SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Haloperidol Oral Solution BP 10mg/5 ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml contains 10mg of Haloperidol

3. PHARMACEUTICAL FORM

Oral Solution

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Psychotic disorders - schizophrenia, mania and hypomania, especially paranoid psychoses. Mental or behavioural problems such as aggression, hyperactivity and self - mutilation in the mentally retarded. As an adjunct to the short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour. Gilles de la Tourette syndrome, intractable hiccup and severe tics. Childhood behaviour disorders, especially when associated with hyperactivity and aggression. Restlessness and agitation in the elderly. Nausea and vomiting.

4.2 Posology and method of administration

For all indications dosage should be individually determined, depending on the patient’s response. The initiation and titration of treatment should be under close clinical supervision.

The minimum clinically effective dose should be used.

The initial dose should be determined with consideration of the patient’s age, severity of symptoms and previous response to neuroleptics. In the elderly and debilitated and those with previously reported adverse reactions to neuroleptic drugs, the recommended starting dose given below should be halved. This can be gradually titrated to achieve an optimal response.

Higher doses than those recommended should only be considered in patients who have responded poorly at a lower dose.

All patients should, once control has been achieved, have their doses gradually reduced and the minimal effective maintenance dose determined.

An oral syringe is included in the pack to assist with administering the correct dose.

IN ADULTS

For the treatment of; -Schizophrenia, mania and hypomania, as an adjunct to the short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour, mental and behavioural problems, restlessness and agitation in the elderly.

Initial Dose;- Moderate Symptomatology - 1.5 - 3.0mg (0.75-1.5ml) bd or tds.

Severe Symptomatology- 3.0 - 5.0 mg (1.5 - 2.5 ml) bd or tds.

For elderly or debilitated patients half the initial adult dose is recommended.

Adolescents should receive the same doses though may in exceptional circumstance require up to a maximum of 30mg(15ml, 3 x 5ml spoonfuls) daily

Maintenance Dose;-

Once the control of symptoms has been achieved the dose should be gradually reduced to the lowest effective maintenance dose, typically 1-2mg (0.5-1.0ml) three to four times daily.

A rapid reduction in dose should be avoided.

For the treatment of;-

Gilles de la Tourette Syndrome, severe tic and intractable hiccup Initial Dose:- 1.5mg (0.75ml) tds adjusted according to response Maintenance Dose:-

Once the control of symptoms has been achieved the dose should be gradually reduced to the lowest effective maintenance dose. In Gilles de la Tourette Syndrome a daily maintenance dose of 5 ml may be required.

In general for all conditions the maximum daily dose is 30 mg.

IN CHILDREN

For the treatment of;-Childhood behavioural disorders

A total daily maintenance dose of 0.025-0.05 mg/kg/day, up to a maximum of 5ml daily. Half the total dose should be given in the morning, the remaining half in the evening.

AGE	IDEAL BODY WEIGHT (kg)	DAILY DOSE (ml) 0.025 - 0.05 mg/kg body weight/day	TWICE DAILY DOSAGE (ml) Morning & Evening
New born	3.4	0.04 - 0.09	0.02 - 0.04
1 month	4.2	0.05 - 0.11	0.03 - 0.05
3 month	5.6	0.07 - 0.14	0.04 - 0.07
6 month	7.7	0.10 - 0.19	0.05 - 0.10
1 year	10	0.13 - 0.25	0.07 - 0.13
3 year	14	0.18 - 0.35	0.09 - 0.18
5 year	18	0.23 - 0.45	0.12 - 0.23
7 year	23	0.29 - 0.58	0.15 - 0.29
12 year	37	0.46 - 0.93	0.23 - 0.46

For the treatment of:-Gilles de la Tourette Syndrome

Daily maintenance doses of up to 5 ml are required in most patients.

4.3 Contraindications

-    Comatose states

-    Patients with Parkinson’s disease

-    Patients with a known sensitivity to haloperidol or any of the product’s ingredients

-    Use during breast feeding

-    CNS depression.

-    Clinically significant cardiac disorders

-    QTc interval prolongation

-    History of ventricular arrhythmia or Torsades de pointes

Bradycardia or 2/3^o heart block Uncorrected hypokalemia Other QT prolonging drugs

4.4. Special warnings and precautions for use

Please also refer to section 4.5 Interactions with other medicinal products and other forms of interaction.

