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Tablet: 1mg pink (approximately 7mm diameter) and 5mg green (approximately 9mm diameter); sugar coated.
Anatensol is the hydrochloride salt of fluphenazine. It is a highly potent antipsychotic agent with activity at all levels of the central nervous system as well as on multiple organ systems. The basic effects of fluphenazine hydrochloride appear to be no different from those of fluphenazine decanoate (Modecate). The only exception is that the esterification of fluphenazine with decanoic acid markedly prolongs the drug's duration of effect without reducing its activity. Like all phenothiazine derivatives, fluphenazine hydrochloride appears to act on the hypothalamus, depressing various components of the mesodiencephalic activating system which is involved in the control of basal metabolism and body temperature, wakefulness, vasomotor tone, emesis, and hormonal balance. In addition, the phenothiazines exert a peripheral autonomic affect to varying degrees. However, the site and mode of action of the phenothiazines have not been completely elucidated.
As with all antipsychotic medications, fluphenazine is characterised by inter-individual variability in pharmacokinetics, most marked with the oral preparations.
Fluphenazine is extensively metabolized, undergoing "first pass" metabolism by the liver, and is excreted in both the urine and faeces. The degree of antipsychotic activity of the metabolites is still unknown. Fluphenazine is highly protein-bound (greater than 90%) in plasma. With oral or IM fluphenazine HCl, peak plasma/serum levels are attained within a few hours. The serum half-life of intramuscular and oral fluphenazine HCl is approximately 15 hours. Phenothiazines cross the blood-brain barrier, cross the placenta easily, and cannot be removed by dialysis. It is not known whether fluphenazine is present in breast milk. However, other phenothiazines have been shown to be excreted in human breast milk.
Anatensol ( Fluphenazine hydrochloride ) is indicated in the management of manifestations of psychotic disorders including schizophrenia and manic psychosis. Anatensol has not been shown to be effective in the management of behavioural complications in patients with mental retardation.
Note: Anatensol should be administered under the direction of a physician who is experienced in the clinical use of neuroleptic agents. The optimal amount of medication and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the medication. Response to treatment may be delayed.
Depending on severity and durations of symptoms, total daily oral dosage for adult psychotic patients may range initially from 2.5 to 10.0 mg and should be divided and given at six-to eight-hour intervals.
The smallest amount that will produce the desired results must be carefully determined for each individual since optimal dosage levels of this potent medication vary from patient to patient. In general, the oral dose has been found to be approximately two to three times the parenteral dose of fluphenazine. Treatment is best instituted with a low initial dosage, which may be increased if necessary, until the desired clinical effects are achieved. Dosage adjustment needs close supervision. Oral dosages exceeding 20.0 mg daily should be used with caution. Daily doses up to 40mg may be necessary; controlled clinical studies have not been performed to demonstrate safety of prolonged administration of such doses.
When symptoms are controlled, dosage can generally be reduced gradually to daily oral maintenance doses of 1.0 to 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.
For psychotic patients who have been stabilised on a fixed daily dosage of Anatensol ( fluphenazine hydrochloride ) tablets, conversion of therapy from oral fluphenazine hydrochloride dosage forms to the long-acting injectable Modecate may be indicated [see Modecate ( fluphenazine decanoate injection) for conversion information].
For geriatric patients, the suggested starting dose is 1.0 to 2.5 mg orally daily in divided doses, gradually adjusted according to the response of the patient. Maintenance doses in the lower range (¼ to 1/3 of those in younger adults) may be sufficient for most elderly patients.
If Anatensol is withdrawn, the recurrence of symptoms may not become apparent for several weeks.
Phenothiazines are contraindicated in patients with marked cerebral atherosclerosis, suspected or established subcortical brain damage, blood dyscrasias, phaeochromocytoma, severe cardiac insufficiency or renal or liver damage, in patients receiving large doses of CNS depressants (alcohol, barbiturates, narcotics, hypnotics, etc.) and in comatosed or severely depressed states. Anatensol ( fluphenazine hydrochloride ) is contraindicated in patients who have shown hypersensitivity to fluphenazine or the inactive ingredients of Anatensol. Caution should be observed in patients with a history of sensitivity to other phenothiazines, as cross-sensitivity may occur.
