Moditen HCl (Fluphenazine HCl)

MODITEN® HCl

Squibb

Fluphenazine HCl

Antipsychotic

Action And Clinical Pharmacology: Fluphenazine hydrochloride exerts activity at various levels of the CNS as well as on peripheral organ systems, which accounts for its antipsychotic action and side effects. Indirect evidence indicates that the antipsychotic effects of phenothiazines are linked to their effect in blocking dopamine and other catecholamine receptor sites.

Fluphenazine has less potentiating effect on CNS depressants and anesthetics and appears to be less sedating than some other phenothiazines. While hypotension may occur less frequently than with other phenothiazines, appropriate precautions should be observed when using fluphenazine hydrochloride (see Precautions). Fluphenazine, however, is among the group of phenothiazines which exhibits a greater propensity for producing extrapyramidal reactions.

Indications And Clinical Uses: For the management of manifestations of psychotic disorders not associated with mental retardation.

Contra-Indications: In patients with suspected or established subcortical brain damage with or without hypothalamic damage, since hyperthermic reactions with temperatures above 40°C may occur, sometimes not until 14 to 16 hours after drug administration; patients receiving large doses of hypnotics, due to the possibility of potentiation; comatose or severely depressed states, and in the presence of blood dyscrasias, bone marrow depression or liver damage; patients who have shown hypersensitivity to fluphenazine. Cross-sensitivity reactions to other phenothiazine derivatives may occur; patients with pheochromocytoma, cerebrovascular or renal insufficiency, or severe cardiac reserve deficiency, such as mitral insufficiency, or in patients who have exhibited idiosyncrasy to other centrally-acting drugs, as these patients may experience severe reactions to phenothiazine compounds and are particularly prone to hypotensive reactions.

Manufacturers’ Warnings In Clinical States: Insidious severe adverse reactions requiring immediate medical attention may occur. Therefore, the evaluation of tolerance and response, and establishment of adequate maintenance therapy require careful stabilization of each patient under continuous, close medical observation and supervision.

Potentiation of CNS depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) may occur.

The antiemetic effect of phenothiazines can obscure signs of toxicity due to overdosage of other drugs, or mask the symptoms of disease such as brain tumor or intestinal obstruction.

Occupational Hazards: Mental and physical abilities required for driving a car or operating heavy machinery may be impaired.

Pregnancy: Safety during pregnancy has not been established. The drug should not be administered to women of childbearing potential, and particularly during the first trimester unless, in the opinion of the physician, the expected benefits outweigh the potential risks to the fetus.

Children: Safety and efficacy of fluphenazine hydrochloride in children have not been established, therefore it is not recommended for use in the pediatric age group.

Precautions: Phenothiazines should be used with caution in patients with a history of convulsive disorders since grand mal seizures have been known to occur.

During the first months of therapy, routine blood counts, renal and hepatic function tests are advised as blood dyscrasias and liver damage, manifested by cholestatic jaundice, may occur. Renal function should be monitored in patients on long term therapy; if BUN becomes abnormal, treatment should be discontinued.

Because of the possibility of cross-sensitivity, fluphenazine hydrochloride should be used with caution in patients who have developed cholestatic jaundice, dermatoses or other allergic reactions to phenothiazine derivatives.

Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. 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. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.

Hypotensive phenomena may develop in psychotic patients treated with large doses of phenothiazines who are undergoing surgery. Careful observation is necessary and it should be remembered that the dosage of anesthetics and CNS depressants may have to be reduced.

Hypotension, which is typically orthostatic, may occur especially in elderly and alcoholic patients. This effect may be additive with other agents that cause a lowering of blood pressure. Fluphenazine hydrochloride may also block the antihypertensive action of guanethidine and similar compounds. Avoid epinephrine in the treatment of phenothiazine induced hypotension because phenothiazines may reverse the action of epinephrine and thereby cause a further decrease in blood pressure.

Hypotension and ECG changes have been associated with the administration of phenothiazines, therefore fluphenazine hydrochloride should be used with caution in patients with cardiovascular or cerebrovascular disorders.

Exercise caution in patients with special medical disorders, such as mitral insufficiency or pheochromocytoma.

