Fluphenazine

FLUPHENAZINE

General Monograph

Antipsychotic

Pharmacology: Fluphenazine is a short-acting piperazine phenothiazine. Phenothiazines are thought to elicit their antipsychotic effects via interference with central dopaminergic pathways in the mesolimbic zone of the brain. Extrapyramidal side effects are a result of interaction with dopaminergic pathways in the basal ganglia.

Fluphenazine has alpha adrenergic blocking activity and can cause orthostatic hypotension.

Compared to other phenothiazines, fluphenazine has weak anticholinergic, sedative and hypotensive activity, weak anti-emetic effects and strong extrapyramidal effects. It is the most potent of the phenothiazine antipsychotics.

Pharmacokinetics: 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 is within 1 hour; duration of action is 6 to 8 hours. The reported half-life ranges from 13 to 33 hours or more. Extensive hepatic metabolism does occur but the exact metabolic fate of fluphenazine is unclear. Metabolites and unchanged drug are excreted in urine and feces.

Esterification of fluphenazine slows its release from fatty tissue. I.M. or s.c. injection of the esters in a sesame oil base also slows their release. The clinical result is a longer duration of action. Two fluphenazine esters are commercially available in a sesame oil vehicle, fluphenazine decanoate and fluphenazine enanthate. Their onset of action is 24 to 72 hours with an average duration of action of 2 to 3 weeks.

Indications: The symptomatic management of psychotic disorders. The long-acting (depot) injectable forms of fluphenazine are most commonly used as maintenance therapy in patients who are unreliable in taking daily oral medications.

Contraindications: Fluphenazine is contraindicated in patients who have a known hypersensitivity to the drug. Cross-sensitivity between fluphenazine and other phenothiazine drugs may occur.

Fluphenazine should not be used in patients who are comatose, in patients with severe CNS depression secondary to use of CNS depressant medications and in patients with blood dyscrasias or bone marrow depression.

Phenothiazines are contraindicated in patients with suspected or established subcortical brain damage with or without hypothalamic damage, since a hyperthermic reaction with temperatures in excess of 40° C may occur in such patients, sometimes not until 14 to 16 hours after drug administration.

Warnings: The antiemetic effect of phenothiazines may mask vomiting as a sign of toxicity due to overdosage of other drugs, or may obscure the cause of vomiting in various disorders such as brain tumor, intestinal obstruction, or Reye’s syndrome.

Precautions: During the first month of therapy, routine blood counts, renal and hepatic function tests are advised as blood dyscrasias and cholestatic jaundice may occur. Renal function should be monitored in patients on long-term therapy.

Fluphenazine may cause agranulocytosis. Most reported cases of agranulocytosis associated with the administration of phenothiazine derivatives have occurred between the fourth and tenth week of treatment. Therefore, observe patients on prolonged therapy with particular care during that time for the appearance of such signs as sore throat, fever and weakness. If these symptoms appear, discontinue the drug and perform WBC and differential counts.

Fluphenazine may cause hypotension. It should be used with caution in the elderly, alcoholics and in patients with cardiovascular disease or in patients undergoing surgery. The dosage of anesthetic and CNS depressants may have to be reduced in the perioperative period. Epinephrine should not be used to treat fluphenazine-induced hypotension (see Drug Interactions).

ECG changes have been associated with the administration of phenothiazines. These changes appear to be reversible and related to a disturbance in repolarization. Use fluphenazine with caution in patients with cardiovascular disease.

Fluphenazine should be used with caution in patients who have impaired liver function or alcoholic liver disease. CNS depression may be potentiated. If bilirubinemia or icterus occurs, discontinue the drug and perform liver function tests.

Use cautiously in patients with respiratory difficulties as CNS depression may cause some respiratory failure in these patients.

Paralytic ileus resulting from the anticholinergic action of fluphenazine may occur, especially in the elderly. Administer with caution also in those patients with glaucoma or prostatic hypertrophy.

Fluphenazine may lower the seizure threshold and should be used cautiously in patients with a history of seizures.

Phenothiazines affect thermoregulation. Use fluphenazine with caution in those patients who may be exposed to extreme heat or cold.

Photosensitivity may occur. Patients should utilize sunscreens when exposed to sunlight for significant lengths of time.

Administer fluphenazine with caution to patients exposed to organophosphate insecticides.

Use with caution in patients with hypocalcemia. These individuals are more susceptible to dystonic reactions.

Phenothiazines have been associated with retinopathy. Discontinue fluphenazine if retinal changes are observed.

Phenothiazines do not produce psychogenic dependence; however, gastritis, nausea and vomiting, dizziness and tremulousness have been reported following abrupt cessation of high-dose therapy; therefore, therapy should be tapered slowly over a period of 1 to 2 weeks. Reports suggest that these symptoms can be reduced if concomitant antiparkinsonian agents are continued for several weeks after the phenothiazine is withdrawn.

Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients.

Occupational Hazards: 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.

Drug Interactions : 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.

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.

