Fluphenazine

Rapid absorption occurs following oral or i.m. administration. Fluphenazine is distributed into most body tissues. It is highly bound to plasma proteins. Onset of action for oral doses and non-depot injections is ≤ 1 hour; duration of action is 6 to 8 hours. The reported half-life ranges from 13 to 33 hours or more.

Fluphenazine is a substrate and inhibitor of the cytochrome P450 isoenzyme, CYP2D6.

Fluphenazine decanoate, a fluphenazine ester, is available in an injectable, sesame oil–based formulation. Both esterification and the oil-based vehicle slow the release of fluphenazine from tissues after i.m. or s.c. injection, resulting in a longer duration of action. The onset of action of fluphenazine decanoate is 24 to 72 hours and the average duration of action is 3 to 4 weeks.

Use reduced dosages. Older patients may be at greater risk for developing extrapyramidal or parkinsonian symptoms, and may be more susceptible to sedation or to the anticholinergic effects of phenothiazines (e.g., constipation, blurred vision, urinary retention, cognitive impairment).

As a substrate and inhibitor of the cytochrome P450 isoenzyme, CYP2D6, fluphenazine may interact with inducers or other inhibitors or substrates of CYP2D6. For more information, see Cytochrome P450 Drug Interactions in the Clin-Info section.

Anticonvulsants: Fluphenazine may lower the seizure threshold. Dosage adjustment of anticonvulsants may be necessary.

Anticholinergics: Anticholinergic drugs such as antihistamines, antiparkinsonian drugs, atropine, MAO inhibitors and tricyclic antidepressants may have additive anticholinergic effects when administered with fluphenazine. Concomitant use of these drugs may increase the predisposition of patients treated with phenothiazines to heat stroke and paralytic ileus.

Antidepressants, Tricyclic: Concomitant use of fluphenazine and tricyclic antidepressants may result in increased plasma concentrations of both drugs, with additive anticholinergic, sedative and hypotensive effects. The risk of neuroleptic malignant syndrome may also be increased.

Antihypertensives: Concomitant use of fluphenazine and antihypertensives may result in additive hypotensive effects and an increase risk of orthostatic hypotension or syncope.

Antipsychotics: The use of fluphenazine with other antipsychotics, particularly with other first-generation agents, may increase the risk of extrapyramidal side effects.

Antithyroid Agents: Concomitant use of fluphenazine and antithyroid agents such as methimazole and propylthiouracil may increase the risk of agranulocytosis.

CNS Depressants: Fluphenazine may enhance the CNS depressant effects of drugs including alcohol, anticonvulsants, antihistamines, barbiturates, benzodiazepines, MAO inhibitors, narcotic analgesics and tricyclic antidepressants. Monitor to avoid excessive sedation or respiratory depression.

CYP2D6 Inducers: may decrease fluphenazine levels (e.g., carbamazepine, phenobarbital, phenytoin). For more information see Cytochrome P450 Drug Interactions in the Clin-Info section.

CYP2D6 Inhibitors: may increase fluphenazine levels, pharmacologic effects and toxicity (e.g., amiodarone, celecoxib, chloroquine, cimetidine, codeine, fluoxetine, imatinab, methadone, moclobemide, paroxetine, quinidine, sertraline). For more information see Cytochrome P450 Drug Interactions in the Clin-Info section.

Levodopa: Fluphenazine may inhibit the antiparkinsonian effects of levodopa as a result of its dopamine blocking effects in the CNS.

Lithium: Patients receiving lithium and fluphenazine for treatment of acute mania should be monitored closely for signs of adverse neurologic effects, especially if serum concentrations of lithium are in the upper range. Rare cases of severe neurotoxicity have been reported.

Metoclopramide: Concomitant use of fluphenazine and metoclopramide may increase the risk of extrapyramidal reactions.

Patients should be warned that mental and physical abilities required for driving a car or operating heavy machinery may be impaired. Potentiation of the effects of alcohol may also occur.

Phenothiazines are distributed into breast milk. Use with caution during lactation because of the possible sedative and anticholinergic side effects in the infant.

Safety and efficacy of fluphenazine in children under 12 years of age has not been established.

Phenothiazines readily cross the placenta. They are generally considered to pose no teratogenic risk and to be relatively safe to use during pregnancy, when considered necessary for the treatment of pyschotic disorders. It is generally recommended that they be avoided late in the 3^rd trimester if possible, to avoid adverse effects on the fetus.

retention, incontinence, inhibition of ejaculation, priapism.

anorexia, increased appetite, gastric irritation, nausea, vomiting, constipation, paralytic ileus.

agranulocytosis, leukopenia, granulocytopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia.

oversedation; impaired psychomotor function; paradoxical effects, such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms; toxic confusional states.

As with other antipsychotics, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported with fluphenazine. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure). Additional signs may include elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure. NMS is potentially fatal, requires intensive symptomatic treatment and immediate discontinuation of antipsychotic therapy.

