Binison

Posology

Since individual response to neuroleptic drugs is variable, dosage for all indications should be individually determined and is best initiated and titrated under close clinical supervision.

To determine the initial dose, consideration should be given to the patient's age, severity of symptoms and previous response to other neuroleptic drugs.

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less Binison solution and half the normal starting dose may be sufficient for therapeutic response.

Binison should be used at the minimum dose that is clinically effective

Method of administration

For Oral Administration Only

Adults

Schizophrenia, psychoses and mania

Use as an antipsychotic agent for schizophrenia, psychoses, mania and hypomania, organic brain damage (depending on symptoms).

Acute phase:

Doses between 2 and 20 mg/day should be administered either as a single dose or in divided doses.

Chronic phase:

1-3 mg orally three times a day, may be increased up to 20 mg per day in divided doses, depending on the response.

Psychomotor anti-agitation

Use as a psychomotor anti-agitation agent for mental or behavioural problems such as aggression, hyperactivity and self-mutilation in the mentally retarded and in patients with organic brain damage (depending on symptoms), violent or dangerously impulsive behaviour.

Acute phase:

Moderate symptomatology 1.5 - 3.0mg bd or tds

Severe symptomatology (resistant patients) 3.0 - 5.0mg bd or tds

Chronic phase:

0.5-1 mg three times a day orally, may be increased to 2-3 mg three times a day, if required, to obtain a response.

Maintenance Dosage:

Once satisfactory control of symptoms has been achieved, dosage should be gradually reduced to the lowest effective maintenance dose. Too rapid a dosage reduction should be avoided.

Restlessness or agitation in the elderly:

Treatment should start with half the dosage stated for adults and adjusted according to the results if necessary.

Gilles de la Tourette Syndrome, severe tics, intractable hiccup:

Starting dose 1.5mg tds adjusted according to response. A daily maintenance dose of 10mg may be required in Gilles de la Tourette Syndrome

The maximum daily dose for all treatment is 20mg

Paediatric population

Childhood Schizophrenia

The recommended doses below provide a total dose in the approximate range 0.03 to 0.15 mg/kg/day, when administered orally in divided doses (two or three times a day).

Children 3 to 12 years of age

The recommended

- starting dose is a total 0.5 mg/day orally, preferably in divided doses

- target dose range is a total 1 to 4 mg/day orally, in divided doses

- maximum dose is a total 6 mg/day orally, in divided doses.

Adolescents 13 to 17 years of age

The recommended

- starting dose is a total 0.5 mg/day orally, preferably in divided doses

- target dose range is a total 1 to 6 mg/day orally, in divided doses

- maximum dose is a total 10 mg/day orally, in divided doses.

Childhood Psychomotor anti-agitation

The recommended doses below provide a total dose in the approximate range 0.02 to 0.075 mg/kg/day when administered orally in divided doses (two to three times a day).

Children 3 to 12 years of age

The recommended

- starting dose is a total 0.25 mg/day orally, preferably in divided doses.

- target dose range is a total 0.5 to 3 mg/day orally, in divided doses.

- maximum dose is a total 3 mg/day orally, in divided doses.

Adolescents 13 to 17 years of age

The recommended

- starting dose is a total 0.25 mg/day orally, preferably in divided doses.

- target dose range is a total 2 to 6 mg/day orally, in divided doses.

- maximum dose is a total 6 mg/day orally, in divided doses.

Gilles de la Tourette Syndrome: Oral maintenance doses of up to 10mg/day in most patients

Posology

Adults

A low initial dose is recommended, which subsequently may be adjusted according to the patient's response. Patients must always be maintained on the minimal effective dose.

Oral solution:

The dose recommendations for Binison oral solution are presented in Table 1.

Table 1: Haloperidol dose recommendations for adults aged 18 years and above

2 mg/ml oral solution:

The Binison 2 mg/ml oral solution in a bottle with an oral syringe is intended to be used for single doses of 0.5 mg haloperidol and above (equivalent to 0.25 ml and above).

The quantity (ml) required to achieve a given single dose using Binison 2 mg/ml oral solution is presented in Table 2.

Table 2: Conversion table for Binison 2 mg/ml oral solution

Treatment withdrawal

Gradual withdrawal of haloperidol is advisable.