Caution is advised in patients with liver disease, renal failure and phaechromocytoma, prostatic hypertrophy, closed angle glaucoma, epilepsy and conditions predisposing to epilepsy or convulsions (e.g. alcohol withdrawal and brain damage). As severe neurotoxicity may result, haloperidol should only be used with great caution in patients with disturbed thyroid function. Antipsychotic therapy in these patients must always be accompanied by adequate management of the underlying thyroid dysfunction.

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; should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment to obtain steady plasma levels. Haloperidol should be used with caution in patients known to be slow metabolisers of CYP2D6, and during the use of cytochrome P450 inhbitors.

Baseline ECG 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 patient basis. Whilst on therapy, the dose should be reduced if QT is prolonged, and Haloperidol injection should be discontinued if the QTc exceeds 500 ms.

Periodic electrolyte monitoring is recommended, particularly if on diuretics or during inter-current illness.

For Patients at increased risk of arrhythmias, (those with hypokalaemia or a prolonged QT interval), and/or with severe cardiovascular disorders. The possibility of transient hypotension exists. Should hypotension occur and a vasopressor be required, adrenaline should not be used. Haloperidol may block adrenalin’s vasopressor activity and cause a further paradoxical lowering of blood pressure.

Depression, unless psychotic or part of the effective component of schizophrenia. As with all antipyschotic agents, haloperidol should not be used alone where depression is predominant. Where depression and psychosis co-exist, haloperidol may be combined with an antidepressant.

Concomitant use of antipsychotics should be avoided.

Please note:

Haloperidol may impair the metabolism of tricyclic antidepressants, (clinical significance unknown.)

Parkinsonism, the syndrome is exacerbated by haloperidol’s blockade of dopamine receptors.

Caution should be taken in extremely hot or cold weather, the drug interfering with the crucial role of dopamine in hypothalamic thermoregulation.

Urinary retention may be exacerbated.

Haloperidol may impair alertness, especially at the start of treatment.

These effects may be potentiated by alcohol.

Doses higher than those recommended, (an oral daily dose of 30 mg), should be considered carefully.

A gradual reduction in dose is recommended. An acute withdrawal should be avoided.

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 and preventative measures undertaken.

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.

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Haloperidol is not licenced for the treatment of dementia-related behavioural disturbances.

4.5 Interaction with other medicinal products and other forms of interaction

Adrenaline: concurrent use may block the alpha-adrenergic effects of adrenaline, severe hypotension and tachycardia may result.

Alcohol: concurrent use may potentiate alcohol intoxication.

Amphetamines: concurrent use may decrease stimulant effects of amphetamines due to alpha-adrenergic blockade, the antipsychotic effects of haloperidol may be reduced.

Anticholinergics (or other medication with anticholinergic activity): concurrent use may intensify anticholinergic effects such as confusion, hallucinations, nightmares,

and intraocular pressure. Paralytic ileus may also occur and the efficacy of haloperidol may be decreased because of reduced gastrointestinal absorption. Anticonvulsants (including barbiturates and carbamazepine): concurrent use may cause a change in the pattern and/or frequency of epileptiform seizures. Dose adjustments of anticonvulsants may be necessary. Serum concentrations

of haloperidol may be significantly reduced, (by up to 50% in the case of carbamazepine)

Antidepressants (including tricyclic antidepressants, 5HT reuptake inhibitors, MAO inhibitors, trazodone, maprotiline, Nefazodone): concurrent use may prolong and intensity the sedative and anticholinergic effects of these medications or of haloperidol.

Bromocriptine: haloperidol may increase serum prolactin concentrations and therefore concurrent use with bromocriptine may limit the effects of bromocriptine.

CNS depression producing medications (including sedatives, hypnotics, opiates): concurrent use may result in increased CNS and respiratory depression and increased hypotensive effects.

Diazoxide: concurrent use antagonises the inhibition of insulin release by diazoxide.

Dopamine: concurrent use may antagonise peripheral vasoconstriction produced by high doses of dopamine because of the alpha-adrenergic blocking action of haloperidol.

Ephedrine: concurrent use may decrease the pressor response to ephedrine. Guanethidine and guanadrel: concurrent use may decrease the hypotensive effects of these agents because of displacement from and inhibition of uptake into alpha-adrenergic neurons.