The use of this medication may impair the mental and physical abilities required for driving a car or operating heavy machinery, particularly during the first days of therapy. Potentiation of the effects of alcohol may occur with the use of this medication.
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with neuroleptic (antipsychotic) medications, including fluphenazine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, medication discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic agents. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
If a patient requires antipsychotic medication after recovery from NMS, the potential reintroduction of medication therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Since there is no adequate experience in children who have received this medication, safety and efficacy in children have not been established.
The safety for the use of Anatensol during pregnancy has not yet been established; therefore the possible hazards should be weighed against the potential benefits when administering this medication to pregnant patients.
Because of the possibility of cross-sensitivity , fluphenazine hydrochloride should be used cautiously in patients who have developed cholestatic jaundice, dermatoses or other allergic reactions to phenothiazine derivatives.
Psychotic patients on large doses of phenothiazine who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that reduced amounts of anaesthetics or central nervous system depressants may be necessary.
The effects of atropine may be potentiated in some patients receiving fluphenazine because of added anticholinergic effects.
Fluphenazine hydrochloride should be used cautiously in patients exposed to extreme heat or phosphorus insecticides; in patients with epilepsy, a history of convulsive disorders or conditions predisposing to epilepsy (since grand mal convulsions have been known to occur); in patients with special medical disorders such as mitral insufficiency, cardiac arrhythmias or other cardiovascular diseases; in patients with severe respiratory disease or thyrotoxicosis and in patients who have exhibited idiosyncrasy to other centrally-acting drugs.
The possibility of liver damage, pigmentary retinopathy, lenticular and corneal deposits, and development of irreversible dyskinesia should be remembered when patients are on prolonged therapy.
Neuroleptic medications 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.
In general, 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 anti-parkinsonian agents are continued for several weeks after the phenothiazine is withdrawn. Facilities should be available for periodic checking of hepatic function, renal function and the blood picture. Renal function of patients on long-term therapy should be monitored; if BUN (blood urea nitrogen) becomes abnormal, treatment should be discontinued.
As with any phenothiazine, the physician should be alert to the possible development of `silent pneumonias' in patients under prolonged treatment with fluphenazine hydrochloride.
Antipsychotic agents should be used with care in elderly patients (>60 years old), as these patients have a greater potential for adverse effects. Response should be monitored and dose adjusted. If an increase is necessary, doses should be gradually increased.
The side effects most frequently reported with phenothiazine compounds are extrapyramidal symptoms including pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyperreflexia. Most often these extrapyramidal symptoms are reversible; however, they may be persistent (see below). With any given phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants.
Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These reactions can usually be controlled by administration of anti-parkinsonism medications, such as benztropine mesylate and by subsequent reduction in dosage.
As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may occur 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 characterised 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 the extremities. There is no known effective treatment for tardive dyskinesia; anti-parkinsonism agents usually do not alleviate the symptoms of this syndrome.
To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of neuroleptic agent should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. It is suggested that all antipsychotic agents 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, the syndrome may be masked. It has been reported that 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.
Occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on neuroleptic therapy. Leukocytosis, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS.
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 of fluphenazine far in excess of the recommended amounts, As with other phenothiazine compounds, reactivation or aggravation of psychotic processes may be encountered.
Phenothiazine derivatives have been known to cause, in some patients, restlessness, excitement, or bizarre dreams. Impairment of judgement and mental skills and epileptiform attacks are occasionally seen. Alterations in electroencephalographic tracings or cerebrospinal fluid proteins may occur; cerebral oedema may rarely occur.
Hypertension and fluctuation in blood pressure have been reported with fluphenazine hydrochloride.
Hypotension has rarely presented a problem with fluphenazine. However, patients with phaeochromocytoma, cerebral vascular or renal insufficiency, or a severe cardiac reserve deficiency such as mitral insufficiency appear to be particularly prone to hypotensive reactions with phenothiazine compounds and should therefore be observed closely when the medication is administered. If severe hypotension should occur, supportive measures including the use of intravenous vasopressor medications should be instituted immediately. Noradrenaline tartrate injection is the most suitable agent for this purpose, adrenaline should not be used since phenothiazine derivatives have been found to reverse its action, resulting in a further lowering of blood pressure (that is, neuroleptics block peripheral alpha-adrenergic receptors, thus inhibiting the alpha vasoconstricting effects of adrenaline and leaving the beta-vasodilator effect relatively unopposed).
