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Fluphenazine


Pronunciation

 (floo FEN a zeen)


U.S. Brand Names

 Prolixin® [DSC]; Prolixin Decanoate®


Synonyms

 Fluphenazine Decanoate


Generic Available

 Yes: Injection, tablet


Canadian Brand Names

 Apo-Fluphenazine®; Apo-Fluphenazine Decanoate®; Modecate®; Moditen® Enanthate; Moditen® HCl; PMS-Fluphenazine Decanoate


Use

 Management of manifestations of psychotic disorders and schizophrenia; depot formulation may offer improved outcome in individuals with psychosis who are nonadherent with oral antipsychotics


Use - Unlabeled/Investigational

 Pervasive developmental disorder


Pregnancy Risk Factor

 C


Lactation

 Enters breast milk/not recommended


Contraindications

 Hypersensitivity to fluphenazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression; coma; subcortical brain damage; blood dyscrasias; hepatic disease


Warnings/Precautions

 May be sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; bone marrow suppression; predisposition to seizures; severe cardiac, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (ie, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines. Hypotension may occur, particularly with I.M. administration. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose). Adverse effects of depot injections may be prolonged.

Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention). Therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other antipsychotics, fluphenazine has a low potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia and tardive dyskinesia (risk of these reactions is high relative to other antipsychotics). May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy.


Adverse Reactions

 Frequency not defined.

Cardiovascular: Tachycardia, fluctuations in blood pressure, hyper-/hypotension, arrhythmia, edema

Central nervous system: Parkinsonian symptoms, akathisia, dystonias, tardive dyskinesia, dizziness, hyper-reflexia, headache, cerebral edema, drowsiness, lethargy, restlessness, excitement, bizarre dreams, EEG changes, depression, seizure, NMS, altered central temperature regulation

Dermatologic: Dermatitis, eczema, erythema, itching, photosensitivity, rash, seborrhea, skin pigmentation, urticaria

Endocrine & metabolic: Changes in menstrual cycle, breast pain, amenorrhea, galactorrhea, gynecomastia, libido (changes in), prolactin increased, SIADH

Gastrointestinal: Weight gain, loss of appetite, salivation, xerostomia, constipation, paralytic ileus, laryngeal edema

Genitourinary: Ejaculatory disturbances, impotence, polyuria, bladder paralysis, enuresis

Hematologic: Agranulocytosis, leukopenia, thrombocytopenia, nonthrombocytopenic purpura, eosinophilia, pancytopenia

Hepatic: Cholestatic jaundice, hepatotoxicity

Neuromuscular & skeletal: Trembling of fingers, SLE, facial hemispasm

Ocular: Pigmentary retinopathy, cornea and lens changes, blurred vision, glaucoma

Respiratory: Nasal congestion, asthma


Overdosage/Toxicology

 Symptoms of overdose include deep sleep, hypo- or hypertension, dystonia, seizures, extrapyramidal symptoms, and respiratory failure. Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated.


Drug Interactions

 Substrate of CYP2D6 (major); Inhibits CYP1A2 (weak), 2C8/9 (weak), 2D6 (weak), 2E1 (weak)

Aluminum salts: May decrease the absorption of phenothiazines; monitor

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms. Avoid concurrent use

Anticholinergics: May inhibit the therapeutic response to phenothiazines and excess anticholinergic effects may occur; includes benztropine, trihexyphenidyl, biperiden, and drugs with significant anticholinergic activity (TCAs, antihistamines, disopyramide)

Antihypertensives: Concurrent use of phenothiazines with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Bromocriptine: Phenothiazines inhibit the ability of bromocriptine to lower serum prolactin concentrations

CNS depressants: Sedative effects may be additive with phenothiazines; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

CYP2D6 inhibitors: May increase the levels/effects of fluphenazine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Epinephrine: Chlorpromazine (and possibly other low potency antipsychotics) may diminish the pressor effects of epinephrine

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by phenothiazines

Levodopa: Phenothiazines may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Lithium: Phenothiazines may produce neurotoxicity with lithium; this is a rare effect

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Phenytoin: May reduce serum levels of phenothiazines; phenothiazines may increase phenytoin serum levels

Propranolol: Serum concentrations of phenothiazines may be increased; propranolol also increases phenothiazine concentrations

Polypeptide antibiotics: Rare cases of respiratory paralysis have been reported with concurrent use of phenothiazines

QTc-prolonging agents: Effects on QTc interval may be additive with phenothiazines, increasing the risk of malignant arrhythmias; includes type Ia antiarrhythmics, TCAs, and some quinolone antibiotics (sparfloxacin, moxifloxacin and gatifloxacin)

Sulfadoxine-pyrimethamine: May increase phenothiazine concentrations

Tricyclic antidepressants: Concurrent use may produce increased toxicity or altered therapeutic response

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

Valproic acid: Serum levels may be increased by phenothiazines


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization). Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).