Levodopa andpergolide: concurrent use may decrease the therapeutic effects of these drugs because of blockade of dopamine receptors by haloperidol Lithium: at high doses of lithium concurrent use has been reported to be associated with irreversible neurological toxicity and brain damage, as well as neuromuscular symptoms and fever. If an unexplained pyrexia occurs in the presence of extrapyramidal side-effects, both lithium and haloperidol should be stopped immediately.

Methoxamine: prior administration of haloperidol may decrease the pressor effect and duration of action of methoxamine because of the alpha-adrenergic blocking action of haloperidol.

Methyldopa: concurrent use may cause unwanted mental effects such as disorientation and slowed or difficult thought processes.

Phenindione: concurrent use has been reported to interfere with the anticoagulant properties of phenindione in an isolated case. Caution is recommended for use with other anticoagulants.

Phenylephrine: prior administration of haloperidol may decrease the pressor effect of phenylephrine because of the alpha-adrenergic blocking action of haloperidol.

Use of haloperidol with concomitant QT prolonging drugs may result in additional QT prolongation and is not recommended (please refer to Section

4.3 - Contraindications).

Use of drugs that cause electrolyte imbalance may increase the risk of ventricular arrhythmias during concomitant use of haloperidol (please refer to Section 4.4 - Special Warnings and Special Precautions for Use).

Metabolic inhibitors of cytochrome P450, and specifically CYP2D6 may increase haloperidol levels.

4.6. Fertility, pregnancy and lactation

Haloperidol’s safe use in pregnancy and lactation has not been established. Reports exist of limb malformations in the first trimester, following the concurrent maternal use of haloperidol with other drugs of suspected teratogenicity. Animal studies have shown reduced fertility, delayed delivery, cleft palate and an increase in the number of stillbirths and newborn deaths at very high doses.

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.

Haloperidol is excreted in breast milk. Animal studies have shown that haloperidol in breast milk causes drowsiness and unusual muscle movements in nursing offspring. If the use of haloperidol is considered essential, breast feeding should be discontinued.

4.7 Effects on ability to drive and use machines

Haloperidol may impair alertness, especially at the start of treatment. The effects may be potentiated by alcohol. Patients should be warned of the risks of sedation and advised not to drive or operate machinery during treatment until their susceptibility is known.

4.8 Undesirable effects

Extrapyramidal Effects (e.g. neuromuscular (extrapyramidal) effects such as Parkinson like symptoms, akathisia, dyskinesia, dystonia, hyperreflexia, rigidity, opisthotonus and occasionally oculogyric crisis). Rarely dystonia has been reported to produce laryngeal/pharyngeal spasm associated with gagging, respiratory distress and asphyxia. Anti-Parkinson agents should not be prescribed routinely, to prevent or reverse the neuromuscular reactions associated with haloperidol. If prescribed, the administration of anti-Parkinson drugs should be based on the likelihood of the patient developing extrapyramidal effects as well as the risk of adverse reactions resulting from the agents extended use. Frequent re-evaluation of anti-Parkinson therapy is recommended.

Tardive dyskinesias and tardive dystonia. Tardive dyskinesias may develop in some patients on long term therapy, possibly in relation to total cumulative dose or following the drug’s withdrawal. The condition is characterised by rhythmical involuntary movements of the tongue, face or jaw, but such movements may be generalised. Its incidence in haloperidol users is reported as being approximately 15%, the elderly and those treated concurrently with anti-Parkinson drugs being at greatest risk. Symptoms may persist for several months to years, and in some patients appear permanent. On condition first being diagnosed consideration should be given to reducing or discontinuing antipyschotic medication. If withdrawal is undertaken this should be gradual, with gradual, with careful observation of both the dyskinesia and psychotic symptoms. In schizophrenia a recurrence of symptoms may not become apparent for several weeks or months.

Behavioural (e.g. motivational, emotional and behavioural changes, insomnia, depressive reactions and toxic confusional states, drowsiness, lethargy, stupor and catalepsy, confusion, restlessness, agitation, anxiety, euphoria and exacerbation of psychotic symptoms including hallucinations, alteration of sleep patterns).

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 been reported.

