily oral antipsychotic therapy is a concern.

Fluphenazine belongs to the phenothiazine class of first-generation (typical) antipsychotics, specifically the piperazine phenothiazine subgroup. It is classified as a long-acting (depot) injectable antipsychotic.

The precise mechanism by which Fluphenazine Decanoate produces its antipsychotic effect is not fully established, but its principal pharmacological action is thought to be post-synaptic dopamine D2-receptor antagonism in the mesolimbic and mesocortical pathways of the central nervous system, which is believed to underlie its efficacy against positive psychotic symptoms (hallucinations, delusions, disorganised thinking).

Fluphenazine also has antagonist activity at alpha-adrenergic, histaminic (H1), and, to a lesser degree, muscarinic cholinergic receptors, which contributes to some of its adverse effect profile (e.g., orthostatic hypotension, sedation). Blockade of dopamine receptors in the nigrostriatal pathway is responsible for extrapyramidal symptoms, and blockade in the tuberoinfundibular pathway raises prolactin.

Pharmacokinetics

• Absorption: Esterification and the oily depot vehicle produce slow, sustained release from the injection site; onset of clinical effect is generally seen 24–72 hours after injection.
• Duration: A single injection of Fluphenazine Decanoate may control symptoms for up to 4 weeks or longer, allowing dosing intervals of roughly 2–4 weeks in most patients.
• Metabolism: The decanoate ester is gradually hydrolysed to free fluphenazine, which undergoes hepatic metabolism.
• Elimination: Because the drug is released slowly from the depot, its effects (both therapeutic and adverse) persist for a prolonged period after the last injection and cannot be rapidly reversed by discontinuing the drug.

Fluphenazine must be administered only by a trained healthcare professional, by deep intramuscular or subcutaneous injection — never intravenously. Use a dry syringe and needle of at least 21-gauge; a wet needle or syringe can cause the oily solution to turn cloudy. Rotate injection sites. Patients should be observed after the first dose for hypersensitivity or unusual reactions, and monitored periodically for extrapyramidal symptoms and other adverse effects for as long as the depot effect persists.

The following interactions with Fluphenazine are clinically significant and well documented for phenothiazine antipsychotics:

• CNS depressants (alcohol, opioids, barbiturates, benzodiazepines, general anesthetics): Fluphenazine potentiates the sedative and respiratory-depressant effects of these agents; concurrent use should be avoided or closely monitored.
• Other QT-prolonging drugs (e.g., certain antiarrhythmics, other antipsychotics, some antibiotics): additive risk of QT-interval prolongation and torsades de pointes; combination should be avoided where possible.
• Anticholinergic agents: additive anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision) may occur with concurrent use.
• Antihypertensive agents: Fluphenazine can cause orthostatic hypotension and may potentiate the hypotensive effect of antihypertensive drugs.
• Drugs that lower seizure threshold: Fluphenazine itself can lower seizure threshold; caution is needed when combined with other agents that do the same (e.g., tramadol, bupropion).
• Lithium: rare reports of an encephalopathic syndrome (confusion, weakness, extrapyramidal symptoms) with concurrent phenothiazine and lithium use; monitor closely if combined.

Adverse effects of Fluphenazine are generally similar to those of oral fluphenazine, but because it is a long-acting depot injection, any reaction that occurs — including hypersensitivity and extrapyramidal reactions — may take considerably longer to resolve than with an oral dose, since the drug cannot be immediately withdrawn from the body.

Common

• Extrapyramidal symptoms — pseudoparkinsonism (tremor, rigidity), dystonia, akathisia (restlessness), oculogyric crisis
• Drowsiness, sedation, lethargy
• Dry mouth, constipation, blurred vision, nasal congestion
• Orthostatic hypotension, dizziness
• Weight gain

Less common but clinically important

• Tardive dyskinesia — potentially irreversible involuntary movements; risk rises with cumulative dose and duration of treatment (see Precautions and Warnings).
• Neuroleptic malignant syndrome (NMS) — a rare, potentially fatal reaction with hyperthermia, muscle rigidity, altered mental status, and autonomic instability; requires immediate medical attention.
• Elevated prolactin — menstrual irregularities, galactorrhea, gynecomastia, decreased libido.
• QT-interval prolongation and, rarely, serious arrhythmia.
• Leukopenia, neutropenia, or (rarely) agranulocytosis, especially in the initial months of therapy.
• Cholestatic jaundice, mainly in the first months of treatment.
• Skin reactions including photosensitivity, urticaria, and rarely exfoliative dermatitis.
• Seizures (in patients with a lowered seizure threshold).

Pregnancy: Adequate, well-controlled studies of Fluphenazine in pregnant women are not available. Neonates exposed to antipsychotic drugs, including Fluphenazine, during the third trimester are at risk of extrapyramidal and/or withdrawal symptoms after delivery, including agitation, abnormally increased or decreased muscle tone, tremor, somnolence, respiratory distress, and feeding difficulty; these effects have been self-limited in some cases but have required intensive care in others. Fluphenazine should be used during pregnancy only if the potential benefit to the mother clearly justifies the potential risk to the fetus, and only under close medical supervision.

Lactation: Fluphenazine is excreted into breast milk. Because of the potential for sedation and other adverse effects in the nursing infant, and because the drug's long-acting depot formulation prolongs infant exposure once the mother is dosed, breastfeeding during Fluphenazine therapy should be discussed with a physician, weighing the benefits of breastfeeding against the potential risk to the infant.