Missed dose

If patients miss a dose, it is recommended that they take the next dose as usual, and do not take a double dose.

Special populations

Elderly

The following initial haloperidol doses are recommended in elderly patients:

- Treatment of persistent aggression and psychotic symptoms in patients with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others - 0.5 mg/day.

- All other indications - half the lowest adult dose.

The haloperidol dose may be adjusted according to the patient's response. Careful and gradual dose up-titration in elderly patients is recommended.

The maximum dose in elderly patients is 5 mg/day.

Doses above 5 mg/day should only be considered in patients who have tolerated higher doses and after reassessment of the patient's individual benefit-risk profile.

Renal impairment

The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. No dose adjustment is recommended, but caution is advised when treating patients with renal impairment. However, patients with severe renal impairment may require a lower initial dose, with subsequent adjustments at smaller increments and at longer intervals than in patients without renal impairment.

Hepatic impairment

The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. Since haloperidol is extensively metabolised in the liver, it is recommended to halve the initial dose, and adjust the dose with smaller increments and at longer intervals than in patients without hepatic impairment.

Paediatric population

The dose recommendations for Binison oral solution are presented in Table 4.

Table 4: Haloperidol dose recommendations for paediatric population

The safety and efficacy of Binison oral solution in children below the ages defined in the indications have not been established. Data are not available for children aged less than 3 years.

Method of administration

Binison oral solution is for oral use. It may be mixed with water to facilitate dose administration, but it must not be mixed with any other liquid. The diluted solution must be taken immediately.

Posology

Adults

A low initial dose is recommended, which subsequently may be adjusted according to the patient's response. Patients must always be maintained on the minimal effective dose.

Oral solution:

The dose recommendations for HALDOL oral solution are presented in Table 1.

Table 1: Haloperidol dose recommendations for adults aged 18 years and above

2 mg/ml oral solution:

The HALDOL 2 mg/ml oral solution in a bottle with an oral syringe is intended to be used for single doses of 0.5 mg haloperidol and above (equivalent to 0.25 ml and above).

The quantity (ml) required to achieve a given single dose using HALDOL 2 mg/ml oral solution is presented in Table 2.

Table 2: Conversion table for HALDOL 2 mg/ml oral solution

Treatment withdrawal

Gradual withdrawal of haloperidol is advisable.

Missed dose

If patients miss a dose, it is recommended that they take the next dose as usual, and do not take a double dose.

Special populations

Elderly

The following initial haloperidol doses are recommended in elderly patients:

- Treatment of persistent aggression and psychotic symptoms in patients with moderate to severe Alzheimer's dementia and vascular dementia when non-pharmacological treatments have failed and when there is a risk of harm to self or others - 0.5 mg/day.

- All other indications - half the lowest adult dose.

The haloperidol dose may be adjusted according to the patient's response. Careful and gradual dose up-titration in elderly patients is recommended.

The maximum dose in elderly patients is 5 mg/day.

Doses above 5 mg/day should only be considered in patients who have tolerated higher doses and after reassessment of the patient's individual benefit-risk profile.

Renal impairment

The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. No dose adjustment is recommended, but caution is advised when treating patients with renal impairment. However, patients with severe renal impairment may require a lower initial dose, with subsequent adjustments at smaller increments and at longer intervals than in patients without renal impairment.

Hepatic impairment

The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. Since haloperidol is extensively metabolised in the liver, it is recommended to halve the initial dose, and adjust the dose with smaller increments and at longer intervals than in patients without hepatic impairment.

Paediatric population

The dose recommendations for HALDOL oral solution are presented in Table 4.

Table 4: Haloperidol dose recommendations for paediatric population

The safety and efficacy of HALDOL oral solution in children below the ages defined in the indications have not been established. Data are not available for children aged less than 3 years.

Method of administration

HALDOL oral solution is for oral use. It may be mixed with water to facilitate dose administration, but it must not be mixed with any other liquid. The diluted solution must be taken immediately.

Please also refer to 'Drug Interactions' section. Caution is advised in patients with renal failure and phaeochromocytoma.

Administer with care to patients with severe cardiovascular disorders, because of the possibility of transient hypotension. Should hypotension occur and a vasopressor be required, adrenaline should not be used since Binison may block its vasopressor activity and further lowering of the blood pressure may occur.

