SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Haloperidol 1.5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1.5 mg of haloperidol. For a full list of excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablet

White, biconvex tablet, embossed 3S2 on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Haloperidol tablets are indicated for the treatment of schizophrenia and other psychotic conditions including paranoid psychoses; mania and hypomania; behavioural or mental disorders including those associated with mental retardation such as aggression, hyperactivity and self-mutilation; and moderate to severe psychomotor agitation, excitement, violent or dangerous impulsive behaviour. They are also indicated for the treatment of Gilles de la Tourette syndrome and severe motor tics; restlessness and agitation in elderly patients; and childhood behavioural disorders especially with associated hyperactivity and aggression.

4.2 Posology and method of administration

For oral administration.

There is considerable inter-patient variation in the dosage requirements and the dosage should be individualised to meet the needs and response of each patient. In determining the initial dose, consideration should be given to the patient’s age, severity of symptoms and any previous response to other antipsychotic therapy. The dosage may be administered in single or divided doses; administration twice daily is usually sufficient.

Adults

Psychotic conditions, behavioural or mental disorders, moderate to severe psychomotor agitation or impulsive behaviour.

The usual initial dosage ranges from 1.5 to 20 mg daily, depending on the individual patient’s characteristics and the severity of symptoms. It may be necessary to increase the dosage gradually to obtain adequate control of symptoms, up to 30 mg daily.

The usual maintenance dosage ranges from 3 to 10 mg daily and this may be achieved by gradually reducing the dosage to the lowest effective maintenance level.

Gilles de la Tourette syndrome.

The initial dosage is usually 1.5 mg three times a day. This may be increased gradually during the acute phase of treatment. In order to obtain maximum control of symptoms a dosage of 6 to 30 mg daily may be required. When a satisfactory response has been achieved, the dosage should be gradually reduced to the lowest effective maintenance level.

Children 25 to 50 micrograms per Kg body weight daily to a maximum of 10 mg. Adolescents may require up to 30 mg daily.

The Elderly

Half the recommended adult starting dose may be sufficient for therapeutic response. As elderly or debilitated patients may be much more sensitive to haloperidol, the maximum and maintenance doses will generally be lower.

4.3 Contraindications

Haloperidol is contra-indicated in patients with a hypersensitivity to haloperidol; comatose states, CNS depression, Parkinson's disease, lesions of basal ganglia, patients who are breast-feeding.

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, bradycardia or second or third degree heart block, uncorrected hypokalaemia and other QT prolonging drugs (see section 4.5, interactions).

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

4.4 Special warnings and precautions for use

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

Care is required when administering haloperidol to patients with hepatic disease, renal failure, phaeochromocytoma, suffering from epilepsy and in conditions predisposing to epilepsy (e.g. alcohol withdrawal or brain damage). Haloperidol may be given to patients with epilepsy but usual anticonvulsant therapy should be continued, (see also section 4.5 interactions).

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.

Caution is advised in patients with cardiac disease, a 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 section 4.8 and 4.9) or with parental use, particularly intravenous administration.

Haloperidol should be used with caution in patients known to be slow metabolisers of CYP 2D6, and in patients receiving concomitant therapy with other drugs known to prolong QT interval such as metabolic inhibitors. Concomitant administration of antipsychotics should be avoided.

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, reduce dose if QT is prolonged and discontinue if QTc is >500ms.

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

An approximately 3-fold increased risk of cerebrovascular adverse events has 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 with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

In common with other neuroleptic drugs, haloperidol has been associated with neuroleptic malignant syndrome, an idiosyncratic response characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and coma. The onset of hyperthermia may be preceded by signs of autonomic dysfunction, such as tachycardia, labile arterial pressure and sweating which may act as warning signs. Recovery usually occurs within five to seven days after drug withdrawal and affected patients should be carefully monitored.

Tardive dyskinesia

As with all antipsychotic agents, tardive dyskinesia may develop in some patients on long-term haloperidol therapy or after withdrawal of the drug. Elderly patients on high dose therapy are at greater risk. Symptoms of tardive dyskinesia may include rhythmical involuntary movements of the tongue, face, mouth or jaw sometimes accompanied by involuntary movements of the extremities. They may persist for months or years and although they may gradually disappear in some patients, they appear to be permanent in others. At the first signs of tardive dyskinesia, which may be orofacial dyskinesia, the benefit of continued treatment should be balanced against the risk of developing persistent dyskinesia. In order to assess the need for continued neuroleptic therapy and to reveal any persisting dyskinesia, the drug may be withdrawn and the patient carefully observed with regard to the dyskinesia and to the psychotic condition. If it is necessary to reintroduce treatment, the antipsychotic agent may mask the syndrome. Anti-parkinsonian agents have proved to be of little value in this syndrome.

