SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Haloperidol 0.5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.5 mg of Haloperidol.

For full list of excipients, see 6.1

3    PHARMACEUTICAL FORM

Tablet

White, biconvex tablets of diameter 6.5 mm plain on one side and A488 on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Haloperidol is a neuroleptic butyrophenone drug indicated for the following conditions:

Adults

1.    Schizophrenia; treatment of symptoms and prevention of relapse.

2.    Other psychoses, especially paranoid.

3.    Mania and hypomania.

4.    Mental or behavioural problems such as aggression, hyperactivity and selfmutilation in the mentally retarded and in patients with organic brain damage.

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

6.    Intractable hiccup.

7.    Restlessness and agitation in the elderly.

8.    Gilles De La Tourette syndrome and severe tics.

Children

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

2.    Gilles De La Tourette syndrome.

3.    Childhood schizophrenia.

4.2 Posology and method of administration

Route of administration: Oral.

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

Adults:

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

Initial dosage:

Moderate symptomatology: 1.5 - 3.0 mg two to three times daily. Severe symptomatology/ Resistant patients: 3.0 - 5.0 mg two to three times daily.

In resistant schizophrenics, a maximum daily dosage of up to 30 mg may be necessary to achieve an optimal response.

The same starting doses may be employed in adolescents, who may, in certain cases require up to 30 mg.

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 mg or 10 mg per day.Too rapid a dosage reduction should be avoided.

Gilles De La Tourette syndrome. severe tics, intractable hiccup: Starting dose:

1.5 mg two times daily adjusted according to response. A daily maintenance dose of 10 mg may be required for Gilles De La Tourette Syndrome.

Children:

Childhood behavioural disorders/ schizophrenia:

The total maintenance dose : 0.025 - 0.05 mg per kg per 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 per day in most patients

Elderly:

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less haloperidol. Half the recommended adult starting dose should be sufficient. The optimal response in such patients is achieved with gradual titration.

Restlessness or agitation: Initial dose 1.5 - 3.0 mg, two to three times daily, titrated as required, to attain an effective maintenance dose (1.5 - 5.0 mg daily).

4.3 Contraindications

•    Comatose states, patients with parkinson’s disease or a sensitivity to haloperidol.

•    Use during breast feeding.

4.4 Special warnings and precautions for use

Antiparkinson agents should not be prescribed routinely, but only be given as required, because of the possible risk of impairing the efficacy of haloperidol

Caution is advised in the use of this drug in patients with liver disease, renal failure, phaeochromocytoma, thyrotoxicosis, depressive illness, severe cardiovascular disease, epilepsy and conditions predisposing to epilepsy or convulsions.

Rare cases of sudden and unexplained death have been reported in psychiatric patients receiving antipsychotic drugs including haloperidol. The nature of the evidence makes it impossible to determine the contributory role, if any, of the drug.

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 preventive measures undertaken

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.

Halaperidol is not licensed for the treatment of dementia-related behavioural disturbances.

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 the drug withdrawal should be gradual.

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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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 has been reported with the combined use of methyldopa and haloperidol.

The metabolism of tricyclic antidepressants and the antiparkinson effects of levodopa may be impaired by haloperidol. The dosage of anticonvulsants may need to be increased to take account of the lowered seizure threshold.

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

Antagonism of the effect of phenindione has been reported. The combined use of lithium and haloperidol has been reported to cause neurotoxic reactions, although there is no known mechanism for this effect. A report showing symptomless EEG (Electro-Encephalogram) abnormalities on such combined therapy has suggested that EEG monitoring might be advisable. It is recommended that lithium levels should always be maintained below 1 mmol/l when combined with haloperidol. If unexplained pyrexia occurs in the presence of extrapyramidal side effects, treatment with both lithium and haloperidol should be stopped immediately.

4.6 Pregnancy and lactation

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.

The safety of haloperidol in pregnancy has not been established. There is some evidence of harmful effects in some but not all animal studies. Human experience suggests there may be teratogenic effects, although a casual relationship has not been established. It should not be used in pregnancy or in women likely to become pregnant unless the benefit clearly justifies the possible hazards to the mother and foetus.

Haloperidol is excreted in breast milk and is not recommended during lactation. If the use of the drug is considered essential, breast feeding should be discontinued.

4.7 Effects on ability to drive and use machines

Haloperidol may impair alertness particularly with higher doses at the start of treatment and may be potentiated by alcohol. Patients should be advised not to drive or operate machinery during treatment until their individual susceptibility is known.

4.8 Undesirable effects

In common with all neuroleptics, extrapyramidal symptoms may occur. Acute dystonias may occur early in treatment. Parkinsonian rigidity, tremor and akathisia tend to appear less rapidly. Oculogyric crises and laryngeal dystonias have been reported. Because of the possible risk of impairing the efficacy of haloperidol, antiparkinson agents should not be prescribed routinely, but only given as required.

