FLUANXOL® DEPOT INJECTION FLUANXOL® TABLETS
Action And Clinical Pharmacology: Flupenthixol is the decanoate ester of a thioxanthene derivative with antipsychotic properties. The esterification of flupenthixol results in the slow release of the drug from the injection site with consequent prolongation of duration of action. The onset of action usually occurs in the range of 24 to 72 hours after injection and the improvement of symptoms continues for 2 to 4 weeks. However, there is considerable variation in the individual response of patients to flupenthixol and its use for maintenance therapy requires careful supervision.
The exact mechanism of action of flupenthixol has not been established. Its effects resemble those of the phenothiazine, fluphenazine, in that it belongs among the antipsychotic drugs which are less likely to cause sedation and hypotension, but have greater propensity for producing extrapyramidal reactions.
In pharmacokinetic studies measuring flupenthixol blood levels, peak concentrations of the drug were found between days 4 and 7, following i.m. injections of 40 mg of flupenthixol 2% or 10%. It could still be detected in the blood 3 weeks after injection. The metabolites of flupenthixol appear to be inactive.
Flupenthixol dihydrochloride is well absorbed from the gastrointestinal tract reaching maximum serum concentrations within 3 to 8 hours. Flupenthixol is excreted mainly in the feces, with some excretion also occurring in the urine.
Indications And Clinical Uses: The maintenance therapy of chronic schizophrenic patients whose main manifestations do not include excitement, agitation or hyperactivity.
Contra-Indications: In patients with known hypersensitivity to the thioxanthenes. The possibility of cross-sensitivity between the thioxanthenes and phenothiazine derivatives should be considered.
Flupenthixol is also contraindicated in the presence of CNS depression due to any cause, comatose states, suspected or established subcortical brain damage, blood dyscrasias, pheochromocytoma, liver damage, cerebrovascular or renal insufficiency, and severe cardiovascular disorders. It is not indicated for the management of severely agitated psychotic patients, psychoneurotic patients or geriatric patients with confusion and/or agitation. As with phenothiazines, flupenthixol should not be used concomitantly with large doses of hypnotics due to the possibility of potentiation.
Pregnancy and Lactation: Safety in pregnancy has not been established. Therefore, it should not be administered to women of childbearing potential or during lactation, unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus or child.
Children: Safety and efficacy in children have not been established, and its use is not recommended in the pediatric age group.
Flupenthixol is not recommended for excitable, overactive or manic patients, and the relative lack of sedating effect may cause restlessness and insomnia. The drug should be used with caution in patients with parkinsonism or severe arteriosclerosis.
Occupational Hazards: Although flupenthixol is a relatively non-sedating drug, sedation may occur in some patients. Therefore, ambulatory patients should be warned about engaging in activities such as driving a car or operating machinery and about the concomitant use of alcohol and other CNS depressant drugs, since potentiation of their effects may occur.
Flupenthixol should be used with caution in patients with a history of convulsive disorders since it may lower the convulsive threshold.
The possibility of the development of irreversible dyskinesia should be borne in mind when patients are on prolonged therapy.
The antiemetic effect observed with flupenthixol in animal studies may also occur in man; therefore, the drug may mask signs of toxicity due to overdosage of other drugs, or it may mask the symptoms of disease, such as brain tumor or intestinal obstruction.
Although its anticholinergic properties are relatively weak, flupenthixol should be used with caution in patients who are known or are suspected to have glaucoma, and in those patients who might be exposed to extreme heat, or organophosphorus insecticides or who are receiving atropine or related drugs. Paralytic ileus has occasionally been reported, particularly in the elderly, when several drugs with anticholinergic effects have been used simultaneously.
Blood dyscrasias and liver damage have been reported with this class of drugs, but only eosinophilia has been reported to date with flupenthixol. Therefore, routine blood counts and hepatic function tests are advisable, particularly during the first months of therapy. Should either of these disorders occur, supportive treatment should be instituted and the drug discontinued.
Photosensitivity reactions, pigmentary retinopathy, and lenticular and corneal deposits, although not reported to date with flupenthixol, have been reported with related drugs.
Caution should be observed when using a drug of this category in patients who may have a propensity for development of defects in cardiac conduction.
Patients on large doses of flupenthixol who are undergoing surgery should be watched carefully for possible hypotensive phenomena, and anesthetic or CNS depressant drug dosages may have to be reduced.
To lessen the likelihood of adverse reactions related to drug accumulation, patients on long-term therapy, particularly on high doses, should be evaluated periodically to decide whether the maintenance dosage can be lowered or drug therapy discontinued.
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 tumorogenesis; the available evidence is considered too limited to be conclusive at this time.
