Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adults:

• Schizophrenia: treatment of symptoms and prevention of relapse

• Other psychoses: especially paranoid

• Mania and hypomania

• Mental or behavioural problems such as aggression, hyperactivity and self mutilation in the mentally retarded and in patients with organic brain damage

• As an adjunct to short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour

• Intractable hiccup

• Restlessness and agitation in the elderly

• Gilles de la Tourette syndrome and severe tics.

Children:

Childhood behavioural disorders, especially when associated with hyperactivity and aggression

• Gilles de la Tourette syndrome

• Childhood schizophrenia.

Adult Dosage

For oral administration.

Dosage for all indications should be individually determined and is best initiated and titrated under close clinical supervision. To determine initial dose, consideration should be given to the patient's age, severity of symptoms and previous response to neuroleptic drugs.

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less Haldol. The normal starting dose should be halved, followed by a gradual titration to achieve optimal response.

Haldol should be used at the minimum dose that is clinically effective.

Adults

Schizophrenia, psychoses, mania and hypomania, mental or behavioural problems, psychomotor agitation, excitement, violent or dangerously impulsive behaviour, organic brain damage

Initial dose:

Moderate symptomatology: 1.5-3.0 mg bd or tds.

Severe symptomatology/resistant patients: 3.0-5.0 mg bd or tds.

The same starting dose may be employed in adolescents and resistant schizophrenics, who may require up to 30 mg/day.

Maintenance dosage:

Once satisfactory control of symptoms has been achieved dosage should be gradually reduced to the lowest effective maintenance dose, often as low as 5 or 10 mg/day. Too rapid a dosage reduction should be avoided.

Restlessness or agitation in the elderly

Initial dose: 1.5-3.0 mg bd or tds titrated as required, to attain an effective maintenance dose (1.5-30 mg daily).

Gilles de la Tourette syndrome, severe tics, intractable hiccup

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

Children

Childhood behavioural disorders and schizophrenia

Total daily maintenance dose of 0.025-0.05 mg/kg/day. Half the total dose should be given in the morning and the other half in the evening, up to a maximum of 10 mg daily.

Gilles de la Tourette syndrome

Oral maintenance doses up to 10 mg/day in most patients.

Contra Indications

Comatose states, CNS depression, Parkinson's disease, known hypersensitivity to haloperidol, lesions of basal ganglia.

In common with other neuroleptics, haloperidol has the potential to cause rare prolongation of the QT interval. Use of haloperidol is therefore contra-indicated in patients with clinically significant cardiac disorders e.g. recent acute myocardial infarction, uncompensated heart failure, arrhythmias treated with class IA and III antiarrhythmic medicinal products, QTc interval prolongation, history of ventricular arrhythmia or torsades de pointes clinically significant bradycardia, second or third degree heart block and uncorrected hypokalaemia. Haloperidol should not be used concomitantly with other QT prolonging drugs

Special Precautions

Cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including haloperidol.

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.

Cardiovascular effects

Very rare reports of QT prolongation and/or ventricular arrhythmias, in addition to rare reports of sudden death, have been reported with haloperidol. They may occur more frequently with high doses and in predisposed patients.

The risk-benefit of haloperidol 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, starvation or alcohol abuse, should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment, to obtain steady plasma levels.The risk of QT prolongation and/or ventricular arrhythmias may be increased with higher doses (see Sections 4.8 and 4.9) or with parenteral use, particularly intravenous administration. ECG monitoring should be performed for QT interval prolongation and for serious cardiac dysrhythmias if Haldol is administered intravenously.

Haloperidol should be used with caution in patients known to be slow metabolisers of CYP2D6, and during use of cytochrome P450 inhibitors. Concomitant use of antipsychotics should be avoided.

Baseline ECG is recommended prior to treatment in all patients, especially in the elderly and patients with a positive personal or family history of cardiac disease or abnormal findings on cardiac clinical examination. During therapy, the need for ECG monitoring (e.g. at dose escalation) should be assessed on an individual basis. Whilst on therapy, the dose should be reduced if QT is prolonged, and haloperidol should be discontinued if the QTc exceeds 500 ms.

Periodic electrolyte monitoring is recommended, especially for patients taking diuretics, or during intercurrent illness.

An approximately 3-fold increase 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. An increased risk cannot be excluded for other antipsychotics or other patient populations. Haloperidol should be used in caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, Haldol 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.

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 Haldol if its excretion is faster than that of Haldol 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 Haldol.

Seizures/Convulsions

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

Hepatobiliary concerns

As Haldol 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 Haldol 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.

Additional considerations

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

As with all antipsychotic agents, Haldol 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.

Caution is advised in patients with renal failure and phaeochromocytoma.

Interactions

In common with all neuroleptics, haloperidol can increase the central nervous system depression produced by other CNS-depressant drugs, including alcohol, hypnotics, sedatives or strong analgesics.

An enhanced CNS effect, when combined with methyldopa, has been reported.