Tardive dyskinesia may develop during therapy or after drug therapy has been discontinued and can be precipitated or aggravated by antiparkinson drugs. The syndrome is unlikely to occur in the short term when recommended low or moderate doses of haloperidol are used. However, since its occurrence may be related to duration of treatment, as well as daily dose, haloperidol 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 prescribing of such agents requires especially careful assessment of risks versus benefit.

In common with other antipsychotics, 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 creatine phosphokinase (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. Dantrolene, bromocriptine, anticholinergics, amantadine or electroconvulsive therapy have been used in the active treatment of neuroleptic malignant syndrome.

Other adverse effects reported include gastrointestinal symptoms, nausea, loss of appetite and dyspepsia.

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo-menorrhoea. Weight changes may occur

Dose related hypotension is uncommon, but can occur, particularly in the elderly who are more susceptible to the sedative and hypotensive effects. Cardiac effects such as ventricular arrhythmias have very rarely been reported. Haloperidol, even in low dosage in susceptible (especially non-psychotic) individulals, may cause unpleasant subjective feelings of being mentally dulled or slowed down, dizziness, headache or paradoxical effects of excitement, agitation or insomia.

Oedema, various skin rashes and reactions, including exfoliative dermatitis and erythema multiforme; j aundice or transient abnormalities of liver function in the absence of jaundice; confusional states or epileptic fits, impairment of sexual function, including erection and ejaculation have been reported very rarely.

Blood dyscrasias including agranulocytosis and transient leucopenia, and photosensitive skin reactions have been reported very rarely.

Autonomic effects such as blurring of vision are uncommon.

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

Pregnancy, Puerperium and Perinatal Conditions such as drug withdrawal syndrome neonatal (see 4.6) - not known.

4.9 Overdose

In general, the signs and symptoms of overdose may be an exaggeration of the pharmacological effects, the most prominent of which would be severe extrapyramidal symptoms, hypotension or sedation. The patient would appear comatose with respiratory depression and hypotension severe enough to produce a shock - like state.

There is no specific antidote to haloperidol. Gastric lavage, establishment of a patient airway and, if necessary, mechanically assisted respiration are advised. Electrocardiographic monitoring should be immediately commenced and continued for as long as clinically indicated.

Hypotension and circulatory collapse may be counteracted by the use of intravenous fluids and vasopressor agents such as noradrenaline. Adrenaline should not be used.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

The mechanism of therapeutic effect of haloperidol is complex and is not clearly established. Haloperidol produces a selective effect on the CNS by competitive blockade of post-synaptic dopamine receptors in the mesolimbic dopaminergic system and increased turn-over of brain dopamine to produce the antipsychotic action.

Blockade of dopamine receptors also take place in the nigrostriatal dopamine pathway producing the extrapyramidal motor reactions. Blockade of the dopamine receptors in the tuberoinfundibular system decreases growth hormone release and increases prolactin release by the pituitary. There is also some blockade of alpha-adrenergic receptors of the autonomic system.

5.2    Pharmacokinetic properties

Haloperidol is readily absorbed from the gastrointestinal tract. Approximately 70% of the oral dose is absorbed. Haloperidol is extensively bound to protein and metabolised in the liver via oxidative N-dealkylation. Due to the first pass effect of metabolism in the liver, plasma concentrations following oral administration are lower than those following intramuscular administration.

There is also a wide interindividual variation in plasma concentration of haloperidol but in practice there is no simple correlation between the plasma concentration and the therapeutic effect.

The reported plasma half-life of haloperidol ranges from 13 to almost 40 hours. It is widely distributed in the body and crosses the blood brain barrier.

Approximately 40% of the single oral dose is excreted in the urine within 5 days, 1% of which is the unchanged drug. About 15 % is excreted via the bile in faeces. There is evidence of enterohepatic recycling of the drug.

5.3    Preclinical safety data

There are no other pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Lactose

Povidone Maize starch Magnesium stearate

Stearic acid

6.2 Incompatibilities

None reported.

6.3    Shelf life

Opaque plastic containers (see 1 and 2 of section 6.5 below): 36 months.

Blister packing: 24 months.

6.4    Special precautions for storage

Opaque plastic containers: Do not store above 25°C. Store in the original container.

Keep container tightly closed.

Blister packs: Do not store above 25°C. Store in the original package. Keep in the

outer carton.

6.5    Nature and contents of container

Haloperidol tablets are packed in the following containers and closures.

1    Opaque plastic containers composed of polypropylene tubes and polyethylene-made tamper-evident closures in pack sizes of 28 and 1000.

2    Opaque plastic containers composed of either high density polypropylene or high density polyethylene with tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene in pack sizes of 28 and 1000 with a packing inclusion of standard polyether foam or polyethylene or polypropylene-made filler.

3    Blister packs of aluminium/opaque PVC. It is subsequently packed in printed boxboard cartons in pack sizes of 28 and 112.

6.6 Special precautions for disposal

None stated.

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR,

United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/0531

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/04/2008

10    DATE OF REVISION OF THE TEXT

12/09/2013