Epinephrine: Epinephrine should not be used to treat fluphenazine-induced hypotension. Fluphenazine blocks peripheral alpha-adrenergic receptors, thereby inhibiting alpha-agonist effects of epinephrine such as vasoconstriction and increased blood pressure. The beta-agonist effects of epinephrine (vasodilation) may be left unopposed and a further fall in blood pressure may result. Agents such as phenylephrine, methoxamine or norepinephrine may be suitable alternatives to raise blood pressure.

Haloperidol: Concomitant use of fluphenazine and haloperidol may increase the risk of extrapyramidal reactions.

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.

Metrizamide: Fluphenazine should not be used in patients receiving the radiopaque contrast agent metrizamide. Concomitant use increases the risk of seizures.

Pregnancy: Safe use of phenothiazines in pregnancy has not been established. Most studies indicate these agents are not teratogenic but there are reports of defects in infants exposed to these drugs during the first trimester. Toxic effects observed after high doses near term include: hypotonia, lethargy, depressed reflexes, paralytic ileus, jaundice, and persistent extrapyramidal syndrome. Therefore, they should be administered cautiously to women of childbearing potential particularly during the first trimester of pregnancy and near term.

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

Children: Safety and efficacy of fluphenazine hydrochloride in children has not been established. It is not recommended for use in pediatric patients.

Geriatrics: Use reduced dosages. Fluphenazine may adversely affect many of the conditions commonly occurring in the aged, including cardiovascular problems (especially orthostatic hypotension). The elderly may be at greater risk for developing extrapyramidal or parkinsonian symptoms, and may be more susceptible to sedation or to the anticholinergic effects (e.g., constipation, blurred vision, urinary retention, mental confusion).

Adverse Effects: Adverse effects with different phenothiazines vary in type, frequency and mechanism of occurrence, i.e., some are dose-related, while others involve individual patient sensitivity. Some adverse effects may be more likely to occur or occur with greater intensity, in patients with special medical problems, i.e., hypotension may be a particular problem in patients with pheochromocytoma or mitral insufficiency. Severe hypotension has occurred with usual dosages of phenothiazines in these patients.

In general, members of the piperazine group of phenothiazines have more marked stimulating effects, are more likely to cause motor disorders associated with extrapyramidal reactions, particularly in children, but are less likely to cause blood dyscrasias, hypotension, tachycardia, and drowsiness than the members of the other phenothiazine groups.

Not all of the following adverse reactions have been observed with every phenothiazine derivative, but they have been reported with one or more and should be borne in mind when drugs of this class are administered.

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

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

Cardiovascular: hypotension, tachycardia, ECG changes (see Precautions).

CNS: 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.

There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome. All antipsychotic agents should be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, tardive dyskinesia may be masked. The effect that masking of the symptoms may have on the long-term course of the syndrome is unknown. The physician may be able to reduce the risk of this syndrome by minimizing the unnecessary use of neuroleptics and reducing the dose or discontinuing the drug, if possible, when manifestations of this syndrome are recognized, particularly in patients over the age of 50. 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 (e.g., every 3 months) for signs and symptoms of tardive dyskinesia and the need for continued phenothiazine and/or anticholinergic therapy is recommended.

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

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

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

Genitourinary: retention, incontinence, inhibition of ejaculation, priapism.

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

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

Neuroleptic Malignant Syndrome: As with other neuroleptic drugs, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported. 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 neuroleptic treatment.

Ophthalmologic: 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.

Miscellaneous: 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.

tag_OverdoseOverdose: Symptoms: Symptoms of fluphenazine overdosage are related to 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. Other symptoms may include: tachycardia, cardiac arrhythmias, seizures, miosis, hypothermia and respiratory and/or vasomotor collapse.

Treatment: Empty stomach using gastric lavage. Administer one dose of activated charcoal and a saline cathartic. Support respiratory and cardiac functions as needed. Maintain fluid and electrolyte balance. Treat hypotension with i.v. fluids and by placing the patient in the Trendelenburg position. If unresponsive, dopamine or norepinephrine may be required. Do not use epinephrine (see Precautions, Drug Interactions). Seizures may be treated with i.v. diazepam or lorazepam. If seizures are uncontrolled or recur, use i.v. phenobarbital or phenytoin. Treat arrhythmias with phenytoin. Extrapyramidal reactions may be treated with i.v. diphenhydramine or benztropine followed by maintenance therapy for 48 hours. Manage hypothermia with external warming. Hemodialysis is of little value in enhancing elimination of phenothiazines.

Dosage: Oral: Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response. Patients on long-term therapy should be evaluated periodically to evaluate the need for continued therapy.

Initial Dose for Adults: 2.5 to 10 mg daily in divided doses every 6 to 8 hours. Doses greater than 20 mg should be used with caution. Dosages up to 40 mg have been used in severe cases.

Maintenance: When satisfactory improvement has been achieved, dosage should be gradually reduced to the lowest dose that will maintain relief of symptoms. The usual maintenance dose is 1 to 5 mg daily as a single dose.

Geriatrics: 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 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.

The usual adult dose of fluphenazine enanthate is 25 mg i.m. or s.c. every 2 weeks.

FLUPHENAZINE General Monograph Antipsychotic

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