Agranulocytosis has been observed with phenothiazines, usually between the fourth and tenth week of treatment. Patients on long-term therapy should be observed with particular care during this period and the drug should be discontinued and WBC and differential counts obtained if the patient develops sore throat, fever, and/or weakness.

The effects of atropine or other drugs with similar action may be potentiated in patients receiving phenothiazines because of added anticholinergic effects.

Paralytic ileus, even resulting in death, may occur, especially in the elderly. This possibility should be kept in mind and appropriate measures should be taken if constipation develops.

Exercise caution in patients exposed to extreme heat or phosphorus insecticides, or with a history of ulcer disease.

The possibility of liver damage, pigmentary retinopathy, lenticular and corneal deposits and the development of irreversible dyskinesia should be borne in mind when patients are on prolonged therapy.

Phenothiazines do not produce psychic dependence; however, gastritis, nausea and vomiting, dizziness and tremulousness have been reported following abrupt cessation of high dose therapy. Reports suggest that these symptoms can be reduced if concomitant antiparkinsonian agents are continued for several weeks after the phenothiazine is withdrawn.

The physician should be alert to the possible development of silent pneumonias in patients under treatment with phenothiazines.

The occasional increase in activity resulting from treatment may augment the severity of pain in angina pectoris patients. Such patients should be observed carefully and the drug withdrawn if necessary.

Adverse Reactions: CNS: Most frequently reported are extrapyramidal symptoms including pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyperreflexia. Fluphenazine produces a higher incidence of extrapyramidal reactions than the less potent piperazine derivatives or the straight chain phenothiazines, such as chlorpromazine. Extrapyramidal reactions tend to occur in the first few days following an injection and the patient should be forewarned and reassured. These reactions are often dose related and tend to subside when the dose is reduced or the drug temporarily withdrawn. Antiparkinsonian medication (such as benztropine mesylate, USP or i.v. caffeine and sodium benzoate injection, USP) may be required to control serious reactions. Drowsiness or lethargy, if they occur, may necessitate a reduction in dosage; the induction of a catatonic like state has been known to occur with dosages in excess of the recommended amounts. Reactivation or aggravation of psychotic processes may be encountered. In some patients phenothiazine derivatives have been known to cause restlessness, excitement, or bizarre dreams.

Persistent Tardive Dyskinesia: May appear in some patients on long-term therapy or after drug therapy has been discontinued. The risk seems to be greater in elderly patients on high dose therapy, especially females. 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). These may be accompanied by involuntary movements of the extremities. Evidence indicates that persistent tardive dyskinesias result from heavy drug overloading of the extrapyramidal system. The lowest effective dose should be used. There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. If it is necessary to reinstitute treatment, increase the dosage of the agent, or change the antipsychotic agent, the syndrome may be masked. The physician may lessen the risk of the syndrome’s occurrence by restricting the use of neuroleptic drugs, reducing the dose, or discontinuing the drug, when possible, particularly in patients over the age of fifty. Fine vermicular movements of the tongue may be an early sign of the syndrome and if the medication is stopped at that time, the syndrome may not develop.

Autonomic Nervous System: Hypotension, hypertension and fluctuations in blood pressure have been reported with phenothiazines. Patients with pheochromocytoma, cerebrovascular or renal insufficiency, or a severe cardiac reserve deficiency such as mitral insufficiency, are prone to hypotensive reactions with phenothiazine compounds, and should therefore be observed closely when the drug is administered. If severe hypotension should occur, supportive measures, including the use of i.v. vasopressor drugs, should be instituted immediately. Levarterenol bitartrate injection, USP, is the drug of choice; epinephrine should not be used since phenothiazine derivatives can reverse its action, resulting in a further lowering of blood pressure.

Nausea, anorexia, salivation, polyuria, perspiration, dry mouth, headache, and constipation may occur. Autonomic effects can usually be controlled by reducing dosage or temporarily discontinuing treatment.

In some patients, blurred vision, glaucoma, bladder paralysis, fecal impaction, paralytic ileus, tachycardia, or nasal congestion have occurred.