Cases of sudden and unexplained death have been reported in psychiatric patients receiving antipsychotic drugs, including Binison. However, the limited nature of the available data makes it difficult to determine the contributory role, if any, of the drug. Ventricular arrhythmias have been reported rarely. In most instances, they were of questionable relationship to Binison treatments, they may occur more frequently with high doses and in pre-disposed patients.

The risk-benefit of Binison treatment should be fully assessed before treatment is commenced and patients with risk factors for ventricular arrhythmias such as cardiac disease, family history of sudden death and/or QT prolongation; uncorrected electrolyte disturbances; subarachnoid haemorrhage, metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia, starvation, alcohol abuse, or those receiving concomitant therapy with other drugs known to prolong the QT interval , should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment, to obtain steady plasma levels. Binison should be used in caution in patients known to be slow metabolisers of CYP2D6, and during the use of cytochrome P450 inhibitors.

Caution should be used in patients with cardiovascular disease or family history of QT prolongation and a baseline ECG should be carried out prior to treatment. During therapy, the need for ECG monitoring should be assessed in an individual patient basis. Whilst on therapy, reduce the dose if QT interval is prolonged and discontinue if QTc is >500ms. Periodic electrolyte monitoring recommended, especially for patients taking diuretics, or during intercurrent illness and avoid concomitant neuroleptics.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Binison 10mg/5ml Oral Solution and preventive measures undertaken.

Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Relapse may also occur and gradual withdrawal is advisable.

In schizophrenia, the response to antipsychotic drug treatment may be delayed. If drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months.

As with all antipsychotic agents, Binison should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist. Binison may impair the metabolism of tricyclic antidepressants (clinical significance unknown). If concomitant anti-parkinson medication is required, it may have to be continued after Binison is discontinued to take account of any differences in excretion rates. The physician should keep in mind the possible anticholinergic effects associated with anti-parkinson agents.

An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. Binison should be used with caution in patients with risk factors for stroke.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. 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.

Binison 10mg/5ml Oral Solution is not licensed for the treatment of dementia-related behavioural disturbances.

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, Binison has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterised by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Tardive dyskinesia

As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterised by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.

Extrapyramidal symptoms

In common with all neuroleptics, extrapyramidal symptoms may occur, e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia.

Available safety data in the paediatric population indicate a risk of extrapyramidal symptoms, including tardive dyskinesia, and sedation. No long-term safety data are available.

Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure. If concomitant antiparkinson medication is required, it may have to be continued after stopping Binison if its excretion is faster than that of Binison in order to avoid the development or aggravation of extrapyramidal symptoms. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with Binison.

Seizures/Convulsions

It has been reported that seizures can be triggered by Binison. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions (e.g., alcohol withdrawal and brain damage).

Hepatobiliary concerns

As Binison is metabolised by the liver, caution is advised in patients with liver disease. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate Binison toxicity. Antipsychotic therapy in patients with hyperthyroidism should be used only with great caution and must always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Very rare cases of hypoglycaemia and of Syndrome of Inappropriate ADH Secretion have been reported.

Excipient Warnings

This product contains parahydroxybenzoates which may cause allergic reactions (possibly delayed)

Increased mortality in elderly people with dementia

Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotics, including haloperidol.

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death. Analyses of seventeen placebo-controlled studies (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled study, the rate of death in patients treated with antipsychotics was about 4.5%, compared to a rate of about 2.6% in the placebo group. 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 treatment of elderly patients with haloperidol is also associated with increased mortality. This association may be stronger for haloperidol than for atypical antipsychotic medicinal products, is most pronounced in the first 30 days after the start of treatment, and persists for at least 6 months. The extent to which this association is attributable to the medicinal product, as opposed to being confounded by patient characteristics, has not yet been elucidated.

Cardiovascular effects

QTc prolongation and/or ventricular arrhythmias, in addition to sudden death, have been reported with haloperidol. The risk of these events appears to increase with high doses, high plasma concentrations, in predisposed patients or with parenteral use, particularly intravenous administration.

Caution is advised in patients with bradycardia, cardiac disease, family history of QTc prolongation or history of heavy alcohol exposure.).