Sudden unexpected and unexplained deaths have been reported in patients receiving phenothiazines, especially during long-term administration of the drugs. In some cases, the death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxia due to failure of the cough reflex. In some patients, the cause could not be determined nor could it be established that the death was due to the phenothiazine.

dry mouth, fainting, stuffy nose, photophobia, blurred vision, miosis, constipation, ileus, salivation, impaired temperature regulation, headache.

extrapyramidal reactions, including pseudoparkinsonism (with motor retardation, rigidity, mask-like facies, pill rolling and other tremors, drooling, shuffling gait,); dystonic reactions (including perioral spasms, and trismus, tics, torticollis, oculogyric crises, protrusion of the tongue, difficulty swallowing, carpopedal spasm and opisthotonos of the back muscles); and akathisia. Persistent dyskinesias resistant to treatment have been reported, particularly in elderly patients with previous brain damage. In addition, altered EEG tracings, disturbed body temperature and lowering of the convulsive threshold have occurred. Dizziness has been reported.

Tardive dyskinesia may appear in some patients on long-term antipsychotic therapy or may appear after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females; it appears that longer durations of therapy and the cumulative dose received may also increase risk. Anticholinergic drugs tend to worsen the symptoms. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities.

All antipsychotic agents should be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, increase the dosage of the agent, or switch to a different antipsychotic agent, tardive dyskinesia may be masked. Fine vermicular movements of the tongue may be an early sign of the syndrome. If the medication is stopped at that time, the syndrome may not develop. Periodic assessment for signs and symptoms of tardive dyskinesia and the need for continued phenothiazine and/or anticholinergic therapy is recommended.

increased prolactin secretion; altered libido, menstrual irregularities, lactation, false positive pregnancy tests, gynecomastia, weight gain.

A skin-eye syndrome has been described following long-term treatment with phenothiazines. This reaction is marked by progressive pigmentation of areas of skin or conjunctiva and/or discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have been reported. Patients expected to receive higher doses of phenothiazines for prolonged periods should have complete eye examinations at baseline and every 6 to 12 months.

itching, rash, hypertrophic papillae of the tongue, angioneurotic edema, erythema, allergic purpura, exfoliative dermatitis, contact dermatitis, skin-eye syndrome (see Ophthalmologic).

cholestatic jaundice; symptoms generally subside following discontinuance of the drug, but cholestasis may be prolonged.

hypotension, tachycardia, ECG changes (see Precautions).

Symptoms of fluphenazine overdosage are an extension of its pharmacologic action. The primary symptoms observed are severe extrapyramidal reactions, hypotension and sedation. Mild or early intoxication may cause restlessness, confusion and excitement. CNS sedation may progress to coma. Disturbed temperature regulation can occur; both hypo- and hyperthermia have been reported. Neuroleptic malignant syndrome can occur in overdose or with therapeutic doses (see Adverse Effects). Other symptoms may include: tachycardia, cardiac arrhythmias, seizures, miosis, and respiratory and/or vasomotor collapse.

Patients who have ingested fluphenazine in overdose occasionally require respiratory and hemodynamic support. This may include intubation, ventilation, boluses of isotonic i.v. fluids, and inotropic support. Patients who seize should be treated with benzodiazepines. Ventricular arrhythmias are uncommon, and should be treated with boluses of sodium bicarbonate as well as conventional arrhythmics such as lidocaine. In the rare patient with torsades de pointes, i.v. magnesium sulfate and/or a pacemaker should be used. Once the patient's airway is adequately protected, 1 dose of activated charcoal can be administered to minimize absorption of orally ingested fluphenazine. Extrapyramidal reactions may be treated with i.v. benztropine or diphenhydramine.

In general, lower dosages are recommended: 1 to 2.5 mg as an initial dose.

Parenteral: Fluphenazine hydrochloride may be given i.m. or s.c. It is not for i.v. use. The i.m. dose of fluphenazine is approximately one-half to one-third the oral dose. The patient should be switched to oral therapy once symptoms are controlled.

Initial Dose for Adults: 1.25 mg. Doses may range from 2.5 mg to 10 mg in divided doses every 6 to 8 hours. Doses greater than 10 mg should be used with caution.

Depot: For maintenance therapy, in patients who have been stabilized on oral fluphenazine therapy and may benefit from switching to long-acting injections because of poor compliance or other reasons. A precise formula for converting patients from oral to depot therapy has not been established. It has been proposed that fluphenazine decanoate 12.5 mg every 3 weeks is approximately equivalent to an oral fluphenazine HCl dosage of 10 mg daily.

The usual adult dose of fluphenazine decanoate in the management of chronic schizophrenia is 12.5 to 25 mg i.m. or s.c. every 2 to 3 weeks. The duration of effect may be longer in some patients.