Cardiac effects such as QT-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 (e.g. nasal stuffiness, dry mouth, constipation, blurred vision, urinary retention and incontinence).

Endocrine (e.g. hyperprolactinaemia leading to oligo/amenorrhoea, gynaecomastia galactorrhoea, infertility (in the female) and impotence (in the male).

Gastrointestinal (e.g. heartburn, nausea, vomiting, weight loss, weight gain, constipation and diarrhoea).

Liver dysfunction with jaundice and eosinophilia. Additionally there may be a possible transient abnormality in liver function tests in the absence of jaundice.

Hyperpyrexia, heat stroke, headache, vertigo and cerebral seizures.

Dermatological (e.g. exfoliative dermatitis, erythema multiforme, and rarely photosensitisation.

Neuroleptic malignant syndrome (e.g. hyperthermia, muscle rigidity, autonomic instability, an altered level consciousness and coma.

i) Symptoms such as tachycardia, a labile arterial pressure and sweating may precede hyperthermia, and act as early warning of the condition.

ii) Recovery usually occurs within five to seven days of antipsychotic withdrawal.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs - Frequency unknown

Pregnancy, puerperium and perinatal conditions: Drug withdrawal syndrome neonatal (see 4.6) (frequency not known).

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.

4.9. Overdose

In general haloperidol overdosage manifests as an extension of its pharmacological action, the most prominent of which are severe extrapyramidal symptoms, hypotension, respiratory difficulty and sedation possibility leading to impaired consciousness. A patient may appear comatose with respiratory depression and hypotension, possibly severe enough to produce a shock-like state. The risk of ECG changes associated with torsades de points should be considered. Unexpected reactions, such as bradycardia and an episode of severe delayed hypertension have been reported.

Haloperidol has no specific antidote. A patent airway should be established and mechanically assisted ventilation supplied if necessary. ECG monitoring is strongly advised in view of isolated reports of haloperidol’s arrythmigenic action. Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures.

ADRENALINE SHOULD NOT BE USED

Body temperature and adequate fluid intake should be maintained.

Severe extrapyramidal symptoms may merit the administration of appropriate anti-Parkinson medication.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Haloperidol is a butyrophenone derivative, it has antagonist action on a variety of receptors including muscarinic cholinergic, a-adrenergic and serotonin, (5HT1a/5HT2), and pronounced extrapyramidal reactions and a low incidence of autonomic side-effects result from the compound’s pharmacological profile. Haloperidol is known to produce a selective effect on the central nervous system, by competitive blockade of postsynaptic dopamine (D2) receptors in the mesolimbic dopaminergic system and an increased turnover of brain dopamine to produce its tranquillizing effects.

5.2. Pharmacokinetic properties

Steady state serum levels of haloperidol are normally achieved within 6 days on a fixed oral dosage. Total elimination takes approximately 28 days. Haloperidol is readily absorbed from the gastrointestinal tract. It is metabolised in the liver and is excreted in the urine, and via the bile, in the faeces: there is evidence of enterohepatic recycling. Haloperidol has been reported to have a plasma half life ranging from about 13 to 40 hours. Haloperidol is about 92% bound to plasma proteins. It is widely distributed in the body and crosses the blood brain barrier. Haloperidol is excreted in breast milk.

5.3. Preclinical safety data

There is no preclinical safety data of relevance to the prescriber.

6.    PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Lactic Acid

Methylhydroxybenzoate Propylhydroxybenzoate Propylene Glycol Purified Water

Incompatibilities

None known.

6.3. Shelf life

36 months.

6.4. Special precautions for storage

Do not store above 25°C. Store in the original container.

6.5. Nature and contents of container

100 ml, 200 ml and 500 ml type III amber glass bottle with 28 x 18 ROPP LDPE plain white or aluminium cap with EPE (expanded polyethylene) wads and epoxy phenolic lacquer or child resistant closures with expanded polyethylene liners.

100 ml, 200 ml and 500 ml high density polyethylene bottle with 28mm white polypropylene closure.

6.6. Instruction for use, handling and disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Pinewood Laboratories Limited

Ballymacarbry

Clonmel

Co Tipperary

Ireland

8.    MARKETING AUTHORISATION NUMBER

04917/0024

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/02/2007

10    DATE OF REVISION OF THE TEXT

22/03/2016