Withdrawal Emergent Neurological Signs: Abrupt withdrawal after short-term administration of antipsychotic drugs does not generally pose problems. However, transient dyskinetic signs are experienced by some patients on maintenance therapy after abrupt withdrawal. The signs are very similar to those described under Tardive Dyskinesia, except for duration. Although it is not known whether gradual withdrawal of antipsychotic drugs will decrease the incidence of withdrawal emergent neurological signs, gradual withdrawal would appear to be advisable.
Adverse Reactions: Extrapyramidal symptoms have occurred in up to 30% of patients.
Flupenthixol shares many of the pharmacologic properties of other thioxanthenes and phenothiazines. Therefore, the known adverse reactions of these drugs should be borne in mind when flupenthixol is used.
CNS: Extrapyramidal symptoms, including hypo- and hyperkinetic states, tremors, pseudoparkinsonism, dystonia, hypertonia, akathisia, oculogyric crises, opisthotonos, hyperreflexia and tardive dyskinesia (see below). The symptoms, if they are to occur, usually appear within the first few days of drug administration and can usually be controlled or totally curtailed by reduction in dosage and/or standard anticholinergic antiparkinsonian medication. The incidence of extrapyramidal symptoms appears to be more frequent with the first few injections of flupenthixol, and diminish thereafter. The routine prophylactic use of antiparkinsonian medication is not recommended. Extrapyramidal reactions may be alarming, and patients should be forewarned and reassured.
Other CNS effects reported with flupenthixol include restlessness, insomnia, overactivity, psychomotor agitation, hypomania, epileptiform convulsions, headache, drowsiness, somnolence, depression, fatigue, and anergia.
Persistent Tardive Dyskinesia: As with other 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 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 the extremities.
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. 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. The physician may be able to reduce the risk of this syndrome by minimizing the unnecessary use of neuroleptic drugs and reducing the dose or discontinuing the drug, if possible, when manifestations of this syndrome are recognized, particularly in patients over the age of fifty. 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.
Autonomic Nervous System: Dry mouth, blurred vision, constipation, excessive salivation, excessive perspiration, nausea, difficulty in micturition, dizziness, palpitations and fainting have been observed with flupenthixol but are uncommon. Miosis, mydriasis, paralytic ileus, polyuria, nasal congestion, glaucoma, tachycardia, hypotension, hypertension, fluctuations in blood pressure, non specific ECG changes and cardiac arrhythmias have been reported with related drugs. If hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result.
Metabolic and Endocrine: Weight change, galactorrhea, elevation in serum prolactin levels, impotence, loss of libido, and sexual excitement have been reported with flupenthixol. Related drugs have been also associated with breast enlargement, menstrual irregularities, false positive pregnancy tests, peripheral edema, gynecomastia, hypo- and hyperglycemia and glycosuria.
Toxic and Allergic: Eosinophilia, jaundice and increased levels of AST, ALT and alkaline phosphatase have been reported with flupenthixol. Other antipsychotic drugs have been associated with leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, hemolytic anemia and pancytopenia. 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.
Skin reactions, such as pruritus, rash, urticaria, erythema, seborrhea, eczema, exfoliative dermatitis, and contact dermatitis have been reported with flupenthixol or related drugs. The possibility of anaphylactoid reactions occurring in some patients should be borne in mind.
Miscellaneous: Sudden, unexpected and unexplained deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. Previous brain damage or seizures may be predisposing factors; high doses should be avoided in known seizure patients. Several patients have shown flare ups of psychotic behavior 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: photosensitivity, systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered ECG and EEG tracings, altered CSF proteins, cerebral edema, asthma, laryngeal edema, and angioneurotic edema. Skin pigmentation, and lenticular and corneal opacities have been seen with long-term use of phenothiazines.
Symptoms And Treatment Of Overdose: Symptoms: Sedation, frequently preceded by extreme agitation, excitement and confusion. Extrapyramidal symptoms may develop, and respiratory and circulatory collapse may occur.
Treatment: Symptomatic. In cases of oral overdosing, gastric lavage should be carried out immediately and measures aimed at supporting the respiratory and cardiovascular systems instituted. If overdosing with parenteral flupenthixol occurs, no further injections should be given until the patient shows signs of relapse and the dosage should then be decreased. An airway should be maintained. Severe hypotension calls for the immediate use of an i.v. vasopressor drug, such as levarterenol. Epinephrine should not be used, as a further lowering of blood pressure may result. Antiparkinsonian medication should be administered only if extrapyramidal symptoms develop.
Dosage And Administration: Injection: Flupenthixol is administered by deep i.m. injection, preferably in the gluteus maximus. Flupenthixol is NOT for i.v. use.