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 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.

Avoid concomitant neuroleptics.

Caution is required when using haloperidol in thyrotoxic patients and those with arteriosclerosis who may have occult or manifest lesions of the basal ganglia; such patients may be more prone to develop extrapyramidal symptoms.

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.

Haloperidol should be used with care in 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 paradoxical further lowering of the blood pressure may occur.

Venous thromboembolism

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.

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

The response to neuroleptic drugs may be delayed in schizophrenia. If these agents are withdrawn, recurrence of symptoms may not appear 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, 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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Haloperidol may potentiate the CNS-depressant effects of other CNS-depressant drugs including hypnotics, sedatives, alcohol, or strong analgesics. Haloperidol may also enhance the CNS effects of methyldopa.

Severe drowsiness is possible if indomethacin is given with haloperidol.

Concurrent use of haloperidol with tricyclic antidepressants, monoamine oxidase inhibitors, maprotiline or trazodone may prolong sedative and antimuscarinic actions. The antimuscarinic side effects of antidyskinetic agents, antihistamines or antimuscarinics would also be intensified.

Neurotoxic effects have been reported when haloperidol and lithium salts are given together.

Use of haloperidol with other medicines that cause extrapyramidal effects such as tricyclic antidepressants, and phenothiazines may cause potentiation of adverse effects. Haloperidol may also antagonise the effect of phenindione, adrenaline and other sympathomimetics and reverse the blood pressure-lowering effects of adrenergic-blocking agents such as guanethidine. The response to levodopa may also be impaired.

Rifampicin, carbamazepine and phenobarbital have been reported to reduce the plasma concentration of haloperidol. Therefore during combination treatment, Haloperidol dose should be adjusted, when necessary. After stopping this drug, it may necessary to reduce the dosage of Haloperidol.

The dosage of anticonvulsants may need to be increased because haloperidol treatment lowers the threshold for seizures. Haloperidol elevates prolactin levels and may interfere with the effects of bromocriptine.

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

Haloperidol may have a synergistic effect with other QT prolonging drugs and may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore coadministration should be avoided. Examples include certain Class IA and III antiarrhythmics, (such as quinidine, disopyramide, procainamide, amiodarone, sotalol and dofetilide), certain antimicrobials (such as sparfloxacin, moxifloxacin and erythromycin IV), tricyclic antidepressants (e.g. amitriptyline), tetracyclic antidepressants (e.g. maprotiline), other neuroleptics (e.g. phenothiazines, pimozide, and sertindole), antihistamines (e.g. terfenadine), cisapride, bretylium and antimalarials (e.g. quinine and mefloquine). This list is not comprehensive.

Concurrent use of drugs causing electrolyte imbalance is not recommended. Diuretics, in particular those causing hypokalaemia, should be avoided but, if necessary, potassiumsparing 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.

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

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 symptom less 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 the anticoagulant phenindione has been reported.

4.6 Pregnancy and lactation

The safety of haloperidol in pregnancy has not been established. There is evidence of harmful effects in some but not all animal studies. There have been a number of reports of birth defects following foetal exposure to haloperidol for which a casual role for haloperidol cannot be excluded. 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 should not be used during pregnancy unless the anticipated benefit clearly outweighs the potential risk to the foetus and duration of treatment should be as low and short as possible.

Haloperidol is excreted in breast milk. There have been isolated cases of extra pyramidal symptoms in breast-fed children. Breast-feeding should be discontinued if the use of haloperidol is considered essential.

4.7 Effects on ability to drive and use machines

Haloperidol may cause some degree of sedation or impaired alertness, particularly at higher doses and at the start of treatment, and may be potentiated by alcohol or other CNS depressants. Patients should be advised not to drive or operate machinery until their response to treatment is known.

4.8 Undesirable effects

The data provided below covers all haloperidol formulations including the Haloperidol Decanoate formulations.

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 and Haloperidol Decanoate. 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 form the available data).

