Source: Health Products and Food Branch (CA) Revision Year: 2017
Flupentixol is not indicated for the management of severely agitated psychotic patients, psychoneurotic patients or geriatric patients with confusion and/or agitation. As with phenothiazines, flupentixol should not be used concomitantly with large doses of hypnotics due to the possibility of potentiation.
Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in elderly patients with dementia showed a mean 1.6 fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Flupentixol is not indicated for the treatment of patients with dementia (see PRECAUTIONS, Use in Elderly, Use in Geriatric Patients with Dementia).
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.
Although its anticholinergic properties are relatively weak, flupentixol should be used with caution in patients who are known or are suspected to have glaucoma. See OPHTHALMOLOGIC for more details.
Caution should also be taken in 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.
The antiemetic effect observed with flupentixol 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 tumour or intestinal obstruction.
Cardiotoxicity: As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalemia, hypomagnesia, or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Concomitant treatment with other antipsychotics should be avoided.
Increases in the QT interval related to antipsychotic treatment may be exacerbated by the coadministration of other drugs known to significantly increase the QT interval. Co-administration of such drugs should be avoided (see DRUG INTERACTIONS).
Cardiovascular Disease: Caution should be used when using flupentixol in patients with severe arteriosclerosis or in those who may have a propensity for development of defects in cardiac conduction.
Cerebrovascular Accidents: An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomized placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Flupentixol is not indicated in patients with dementia.
Vascular disease: Flupentixol should be used with caution in patients with risk factors for stroke or with a history of stroke.
Venous Thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. All possible risk factors for VTE should be identified before and during treatment with flupentixol and preventive measures undertaken.
Elderly Patients with Dementia: (See section beneath the Serious Warnings and Precautions box.)
Hyperprolactemia: 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.
Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone mineral density in both female and male subjects.
Hyperglycemia: Diabetic ketoacidosis (DKA) has occurred in patients with no reported history of hyperglycemia. Patients should have baseline and periodic monitoring of blood glucose and body weight.
Genitourinary: Rare cases of priapism have been reported with antipsychotic use, such as flupentixol. This adverse reaction, as with other psychotropic drugs, did not appear to be dosedependent and did not correlate with the duration of treatment.
Severe adverse reactions requiring immediate medical attention may occur and are difficult to predict. 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.
Neutropenia, leukopenia, granulocytopenia and agranulocytosis have been reported during antipsychotic use, including with flupentixol decanoate. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting flupentixol and then periodically throughout the treatment.
Liver damage has been reported with this class of drugs. Therefore, hepatic function tests are advisable, particularly during the first months of therapy. Should this disorder occur, supportive treatment should be instituted and the drug discontinued.
Flupentixol is not recommended for excitable, overactive or manic patients, and the relative lack of sedating effect may cause restlessness and insomnia.
Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with neuroleptic drugs (see ADVERSE REACTIONS). The clinical manifestations of neuroleptic malignant syndrome are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregularity of pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. Cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms should be identified. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system pathology.
The management of neuroleptic malignant syndrome should include the immediate discontinuation of antipsychotic drugs and nonessential concurrent therapies. Intensive symptomatic treatment and medical monitoring is required. Concomitant serious medical problems for which specific treatments are available should be dealt with appropriately. No general agreement exists regarding specific pharmacological treatment regimens for uncomplicated neuroleptic malignant syndrome.
If a patient requires antipsychotic drug treatment following recovery from neuroleptic malignant syndrome, the potential reintroduction of drug therapy should be carefully considered. As recurrences of neuroleptic malignant syndrome have been reported, careful patient monitoring is necessary.
Occupational Hazards Sedative Effects: Although flupentixol 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.
Patients with Parkinson’s Disease: Flupentixol should be used with caution in patients with Parkinsonism, as it is known that dopamine antagonists such as flupentixol, can cause a deterioration of the disease.
Seizures: Flupentixol should be used with caution in patients with a history of convulsive disorders, as drugs of this class are known to lower seizure threshold.
Tardive Dyskinesia: Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movement that may develop in patients receiving treatment with antipsychotic drugs (see ADVERSE REACTIONS).