Boxed warning

Increased mortality in elderly patients with dementia-related psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs, including Fluphenazine, are at an increased risk of death compared with placebo, most commonly from cardiovascular or infectious (e.g., pneumonia) causes. Fluphenazine is not approved for the treatment of dementia-related psychosis.

Depot-specific counseling point

Because Fluphenazine is a long-acting injectable, any adverse reaction that occurs — including extrapyramidal symptoms, allergic/hypersensitivity reactions, or neuroleptic malignant syndrome — may take substantially longer to resolve than a reaction to an oral dose of fluphenazine, since the depot cannot be rapidly removed from the body once injected. Patients and caregivers should be counselled about this before the first injection.

Tardive dyskinesia

Prolonged use of Fluphenazine may lead to tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements. Risk appears to increase with duration of treatment and total cumulative dose, and is highest in elderly patients, especially women, although it can occur (rarely) even after short-term treatment. There is no known reliable treatment for established tardive dyskinesia; the drug should be discontinued at the first sign, if clinically feasible.

Neuroleptic malignant syndrome (NMS)

A rare but potentially fatal reaction that can occur with any antipsychotic, including Fluphenazine. Signs include hyperthermia, severe muscle rigidity, altered consciousness, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac arrhythmia). Immediate discontinuation and intensive supportive treatment are required. Because of the depot formulation, recovery from NMS induced by Fluphenazine may take longer than with oral antipsychotics.

Other precautions

• QT prolongation: Use with caution in patients with cardiac disease, electrolyte disturbances, or concomitant QT-prolonging drugs.
• Seizure threshold: Fluphenazine may lower the seizure threshold; use with caution in patients with a seizure disorder or other predisposing factors.
• Orthostatic hypotension: may increase risk of falls, particularly in elderly or debilitated patients.
• Hepatic and hematologic monitoring: periodic liver function tests and complete blood counts are advisable, especially during the initial months of therapy.
• Heat exposure: Fluphenazine may impair the body's ability to reduce core temperature; avoid extreme heat exposure and strenuous activity in hot conditions.
• Driving/operating machinery: sedation and motor impairment may occur; caution patients accordingly.
• Alcohol: avoid concurrent use, as effects are potentiated.

Overdose with Fluphenazine is a medical emergency. Because it is a long-acting depot injection, toxic effects may develop and persist over an extended period compared with oral overdose, and cannot be rapidly terminated by drug removal.

Symptoms of overdose may include severe extrapyramidal reactions, deep sedation or coma, hypotension, agitation, seizures, hyperthermia or hypothermia, and cardiac arrhythmias (including QT prolongation).

If overdose is suspected, seek immediate emergency medical attention or contact a poison control center right away. Management is supportive and symptomatic, with continuous monitoring of vital signs, ECG, and airway/respiratory status, generally in a hospital setting; there is no specific antidote. Because of the prolonged depot effect, extended observation and monitoring are typically required.

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); brief excursions between 15°C and 30°C are permitted. Protect from light — keep the vial in its outer carton until use. Do not freeze. Keep out of reach of children.

Pregnant women

Use Fluphenazine during pregnancy only if the potential benefit justifies the potential risk to the fetus. Monitor neonates exposed during the third trimester for extrapyramidal or withdrawal symptoms (see Pregnancy and Lactation).

Breastfeeding women

Fluphenazine passes into breast milk; discuss the risks and benefits of breastfeeding with a physician before using Fluphenazine while nursing.

Pediatric patients

Fluphenazine is not recommended for children under 12 years of age. Safety and efficacy in the pediatric population have not been established.

Elderly patients

Elderly patients, particularly women, have a higher risk of tardive dyskinesia and are generally more susceptible to hypotension, sedation, and anticholinergic effects. Fluphenazine carries a boxed warning against use in elderly patients with dementia-related psychosis due to increased risk of death, and is not approved for this indication. Use the lowest effective dose in this population.

Hepatic impairment

Fluphenazine is contraindicated in severe liver disease; use with caution and monitor liver function in any degree of hepatic impairment.

Renal impairment

No specific dose adjustment has been established; use with caution and monitor clinical response.

Fluphenazine is intended for long-term maintenance therapy of schizophrenia. There is no fixed treatment duration — therapy is typically continued for as long as maintenance antipsychotic treatment is clinically indicated, with the dose and injection interval (commonly every 2 to 4 weeks) individualised and periodically reassessed by the treating physician based on symptom control and tolerability. Any decision to discontinue or taper should be made by the prescribing physician, since therapeutic and adverse effects of a depot injection persist for weeks after the last dose.

Phenothiazine antipsychotic (first-generation/typical antipsychotic), piperazine subgroup; long-acting depot injectable formulation.

Fluphenazine Decanoate exerts its antipsychotic effect primarily through post-synaptic blockade of dopamine D2 receptors in the mesolimbic/mesocortical pathways, reducing dopaminergic overactivity thought to underlie positive psychotic symptoms. It also has antagonist activity at alpha-1 adrenergic, histamine H1, and muscarinic cholinergic receptors, contributing to its side-effect profile. The decanoate ester formulation, delivered in an oily depot vehicle, is slowly hydrolysed to release free fluphenazine over an extended period, producing a long duration of action (roughly 2–4 weeks per injection) compared with oral fluphenazine.

Fluphenazine is not recommended for children under 12 years of age. There is no adequate clinical experience with this drug in children, and its safety and efficacy in the pediatric population have not been established. If antipsychotic treatment is required in a child or adolescent, the prescribing physician will select an appropriate agent and monitor closely for extrapyramidal symptoms, sedation, and other adverse effects, which pediatric patients may be more sensitive to than adults.