Stability

 Avoid freezing; protect all dosage forms from light; clear or slightly yellow solutions may be used; should be dispensed in amber or opaque vials/bottles. Solutions may be diluted or mixed with fruit juices or other liquids but must be administered immediately after mixing; do not prepare bulk dilutions or store bulk dilutions.


Compatibility

 Compatibility in syringe: Compatible: Benztropine, diphenhydramine, hydroxyzine


Mechanism of Action

 Fluphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones; believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis


Pharmacodynamics/Kinetics

Onset of action: I.M., SubQ (derivative dependent): Hydrochloride salt: ~1 hour

Peak effect: Neuroleptic: Decanoate: 48-96 hours

Duration: Hydrochloride salt: 6-8 hours; Decanoate: 24-72 hours

Absorption: Oral: Erratic and variable

Distribution: Crosses placenta; enters breast milk

Protein binding: 91% and 99%

Metabolism: Hepatic

Half-life elimination (derivative dependent): Hydrochloride: 33 hours; Decanoate: 163-232 hours

Excretion: Urine (as metabolites)


Dosage

Children: Oral: Childhood-onset pervasive developmental disorder (unlabeled use): 0.04 mg/kg/day

Adults: Psychoses:

Oral: 0.5-10 mg/day in divided doses at 6- to 8-hour intervals; some patients may require up to 40 mg/day

I.M.: 2.5-10 mg/day in divided doses at 6- to 8-hour intervals (parenteral dose is 1 /3 to 1 /2 the oral dose for the hydrochloride salts)

I.M. (decanoate): 12.5 mg every 2 weeks

Conversion from hydrochloride to decanoate I.M. 0.5 mL (12.5 mg) decanoate every 3 weeks is approximately equivalent to 10 mg hydrochloride/day

Hemodialysis: Not dialyzable (0% to 5%)


Administration

 Avoid contact of oral solution or injection with skin (contact dermatitis). Oral liquid should be diluted in the following only : Water, saline, homogenized milk, carbonated orange beverages, pineapple, apricot, prune, orange, tomato, and grapefruit juices. Do not dilute in beverages containing caffeine, tannics, or pectinate. Watch for hypotension when administering I.M.


Monitoring Parameters

 Vital signs; lipid profile, fasting blood glucose/Hgb A1c; BMI; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS)


Reference Range

 Therapeutic: 5-20 ng/mL; correlation of serum concentrations and efficacy is controversial; most often dosed to best response


Patient Education

 Use exactly as directed; do not increase dose or frequency. Do not discontinue without consulting prescriber. Dilute with water, milk, orange or grapefruit juice; do not dilute with beverages containing caffeine, tannin, or pectinate (eg, coffee, colas, tea, or apple juice). Do not take within 2 hours of any antacid. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Avoid skin contact with medication; may cause contact dermatitis (wash immediately with warm, soapy water). Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience excess drowsiness, lightheadedness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); dry mouth, upset stomach, nausea, vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruits, or fiber may help); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); urinary retention (void before taking medication); ejaculatory dysfunction (reversible); decreased perspiration (avoid strenuous exercise in hot environments); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); chest pain, palpitations, rapid heartbeat, severe dizziness; unresolved urinary retention or changes in urinary pattern; altered menstrual pattern, change in libido, swelling or pain in breasts (male or female); vision changes; skin rash or irritation or yellowing of skin; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.


Additional Information

 Less sedative and hypotensive effects than chlorpromazine.


Anesthesia and Critical Care Concerns/Other Considerations

 Less sedative and hypotensive effects than chlorpromazine


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Xerostomia and increased salivation (normal salivary flow resumes upon discontinuation). Orthostatic hypotension and nasal congestion are possible and since the drug is a dopamine antagonist, extrapyramidal symptoms of the TMJ are a possibility.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called "epinephrine reversal" phenomenon. This has never been observed when epinephrine is given by infiltration as part of the anesthesia procedure.


Mental Health: Child/Adolescent Considerations

 Twelve hospitalized children 7-11 years of age with childhood-onset pervasive developmental disorder received haloperidol or fluphenazine at an average dose of 0.04 mg/kg/day (Joshi, 1988).