A baseline ECG is recommended before treatment. During therapy, the need for ECG monitoring for QTc interval prolongation and for ventricular arrhythmias must be assessed in all patients. Whilst on therapy, it is recommended to reduce the dose if QTc is prolonged, but haloperidol must be discontinued if the QTc exceeds 500 ms.

Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for ventricular arrhythmias and must be corrected before treatment with haloperidol is started. Therefore, baseline and periodic electrolyte monitoring is recommended.

Tachycardia and hypotension (including orthostatic hypotension) have also been reported. Caution is recommended when haloperidol is administered to patients manifesting hypotension or orthostatic hypotension.

Cerebrovascular events

In randomised, placebo-controlled clinical studies in the dementia population, there was an approximately 3-fold increased risk of cerebrovascular adverse events with some atypical antipsychotics. Observational studies comparing the stroke rate in elderly patients exposed to any antipsychotic to the stroke rate in those not exposed to such medicinal products found an increased stroke rate among exposed patients. This increase may be higher with all butyrophenones, including haloperidol. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. Binison must be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

Haloperidol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterized by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Tardive dyskinesia

Tardive dyskinesia may appear in some patients on long-term therapy or after discontinuation of the medicinal product. The syndrome is mainly characterized by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dose is increased or when a switch is made to a different antipsychotic. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including Binison, must be considered.

Extrapyramidal symptoms

Extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia). The use of haloperidol has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Acute dystonia may occur during the first few days of treatment with Binison, but later onset as well as onset after dose increases has been reported. Dystonic symptoms can include, but are not limited to, torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis. Males and younger age groups are at higher risk of experiencing such reactions. Acute dystonia may necessitate stopping the medicinal product.

Antiparkinson medicinal products of the anticholinergic type may be prescribed as required to manage extrapyramidal symptoms, but it is recommended that they are not prescribed routinely as a preventive measure. If concomitant treatment with an antiparkinson medicinal product is required, it may have to be continued after stopping Binison if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms. The possible increase in intraocular pressure must be considered when anticholinergic medicinal products, including antiparkinson medicinal products, are administered concomitantly with Binison.

Seizures/convulsions

It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to seizures (e.g. alcohol withdrawal and brain damage).

Hepatobiliary concerns

As haloperidol is metabolised by the liver, dose adjustment and caution is advised in patients with hepatic impairment. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism must be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhea or amenorrhoea. Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics and human breast tumours has been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Binison must be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.

Hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported with haloperidol.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Binison and preventive measures undertaken.

Treatment response and withdrawal

In schizophrenia, the response to antipsychotic treatment may be delayed.

If antipsychotics are withdrawn, recurrence of symptoms related to the underlying condition may not become apparent for several weeks or months.

There have been very rare reports of acute withdrawal symptoms (including nausea, vomiting and insomnia) after abrupt withdrawal of high doses of antipsychotics. Gradual withdrawal is advisable as a precautionary measure.

Patients with depression

It is recommended that Binison is not used alone in patients in whom depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist.

Switch from mania to depression

There is a risk in the treatment of manic episodes of bipolar disorder for patients to switch from mania to depression. Monitoring of patients for the switch to a depressive episode with the accompanying risks such as suicidal behaviour is important in order to intervene when such switches occur.

Poor metabolisers of CYP2D6

Binison should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.

Paediatric population

Available safety data in the paediatric population indicate a risk of developing extrapyramidal symptoms, including tardive dyskinesia, and sedation. Limited long-term safety data are available.

Increased mortality in elderly people with dementia

Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotics, including haloperidol.

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death. Analyses of seventeen placebo-controlled studies (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled study, the rate of death in patients treated with antipsychotics was about 4.5%, compared to a rate of about 2.6% in the placebo group. 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 treatment of elderly patients with haloperidol is also associated with increased mortality. This association may be stronger for haloperidol than for atypical antipsychotic medicinal products, is most pronounced in the first 30 days after the start of treatment, and persists for at least 6 months. The extent to which this association is attributable to the medicinal product, as opposed to being confounded by patient characteristics, has not yet been elucidated.

Cardiovascular effects

QTc prolongation and/or ventricular arrhythmias, in addition to sudden death, have been reported with haloperidol. The risk of these events appears to increase with high doses, high plasma concentrations, in predisposed patients or with parenteral use, particularly intravenous administration.