The possibility of the development of irreversible dyskinesia should be borne in mind when patients are on prolonged therapy. Although the syndrome appears to be most prevalent in the elderly, especially elderly female patients, it is impossible to predict at the onset of treatment which patients are likely to develop tardive dyskinesia.
Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible, increase with the total cumulative dose of the antipsychotic agent and the duration of treatment. However, less commonly, the syndrome can develop after relatively brief periods of treatment at low doses. Although there is no established treatment of tardive dyskinesia, the syndrome may remit, partially or completely, following withdrawal of the antipsychotic drug. Antipsychotic treatment may itself suppress the signs and symptoms of tardive dyskinesia, possibly masking the underlying process. However, the effects of symptomatic suppression on the long-term course of the syndrome are not known.
In view of these considerations, flupentixol should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. As with any antipsychotic drug, flupentixol should be administered at the smallest dose and for the shortest duration of treatment that is consistent with a satisfactory clinical response. Chronic use should be reserved for patients who appear to be obtaining a substantial benefit from the drug. The need for continued treatment should be reassessed at periodic intervals.
If the signs and symptoms of tardive dyskinesia develop during treatment with flupentixol, withdrawal of the drug should be considered. However, some patients may require continued antipsychotic treatment despite the presence of this syndrome.
Anticholinergic Effects: Although its anticholinergic effects are weak, flupentixol use should be avoided in patients who are known to have, or suspected of having narrow angle glaucoma.
Photosensitivity Reactions: Photosensitivity reactions, pigmentary retinopathy and lenticular and corneal deposits have been reported with related drugs. Lens opacity has been reported rarely with flupentixol.
Patients on large doses of flupentixol who are undergoing surgery should be watched carefully for possible hypotensive phenomena and anesthetic or central nervous system depressant drug dosages may have to be reduced.
Adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, libido decreased, erectile dysfunction and ejaculation failure have been reported in patients. These events may have a negative impact on female and/or male sexual function and fertility.
If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunction occurs, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.
Animal reproduction studies have shown reproductive toxicity. In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats; effects were seen at doses well in excess of those applied during clinical use (See TOXICOLOGY, Reproductive Toxicity).
Cerebrovascular Adverse Events (CVAEs) including stroke in Elderly Patients with Dementia: An increased risk of cerebrovascular adverse events has been seen in the dementia population in clinical trials with some atypical antipsychotics. The mechanism for this increased risk is not known. There is insufficient data to know if there is an increased risk of cerebrovascular events associated with flupentixol. An increased risk however cannot be excluded. Flupentixol is not indicated in elderly patients with dementia.
Geriatrics (>65 years of age): The pharmacokinetics, safety, and efficacy of flupentixol in elderly patients with schizophrenia have not been systematically evaluated in clinical trials. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic, renal and cardiac dysfunctions in this population.
Mortality in Geriatric Patients with Dementia-related Psychosis: In elderly patients with dementia-related psychosis, the efficacy and safety of flupentixol has not been studied. Observational studies suggest that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Flupentixol is not indicated for the treatment of patients with dementia-related psychosis.
Pregnant and Nursing Women: The safety of flupentixol in pregnancy and breastfeeding women has not been established. As flupentixol is found in breast milk in low concentrations, it is not likely to affect the infant when therapeutic doses are used.
Neonates exposed to antipsychotic drugs (including flupentixol) during the third trimester of pregnancy are at a risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Flupentixol should not be administered to women of childbearing potential, unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus or child.
Pediatrics (<18 years): Since the safety and efficacy of flupentixol in children has not been established, its use is not recommended in the pediatric age group.
Reduced renal function: Based on the characteristics for elimination it is reasonable to assume that reduced kidney function is likely not to have much influence on the serum levels of parent drug.
Reduced hepatic function: No data available.
Undesirable effects are for the majority dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.
The most common adverse reactions reported with flupentixol have been extrapyramidal symptoms, occurring in up to 30% of patients.
Flupentixol 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 flupentixol is used.
