Haloper

Haloperidol 10mg/5ml Oral Solution

Oral Solution

Haloperidol is a neuroleptic butyrophenone drug with a wide range of actions and is indicated in the following conditions:

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.

Paediatric population

- Childhood behavioural disorders especially when associated with hyperactivity and aggression.

- Gilles de la Tourette Syndrome.

-Childhood Schizophrenia.

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 haloperidol solution and half the normal starting dose may be sufficient for therapeutic response.

Haloperidol 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

Comatose states; CNS depression; Parkinsons disease; known hypersensitivity to haloperidol or any of the products ingredients; lesions of the basal ganglia. Clinical 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, uncorrected hypokalaemia and use of other QT prolonging drugs.

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 haloperidol 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 haloperidol. 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 haloperidol treatments, they may occur more frequently with high doses and in pre-disposed 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, 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. Haloperidol 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 Haloperidol 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, haloperidol 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. Haloperidol may impair the metabolism of tricyclic antidepressants (clinical significance unknown). If concomitant anti-parkinson medication is required, it may have to be continued after haloperidol 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. Haloperidol 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.

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

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, Haloperidol 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 Haloperidol if its excretion is faster than that of Haloperidol 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 Haloperidol.

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 convulsions (e.g., alcohol withdrawal and brain damage).

Hepatobiliary concerns

As Haloperidol 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 Haloperidol 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)

There is an increased risk of arrhythmias when haloperidol is used with drugs that prolong the QT interval.-Special Warnings and Precautions for Use). Diuretics, in particular those causing hypokalaemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.

Haloperidol is metabolised by several routes, including glucuronidation and the cytochrome P450 enzyme system (particularly CYP 3A4 or CYP 2D6). Inhibition of these routes of metabolism by another drug or a decrease in CYP 2D6 enzyme activity may result in increased haloperidol concentrations and an increased risk of adverse events, including QT-prolongation. In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterised as substrates or inhibitors of CYP 3A4 or CYP 2D6 isozymes, such as, itraconazole, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. Increases in QTc and extrapyramidal symptoms have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage.

Effect of Other Drugs on Haloperidol

Co-administration of enzyme-inducing drugs such as carbamazepine, phenobarbital and rifampicin with haloperidol may result in a significant reduction in 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 re-adjust the dose of haloperidol.

Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.

Effect of Haloperidol on Other Drugs

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.

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

Other Forms of Interaction

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 dose and lithium levels should be monitored and kept below 1 mmol/l. If symptoms of encephalopathy-like syndrome occur, therapy should be stopped immediately.

Antagonism of the effect of phenindione has been reported.

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

The safety of haloperidol in pregnancy has not been established. There is some evidence of harmful effects in some but not all animal studies. Neonates exposed to antipsychotics (including Haloperidol) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

There have been a number of reports of birth defects following foetal exposure to haloperidol for which a causal role for haloperidol cannot be excluded. Reversible extrapyramidal symptoms have been observed in neonates exposed to haloperidol in utero during the last trimester of pregnancy. Haloperidol should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.

Haloperidol is excreted in breast milk. There have been isolated cases of extrapyramidal symptoms in breast-fed children. If the use of haloperidol is essential, the benefits of breast feeding should be balanced against its potential risks.

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.

The safety of Haloperidol was evaluated in 284 haloperidol-treated subjects who participated in 3 placebo-controlled, and in 1295 haloperidol-treated subjects who participated in sixteen double blind active comparator-controlled clinical trials. The safety of Haloperidol decanoate was evaluated in 410 subjects who participated in 3 comparator trials (one comparing haloperidol vs. fluphenazine and two comparing the decanoate formulation to the oral formulation), 9 open label trials and 1 dose responsive trial. Based on pooled safety data from these clinical trials, the most commonly reported (% incidence) Adverse Drug Reactions (ADRs) were: Extrapyramidal disorder (34), Insomnia (19), Agitation (15), Hyperkinesia (13), Headache (12), Psychotic disorder (9), Depression (8), Weight increased (8), Orthostatic hypotension (7) and Somnolence (5).

Including the above mentioned ADRs, the following ADRs have been observed from clinical trials and post-marketing experiences reported with the use of Haloperidol. Frequencies displayed use the following convention:

Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Central Nervous System: In common with all neuroleptics, extrapyramidal symptoms may occur. Acute dystonia may occur early in treatment. Parkinsonian rigidity, tremor and akathisia tend to appear less rapidly. Oculogyric crises and laryngeal dystonia have been reported. Anti-parkinson agents should not be prescribed routinely, but only be given as required, because of the possible risk of impairing the efficacy of Haloperidol Oral Solution.

Tardive dyskinesia may occur during administration, particularly in patients over 50 years, or after withdrawal of neuroleptic drugs, including haloperidol and can be precipitated or aggravated by anti-parkinson drugs. The syndrome is unlikely to occur in the short term when low or moderate doses of haloperidol are used as recommended. However since its occurrence may be related to duration of treatment, as well as daily dose, Haloperidol Oral Solution 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.

The potential seriousness and unpredictability of tardive dyskinesia, and the fact that it has occasionally been reported to occur when neuroleptic antipsychotic drugs have been prescribed for relatively short periods in low doses, means that the prescribing of such agents requires especially careful assessment of risk versus benefit. 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.

In common with other antipsychotic drugs, haloperidol has been associated with rare cases of neuroleptic malignant syndrome (NMS), an idiosyncratic response characterised by hyperthermia, 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.

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. ECG changes have been reported, including prolongation of the Q-T interval, ventricular arrhythmias - VF, VT (rare) and Torsades de pointes. Sudden unexplained death and cardiac arrest have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

Symptoms: In general, the manifestations of haloperidol overdosage are an extension of its pharmacological actions, the most prominent of which would be severe extrapyramidal symptoms, hypotension and psychic indifference with a transition to sleep. The risk of cardiac arrhythmias should be considered. The patient may appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. Paradoxically hypertension rather than hypotension may occur. Convulsions may also occur.

Treatment: There is no specific antidote to haloperidol. A patent airway should be established and maintained with mechanically assisted ventilation if necessary. In view of isolated reports of arrhythmia, ECG monitoring is strongly advised. Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures. Adrenaline should not be used. The patient should be monitored carefully for 24 hours or longer, body temperature and adequate fluid intake should be maintained.

In case of severe extrapyramidal symptoms, appropriate anti-parkinson medication should be administered.

Haloperidol is a neuroleptic of the butyrophenone class. The mechanism of the therapeutic effect is not clearly established, haloperidol is known to produce a selective effect on the CNS by competitive blockade of postsynaptic dopamine receptors and an increased turnover of brain dopamine.

Haloperidol is readily absorbed from the gastrointestinal tract. It is metabolised in the liver and is excreted in the urine and faeces: there is evidence of enterohepatic recirculation. Haloperidol is very extensively bound to plasma proteins. It is widely distributed in the body and crosses the blood brain barrier.

There is wide interindividual variation in the pharmacokinetics of haloperidol and it is metabolised by the pathway of oxidative N-dealkylation and it has been reported to have a plasma half-life ranging from 13 to nearly 40 hours; its plasma half-life is prolonged during the night.

Steady state serum levels were usually achieved within 6 days on a fixed oral dosage.

There is no further information not included on other sections of this Summary of Product Characteristics.

Propylene glycol,

Methyl hydroxybenzoate,

Propyl hydroxybenzoate,

Lactic acid

Purified water.

None known.

36 months

Store below 25°C, protected from light.

Not applicable

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

PL 0427/0070

Date of first authorisation: 21 February 1984

Date of latest renewal: 15 December 1995

14^th October 2015