Caution is advised in patients with bradycardia, cardiac disease, family history of QTc prolongation or history of heavy alcohol exposure.).

A baseline ECG is recommended before treatment. During therapy, the need for ECG monitoring for QTc interval prolongation and for ventricular arrhythmias must be assessed in all patients. Whilst on therapy, it is recommended to reduce the dose if QTc is prolonged, but haloperidol must be discontinued if the QTc exceeds 500 ms.

Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for ventricular arrhythmias and must be corrected before treatment with haloperidol is started. Therefore, baseline and periodic electrolyte monitoring is recommended.

Tachycardia and hypotension (including orthostatic hypotension) have also been reported. Caution is recommended when haloperidol is administered to patients manifesting hypotension or orthostatic hypotension.

Cerebrovascular events

In randomised, placebo-controlled clinical studies in the dementia population, there was an approximately 3-fold increased risk of cerebrovascular adverse events with some atypical antipsychotics. Observational studies comparing the stroke rate in elderly patients exposed to any antipsychotic to the stroke rate in those not exposed to such medicinal products found an increased stroke rate among exposed patients. This increase may be higher with all butyrophenones, including haloperidol. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. HALDOL must be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

Haloperidol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterized by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Tardive dyskinesia

Tardive dyskinesia may appear in some patients on long-term therapy or after discontinuation of the medicinal product. The syndrome is mainly characterized by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dose is increased or when a switch is made to a different antipsychotic. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including HALDOL, must be considered.

Extrapyramidal symptoms

Extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia). The use of haloperidol has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Acute dystonia may occur during the first few days of treatment with HALDOL, but later onset as well as onset after dose increases has been reported. Dystonic symptoms can include, but are not limited to, torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis. Males and younger age groups are at higher risk of experiencing such reactions. Acute dystonia may necessitate stopping the medicinal product.

Antiparkinson medicinal products of the anticholinergic type may be prescribed as required to manage extrapyramidal symptoms, but it is recommended that they are not prescribed routinely as a preventive measure. If concomitant treatment with an antiparkinson medicinal product is required, it may have to be continued after stopping HALDOL if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms. The possible increase in intraocular pressure must be considered when anticholinergic medicinal products, including antiparkinson medicinal products, are administered concomitantly with HALDOL.

Seizures/convulsions

It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to seizures (e.g. alcohol withdrawal and brain damage).

Hepatobiliary concerns

As haloperidol is metabolised by the liver, dose adjustment and caution is advised in patients with hepatic impairment. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism must be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhea or amenorrhoea. Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics and human breast tumours has been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. HALDOL must be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.

Hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported with haloperidol.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with HALDOL and preventive measures undertaken.

Treatment response and withdrawal

In schizophrenia, the response to antipsychotic treatment may be delayed.

If antipsychotics are withdrawn, recurrence of symptoms related to the underlying condition may not become apparent for several weeks or months.

There have been very rare reports of acute withdrawal symptoms (including nausea, vomiting and insomnia) after abrupt withdrawal of high doses of antipsychotics. Gradual withdrawal is advisable as a precautionary measure.

Patients with depression

It is recommended that HALDOL is not used alone in patients in whom depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist.

Switch from mania to depression

There is a risk in the treatment of manic episodes of bipolar disorder for patients to switch from mania to depression. Monitoring of patients for the switch to a depressive episode with the accompanying risks such as suicidal behaviour is important in order to intervene when such switches occur.

Poor metabolisers of CYP2D6

HALDOL should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.

Paediatric population

Available safety data in the paediatric population indicate a risk of developing extrapyramidal symptoms, including tardive dyskinesia, and sedation. Limited long-term safety data are available.

Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol or other CNS depressants. Patients should be advised not to undertake activities requiring alertness such as driving or operating machinery during treatment, until their susceptibility is known.

Binison has a moderate influence on the ability to drive and use machines. Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol. It is recommended that patients be advised not to drive or operate machines during treatment, until their susceptibility is known.

HALDOL has a moderate influence on the ability to drive and use machines. Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol. It is recommended that patients be advised not to drive or operate machines during treatment, until their susceptibility is known.