Joshi PT, Capozzoli JA, and Coyle JT, "Low-Dose Neuroleptic Therapy for Children With Childhood-Onset Pervasive Developmental Disorder," Am J Psychiatry , 1988, 145(3):335-8.


Dosage Forms

 [DSC] = Discontinued product

Elixir, as hydrochloride (Prolixin®): 2.5 mg/5 mL (60 mL) [contains alcohol 14% and sodium benzoate] [DSC]

Injection, oil, as decanoate: 25 mg/mL (5 mL) [may contain benzyl alcohol, sesame oil]

Prolixin Decanoate®: 25 mg/mL (5 mL) [contains benzyl alcohol, sesame oil]

Injection, solution, as hydrochloride (Prolixin® [DSC]): 2.5 mg/mL (10 mL)

Solution, oral concentrate, as hydrochloride (Prolixin®): 5 mg/mL (120 mL) [contains alcohol 14%] [DSC]

Tablet, as hydrochloride: 1 mg, 2.5 mg, 5 mg, 10 mg

Prolixin®: 1 mg, 2.5 mg, 5 mg [contains tartrazine], 10 mg [DSC]


References

Cheung HK and Yu EC, "Effect of 1050 mg Fluphenazine Decanoate Given Intramuscularly Over Six Days," Br Med J (Clin Res Ed) , 1983, 286(6370):1016-7.

Fishbain DA, "Priapism Resulting From Fluphenazine Hydrochloride Treatment Reversed by Diphenhydramine," Ann Emerg Med , 1985, 14(6):600-2.

Joshi PT, Capozzoli JA, and Coyle JT, "Low-Dose Neuroleptic Therapy for Children With Childhood-Onset Pervasive Developmental Disorder," Am J Psychiatry , 1988, 145(3):335-8.

Oshika T, "Ocular Adverse Effects of Neuropsychiatric Agents. Incidence and Management," Drug Saf , 1995, 12(4):256-63.

Peabody CA, Warner MD, Whiteford HA, et al, "Neuroleptics and the Elderly," J Am Geriatr Soc , 1987, 35(3):233-8.

Risse SC and Barnes R, "Pharmacologic Treatment of Agitation Associated With Dementia," J Am Geriatr Soc , 1986, 34(5):368-76.

Saltz BL, Woerner MG, Kane JM, et al, "Prospective Study of Tardive Dyskinesia Incidence in the Elderly," JAMA , 1991, 266(17):2402-6.

Seifert RD, "Therapeutic Drug Monitoring: Psychotropic Drugs," J Pharm Pract , 1984, 6:403-16.


International Brand Names

 Anatenazine® (JP); Anatensol® (AU, CN, ID, IN, IT, NL, PT); Apo-Fluphenazine® (CA); Apo-Fluphenazine Decanoate® (CA); Dapotum® (AT, CH, DE); Dapotum D® [inj.] (CH, DE); Deca® (TH); Decazate® (GB); Fludecate® (CL, IL, ZA); Flufenan® (BR); Flufenan Depot® (BR); Flufenazina® (CL); Flufenazina Decanoato® (CL); Flufenazin Dekanoat Squibb® (DK); Flufenazin® (YU); Flunanthate® (IL); Fluphenazine DBL® (BD, SG); Fluphenazine Decanoate® (AU, GB, NZ, TR); Fluphenazin-neuraxpharm D® (DE); Fluphenazin Strallhofer® (AT); Fluzine-P® (TH); Lyogen Depot® (DE); Lyogen® (DE, RO, SI, YU); Lyogen-retard® (HR); Lyorodin Depot® (DE); Lyorodin® (DE, RO); Metoten® (YU); Mirenil® (PL, RO); Mirenil Retard® (RO); Modecate® (AU, CA, CL, CN, ES); Modécate® (FR); Modecate® (GB, ID, IE, NZ, SG, ZA); Moditen Action Prolongée® (FR); Moditen® (CZ, FR, GB, HR, SI, TR, YU); Moditen decanoate® (CZ); Moditen-Depo® (HU, RU); Moditen Depot® (CZ, IT); Moditen® Enanthate (CA); Moditen® HCl (CA); Motival® (IE); Omca® (DE); Pacinol® (DK, FI, SE); Pharnazine® (TH); PMS-Fluphenazine Decanoate (CA); Potensone® (TH); Prolinate® (RU); Prolixin® (CO, TR); Seditin® (IL); Selecten® (IL); Sevinol® (BE, LU); Siqualone Decanoat® (FI, NO); Siqualone decanoat® (SE); Siqualone® (DK, NO, SE)


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