Haloperidol may antagonise the action of adrenaline and other sympathomimetic agents and reverses the blood pressure lowering effects of adrenergic-blocking agents such as guanethidine.

The dosage of anticonvulsants may need to be increased to take account of the lowered seizure threshold.

Co-administration of enzyme-inducing drugs such as carbamazepine, phenobarbital and rifampicin with haloperidol may result in a significant reduction of haloperidol plasma levels. The haloperidol dose may therefore need to be increased, according to the patient's response. After stopping such drugs, it may be necessary to readjust the dosage of haloperidol.

Haloperidol may impair the metabolism of tricyclic antidepressants (clinical significance unknown) and the anti-Parkinson effects of levodopa.

In pharmacokinetic studies, increased haloperidol levels have been reported when haloperidol was given concomitantly with the following drugs: quinidine, buspirone and fluoxetine. Haloperidol plasma levels should therefore be monitored and reduced if necessary. Metabolic inhibitors of cytochrome P450, and specifically CYP2D6 may increase haloperidol levels.

Use of haloperidol with concomitant QT prolonging drugs may result in additional QT prolongation and is not recommended. Use of drugs that cause electrolyte imbalance may increase the risk of ventricular arrhythmias during concomitant use of haloperidol.

Antagonism of the effect of phenindione has been reported.

In rare cases, an encephalopathy-like syndrome has been reported in combination with lithium and haloperidol. It remains controversial whether these cases represent a distinct clinical entity or whether they are in fact cases of NMS and/or lithium toxicity. Signs of encephalopathy-like syndrome include confusion, disorientation, headache, disturbances of balance and drowsiness. One report showing symptomless EEG abnormalities on the combination has suggested that EEG monitoring might be advisable. When lithium and haloperidol therapy are used concomitantly, haloperidol should be given in the lowest effective dosage and lithium levels should be monitored and kept below 1 mmol/l. If symptoms of encephalopathy-like syndrome occur, therapy should be stopped immediately

Adverse Reactions

Central nervous system

In common with all neuroleptics, extrapyramidal symptoms may occur, eg tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia, oculogyric crisis and laryngeal dystonia.

Anti-Parkinson agents should not be prescribed routinely.

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 rhythmical 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.

However, since its occurrence may be related to duration of treatment, as well as daily dose, Haldol should be given in the minimum effective dose for the minimum possible time, unless it is established that long term administration for the treatment of schizophrenia is required.

It has been reported that fine vermicular movements of the tongue may be an early sign of tardive dyskinesia and that the full syndrome may not develop if the medication is stopped at that time.

The following effects have been reported rarely: confusional states or epileptic fits, depression, sedation, agitation, drowsiness, insomnia, headache, vertigo and apparent exacerbation of psychotic symptoms.

In common with other antipsychotic drugs, haloperidol has been associated with neuroleptic malignant syndrome (NMS), an idiosyncratic response characterised by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness, coma and elevated CPK. Signs of autonomic dysfunction such as tachycardia, labile arterial pressure and sweating may precede the onset of hyperthermia, acting as early warning signs. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Haloperidol, even in low dosage in susceptible (especially non-psychotic) individuals, may cause unpleasant subjective feelings of being mentally dulled or slowed down, dizziness, headache or paradoxical effects of excitement, agitation or insomnia.

Gastro-intestinal system

Gastro-intestinal symptoms, nausea, loss of appetite, constipation and dyspepsia have been reported.

Endocrinological system

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Hypoglycaemia and the syndrome of inappropriate antidiuretic hormone secretion have been reported rarely. Impairment of sexual function including erection and ejaculation has also been occasionally reported.

Cardiovascular system

Tachycardia and dose related hypotension are uncommon, but can occur, particularly in the elderly, who are more susceptible to the sedative and hypotensive effects. Less commonly, hypertension has also been reported.

Cardiac effects such as QT-interval prolongation, Torsade de Pointes, ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia, and cardiac arrest have been reported rarely. Cases of sudden unexplained death have also occurred. These effects may occur more frequently with high doses, intravenous administration and in predisposed patients (see 4.4 Special Warnings and Special Precautions for Use).

Autonomic nervous system

Dry mouth as well as excessive salivation, blurred vision, urinary retention and hyperhidrosis have been reported.

Dermatological system

The following effects have been reported rarely: oedema, various skin rashes and reactions including urticaria, exfoliative dermatitis and erythema multiforme. Photosensitive skin reactions have been reported very rarely.

Other adverse reactions

The following effects have been reported rarely: jaundice, cholestatic hepatitis or transient abnormalities of liver function in the absence of jaundice; priapism and weight changes. Temperature disorders may also occur, characteristically hyperthermia associated with NMS, although hypothermia has also been reported.

The following have been reported very rarely: blood dyscrasias, including agranulocytosis, thrombocytopenia and transient leucopenia; hypersensitivity reactions including anaphylaxis.

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