Autonomic reactions including nausea and loss of appetite, salivation, polyuria, perspiration, dry mouth, headache, and constipation may occur. Autonomic effects can usually be controlled by reducing or temporarily discontinuing dosage.
In some patients, phenothiazine derivatives have caused blurred vision, glaucoma, bladder paralysis, faecal impaction, paralytic ileus, tachycardia or nasal congestion.
Weight change, peripheral oedema, abnormal lactation, gynaecomastia, menstrual irregularities, false results on pregnancy tests, impotency in men and increased libido in women have all been known to occur in some patients on phenothiazine therapy.
Skin disorders such as itching, erythema, urticaria, seborrhoea, photoesensitivity, eczema and even exfoliative dermatitis have been reported with phenothiazine derivatives. The possibility of anaphylactoid reactions occurring in some patients should be borne in mind. Asthma, laryngeal oedema, and angioneurotic oedema may rarely occur.
Routine blood counts are advisable during therapy since blood dyscrasias including leucopenia, agranulocytosis, thrombocytopenic or non-thrombocytopenic purpura, eosinophilia, and pancytopenia have been observed with phenothiazine derivatives. Furthermore, if any soreness of the mouth, gums or throat, or any symptoms of upper respiratory infection occur and confirmatory leucocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.
Liver damage as manifested by cholestatic jaundice may be encountered, particularly during the first months of therapy, treatment should be discontinued if this occurs. An increase in cephalin flocculation, sometimes accompanied by alterations in other liver function tests, have been reported in patients receiving fluphenazine hydrochloride who have had no clinical evidence of liver damage.
Sudden, unexpected and unexplained deaths have been reported in hospitalised 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 sudden flare-ups of psychotic behaviour patterns shortly before death. Autopsy findings have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents, or intramyocardial lesions.
Although this is not a general feature of fluphenazine, potentiation of central nervous system depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) may occur. The following uncommon adverse reactions have also occurred with phenothiazine derivatives; systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, ECG changes (particularly prolongation of the QT interval which may lead to serious arrhythmias), laryngeal oedema and angioneurotic oedema, systemic lupus erythematosus-like syndrome; with long-term use, skin pigmentation and lenticular and corneal opacities have occurred.
The possibility should be borne in mind that phenothiazines may:
Interact with anticholinergic drugs with possible enhancement of its anticholinergic effects. For example, an anti-Parkinson drug, such as benserazide, used to manage extrapyramidal side effects, may exacerbate the antimuscarinic effects of fluphenazine.
In general, the symptoms of overdose are extensions of known pharmacologic effects and adverse reactions, the most prominent of which would be:
CNS depression may progress to coma with areflexia. Restlessness, confusion and excitement may occur with early or mild intoxication. The drug should be withdrawn and the symptoms of overdose treated supportively. Up to several hours after an oral overdose, gastric lavage should be attempted, followed by activated charcoal and then cathartics. If severe hypotension should occur, supportive measures, including the use of intravenous vasopressor drugs, should be instituted immediately. Noradrenaline tartrate is the most suitable drug for this purpose; adrenaline should not be used, since phenothiazine derivatives have been found to reverse its action, resulting in a further lowering of blood pressure. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks. Antiparkinson medication should be withdrawn gradually to avoid the emergence of rebound extrapyramidal symptoms. Limited experience indicates that phenothiazines are not dialyzable.
Store the tablets at room temperature (15-30°C); protect from light; keep tightly closed and avoid excessive heat.
Prescription Medicine.
Tablet 1mg & 5mg, in bottles of 50s fitted with tamper evident closures or in PVC/PVDC/Al foil blister pack.
Bristol-Myers Squibb (NZ) Ltd
Stanway Business Park
Tower 2, Level 1
646 Great South Road
Ellerslie, AUCKLAND
Telephone: (09) 571 5250; Toll Free: 0800 80 40 80
18 May 1994.
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