Metabolic and Endocrine: Weight change, peripheral edema, abnormal lactation, gynecomastia, menstrual irregularities, false pregnancy test results, impotency in men and increased libido in women have all been known to occur in some patients on phenothiazine therapy.

Allergic: Skin disorders such as itching, hypertrophic papillae of the tongue, angioneurotic edema, contact dermatitis, allergic purpura, erythema, urticaria, seborrhea, photosensitivity, eczema and exfoliative dermatitis have been reported. Fevers, laryngeal edema, and asthma have also been reported. The possibility of anaphylactoid reactions, occurring in some patients, should be borne in mind.

Hematologic: Leukopenia, agranulocytosis, thrombocytopenic or non-thrombocytopenic purpura, eosinophilia, anemia, granulocytopenia and pancytopenia have been observed. If any soreness of the mouth, gums, or throat or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.

Hepatic: Treatment should be discontinued if liver damage (as manifested by cholestatic jaundice) occurs, particularly during the first months of therapy. An increase in cephalin flocculation, sometimes accompanied by alterations in other liver function tests, has been reported in patients receiving the enanthate ester of fluphenazine (a closely related compound). They have had no clinical evidence of liver damage.

Others: Sudden, unexpected and unexplained deaths have been reported in hospitalized psychotic patients receiving phenothiazines. Previous brain damage or seizures may be predisposing factors; high doses should be avoided in known seizure patients. Several patients have shown flareup of psychotic behaviour patterns shortly before death. Autopsy findings have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents or intramyocardial lesions.

The following adverse reactions have also occurred with phenothiazine derivatives: systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered ECG and EEG tracings, altered CSF proteins, cerebral edema. Skin pigmentation, and lenticular and corneal opacities have been seen with long-term use.

Symptoms And Treatment Of Overdose: Symptoms: Manifested as extrapyramidal signs, hypotension and sedation. Initial hospitalization may be required in cases of large overdose and close medical supervision should be maintained throughout the duration of drug action.

Treatment: Supportive and symptomatic: the drug should be discontinued until the patient shows signs of relapse and treatment may be reinstituted at lower doses. In severe cases of oral overdosing vomiting should be induced or gastric lavage instituted if the patient is conscious. An airway should be maintained. Severe hypotension calls for the immediate use of an i.v. vasopressor drug, such as levarterenol bitartrate U.S.P. Epinephrine should not be used, as a further lowering of blood pressure may result. Extrapyramidal symptoms may be treated with antiparkinsonian agents.

Dosage And Administration: The smallest amount of drug that will produce the desired results must be carefully determined for each individual since optimal dosage levels of this potent drug vary from patient to patient.

Adults: Depending on severity and duration of symptoms, total daily oral dose for psychotic patients may range initially from 2.5 to 10 mg, administered in divided doses every 6 to 8 hours. Treatment is best instituted with a low initial dosage, which may be increased, if necessary, until the desired clinical effects are achieved. Oral doses exceeding 20 mg daily should be used with caution.

When symptoms are controlled, dosage can generally be reduced gradually to daily oral maintenance doses of 1.0 or 5.0 mg, often given as a single daily dose. Continued treatment is needed to achieve maximum therapeutic benefits; further adjustments in dosage may be necessary during the course of therapy to meet the patient’s requirements.

Geriatrics: The suggested starting dose is 1.0 to 2.5 mg orally/day, adjusted according to the response of the patient. Fluphenazine enanthate or fluphenazine decanoate, both long acting injectables may be a better alternative to oral fluphenazine hydrochloride when patients are unable or unwilling to take oral therapy.

Availability And Storage: Each sugar-coated, coral tablet contains: fluphenazine hydrochloride 10 mg. Nonmedicinal ingredients: acacia, calcium carbonate, castor oil, cornstarch, D&C red No. 27, ethyl cellulose, FD&C yellow No. 5, gelatin, lactose, magnesium carbonate, magnesium stearate, pharmaceutical glaze, povidone, printing ink, sodium benzoate, sucrose, talc and titanium dioxide. Bottles of 100. Store at room temperature, keep tightly closed, protect from light, and avoid excessive heat. (Shown in Product Recognition Section)

MODITEN® HCl Squibb Fluphenazine HCl Antipsychotic

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