As a long acting depot preparation, flupenthixol has been found useful in the maintenance treatment of non agitated chronic schizophrenic patients who have been stabilized with short acting neuroleptics and might benefit from transfer to a longer acting injectable medication. The changeover of medication should aim at maintaining a clinical outcome similar to or better than that obtained with the previous therapy. To achieve and maintain the optimum dose, the changeover from other neuroleptic medication should proceed gradually and constant supervision is required during the period of dosage adjustment in order to minimize the risk of overdosage or insufficient suppression of psychotic symptoms before the next injection.
Patients not previously treated with long acting depot neuroleptics should be given an initial test dose of 5 mg (0.25 mL) to 20 mg (1.0 mL). An initial dose of 20 mg (1.0 mL) is usually well tolerated; however, a 5 mg (0.25 mL) test dose is recommended in elderly, frail and cachectic patients, and in patients whose individual or family history suggests a predisposition to extrapyramidal reactions. In the subsequent 5 to 10 days, the therapeutic response and the appearance of extrapyramidal symptoms should be carefully monitored. Oral neuroleptic drugs may be continued, but in diminishing dosage, during this period.
In patients previously treated with long acting depot neuroleptics who displayed good tolerance to these drugs, an initial dose of 20 to 40 mg (1.0 to 2.0 mL) may be adequate.
Subsequent doses and the frequency of administration must be determined for each patient. There is no reliable dosage comparability between a shorter acting neuroleptic and depot flupenthixol, and, therefore, the dosage of the long acting drug must be individualized.
Except in particularly sensitive patients, a second dose of 20 (1.0 mL) to 40 mg (2.0 mL) can be given 4 to 10 days after the initial injection. Subsequent dosage adjustments are made in accordance with the response of the patient, but the majority of patients can be adequately controlled by 20 to 40 mg (1.0 to 2.0 mL) of flupenthixol 2% every 2 to 3 weeks. The optimal amount of the drug has been found to vary with the clinical circumstances and individual response. Doses greater than 80 mg (4.0 mL) are usually not deemed necessary, although higher doses have been used occasionally in some patients.
Although the response to a single injection usually lasts for 2 to 3 weeks, it may last for 4 weeks or more, particularly when higher doses are used. Since higher doses increase the incidence of extrapyramidal reactions and other adverse effects, the amount of drug used should not be increased merely in order to prolong the intervals between injections. With higher doses there may also be more variability in the action of flupenthixol and, therefore, unit dose increments should not exceed 20 mg (1.0 mL). After an appropriate dosage adjustment is achieved, regular and continuous supervision and reassessment is considered essential in order to permit any further dosage adjustments that might be required to ensure use of the lowest effective individual dose and avoid troublesome side effects.
Patients who require higher doses of flupenthixol to control symptoms of schizophrenia and/or those who complain of discomfort with a large injection volume may be administered flupenthixol 10% (100 mg/mL) in preference to flupenthixol 2% (20 mg/mL).
As with all oily injections it is important to ensure, by aspiration before injection, that inadvertent intravascular injection does not occur.
Tablets: The dosage should be individualized and adjusted according to the severity of symptoms and tolerance to the drug. The initial recommended dose is 1 mg, 3 times daily. This may be increased, if necessary by 1 mg every 2 to 3 days until there is effective control of psychotic symptoms. The usual maintenance dosage is 3 to 6 mg daily in divided doses, although doses of up to 12 mg daily or more have been used in some patients.
During the initial therapeutic period, disturbance of sleep may occur, especially in those patients who have previously received neuroleptics possessing a marked sedative effect. In this event, the evening dose may be reduced.
Until further clinical evidence is available, it is not recommended for use in children.
Following stabilization on flupenthixol dihydrochloride tablets, patients may be treated with flupenthixol decanoate administered by the i.m. route.
Availability And Storage: Depot Injection: 2% Solution: Each mL contains: flupenthixol decanoate 20 mg. Vials of 10 mL.
10% Solution: Each mL contains: flupenthixol decanoate 100 mg. Vials of 2 mL.
Solutions are yellowish and oil based. Store at room temperature. Protect from light.
Tablets: 0.5 mg: Each ochre-yellow, sugar-coated, biconvex tablet contains: flupenthixol dihydrochloride 0.5 mg. Also contains sucrose. Bottles of 100.
3 mg: Each ochre-yellow, sugar-coated, biconvex tablet contains: flupenthixol dihydrochloride 3 mg. Also contains sucrose. Bottles of 100. (Shown in Product Recognition Section)
FLUANXOL® DEPOT INJECTION FLUANXOL® TABLETS Lundbeck Flupenthixol DecanoateFlupenthixol Dihydrochloride Antipsychotic