Dry mouth, blurred vision, constipation, excessive salivation, excessive perspiration, nausea, difficulty in micturition, dizziness, palpitations and fainting have been observed with flupentixol 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 pressor agent since a paradoxical further lowering of blood pressure may result.
Extrapyramidal symptoms, including hypo- and hyperkinetic states, tremors, pseudoparkinsonism, dystonia, hypertonia, akathisia, oculogyric crises, opisthotonos, hyperreflexia and tardive dyskinesia (see WARNINGS AND PRECAUTIONS, Tardive Dyskinesia and below) have been reported with flupentixol. The symptoms, if they are to occur, usually appear within the first few days of a 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 Fluanxol Depot (flupentixol decanoate), and diminishes 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 flupentixol include restlessness, insomnia, overactivity, psychomotor agitation, hypomania, epileptiform convulsions, headache, drowsiness, somnolence, depression, fatigue, and anergia.
Persistent Tardive Dyskinesia: 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 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 and may aggravate them. 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 (see WARNINGS AND PRECAUTIONS, Tardive Dyskinesia).
Weight change, galactorrhea, elevation in serum prolactin levels, impotence, loss of libido, and sexual excitement have been reported with flupentixol. Related drugs have been also associated with breast enlargement, menstrual irregularities, false positive pregnancy tests, peripheral edema, gynecomastia, hypo- and hyperglycemia and glycosuria.
Patients should be advised of the risk of severe constipation during flupentixol treatment, and that they should tell their doctor if constipation occurs or worsens, as they may need laxatives.
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 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: photosensitivity, systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered electrocardiographic and electroencephalographic tracings, altered cerebrospinal fluid 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.
Eosinophilia, leukopenia, agranulocytosis, jaundice and increased levels of ALT, AST and alkaline phosphatase have been reported with flupentixol. Other antipsychotic drugs have been associated with 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 flupentixol or related drugs. The possibility of anaphylactoid reactions occurring in some patients should be borne in mind.
Adverse events not listed above that have been reported since flupentixol was introduced on the market are provided below.
Blood and Lymphatic System Disorders: Thrombocytopenia, leukopenia, neutropenia, granulocytopenia, agranulocytosis have been reported during antipsychotic use. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting flupentixol and then periodically throughout the treatment.
Cardiac Disorders: As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias – ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol.
Eye Disorders: Accomodation disorder
Gastrointestinal Disorders: Vomiting, dyspepsia, diarrhoea, abdominal pain, flatulence
General Disorders: Asthenia
Metabolism and Nutrition Disorders: Hyperglycaemia, glucose tolerance abnormal, increased appetite
Musculoskeletal and Connective Tissue Disorders: Muscle rigidity, myalgia
Nervous System Disorders: Speech disorder, Neuroleptic Malignant Syndrome (NMS) (see WARNINGS AND PRECAUTIONS)
Psychiatric Disorders: Nervousness, confusional state
Renal and Urinary Disorders: Urinary retention
Reproductive System Disorders: Ejaculation failure, erectile dysfunction, gynaecomastia, amenorrhoea
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea
Vascular Disorders: Hot flush
Flupentixol enhances the sedative response to alcohol and the effects of barbiturates and other CNS depressants. It should not be administered with high doses of hypnotics due to the possibility of potentiation.
Flupentixol should not be given concomitantly with guanethidine or similar acting compounds, since antipsychotic drugs such as flupentixol may block the antihypertensive effect of these compounds.
Many antipsychotic and tricyclic antidepressant drugs may mutually inhibit the metabolism of each other.
Concomitant use of metoclopramide increases the risk of extrapyramidal symptoms.
Flupentixol may antagonize the effects of levodopa and dopamine agonists.
Long-acting depot antipsychotics (such as Fluanxol Depot) should be used with caution in combination with other medicines known to have a myelosuppressive potential, as these cannot rapidly be removed from the body in conditions where this may be required.
Increases in the QT interval related to antipsychotic treatment may be exacerbated by the coadministration of other drugs known to significantly increase the QT interval. Co-administration of such drugs should be avoided. Relevant classes include:
The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. lithium) should be avoided.
Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrhythmias.
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