Blood and lymphatic system disorders

Uncommon: Leukopenia

Not Known: Agranulocytosis; neutropenia; pancytopenia; thrombocytopenia

Immune system disorders

Uncommon: Hypersensitivity Not known: Anaphylactic reaction

Endocrine disorders

Rare: Hyperprolactinaemia

Not known: Inappropriate anti-diuretic hormone secretion

Metabolism and nutrition disorders

Not known: Hypoglycaemia

Psychiatric disorders

Very common: Agitation; Insomnia Common: Depression; Psychotic disorder

Uncommon: confusional states; Libido Decreased; Loss of libido; Restlessness

Not known: excitement

Nervous system disorders

Very common: Extrapyramidal disorder; Hyperkinesia; Headache Common: Tardive dyskinesia; Oculogyric Crisis; Dystonia; Dyskinesia; Akathisia; Bradykinesia; Hypokinesia; Hypertonia; Somnolence; Masked Faces, Tremor; Dizziness

Uncommon: Convulsion; Parkinsonism; Akinesia; Cogwheel rigidity; Sedation; Muscle Contractions Involuntary

Rare: Motor dysfunction; Neuroleptic malignant syndrome; Nystagmus;

Not known: mental dulled or slowed down, Dystonia producing Laryngeal/pharyngeal spasm associated with cyanosis, gagging, respiratory distress and asphyxia

Eye Disorders

Common: Visual disturbance Uncommon: Vision blurred

Cardiac disorders

Uncommon: Tachycardia

Not known: Ventricular Fibrillation; Torsade de pointes; Ventricular Tachycardia; Extrasystoles

Vascular disorders

Common: Orthostatic Hypotension; Hypotension

Respiratory, Thoracic and mediastinal

Uncommon: Dyspnoea Rare: Bronchospasm

Not known: Laryngeal Oedema; Laryngospasm

Gastrointestinal disorders

Common: Constipation; Dry mouth; salivary hypersecretion; Nausea; Vomiting

Not known: Gastrointestinal disturbance

Hepatobiliary disorders

Common: Liver function test abnormal Uncommon: Hepatitis; Jaundice

Not known: Acute Hepatic Failure; Cholestasis; Transient abnormalities of liver function in the absence of jaundice

Skin and subcutaneous tissue disorders

Common: Rash

Uncommon: Photosensitivity Reaction; Urticaria; Pruritis; Hyperhidrosis Not known: Leukocytoclastic Vasculitis; Dermatitis Exfoliative and erythema multiforme.

Musculoskeletal and connective tissue disorders

Uncommon: Torticollis; Muscle rigidity; Muscle Spasms; Musculoskeletal stiffness

Rare: Trismus; Muscle Twitching

Renal and urinary disorders

Common: Urinary retention

Pregnancy, puerperium and perinatal conditions

Not Known: Drug withdrawal syndrome neonatal (see 4.6)

Reproductive system and breast disorders

Common: Erectile dysfunction

Uncommon:    Amenorrhoea; Dysmenorrhoea; Galactorrhoea; Breast

discomfort; Breast Pain;

Rare: Menorrhagia; Menstrual Disorder; Sexual Dysfunction Not known: Gynaecomastia; priapism

General disorders and administration site conditions

Uncommon: Gait disturbance; Hyperthermia; Oedema Not known: Sudden Death; Face Oedema; Hypothermia

Investigations

Common: Weight increased; Weight decreased Rare: Electrocardiogram QT prolonged

Additional Information

Cardiac effects such as QT-interval prolongation, torsade de pointes, ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia), and cardiac arrest have been reported. These effects may occur more frequently with high doses, and in predisposed patients.

Toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported in patients taking haloperidol. The true incidence of these reports in not known.

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

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.

Overdose

Overdosage causes intensification of the pharmacological and adverse effects of the drug. Severe extrapyramidal symptoms, hypotension or sedation are likely to be most prominent. The patient may appear comatose with respiratory depression and hypotension. Extrapyramidal reactions may include muscle weakness or rigidity and localised or generalised tremor. With accidental overdosage in young children, hypothermia, bradycardia, sinus arrhythmia and hypertension have been reported.

There is no specific antidote. Treatment should be symptomatic and supportive. The stomach should be emptied by gastric aspiration and lavage. Establishment of a patent airway and artificial ventilation may be required. Hypotension may be counteracted by placing the patient in the head-down position and by use of a plasma expander and careful use of a vasopressor drug such as noradrenaline. Adrenaline should not be used. Severe extrapyramidal reactions should be treated with antiparkinsonian drugs.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Haloperidol is a member of the butyrophenone class of neuroleptic drugs and has anti-psychotic, anti-anxiety and antiemetic properties. Although the precise central mechanism of action has not been elucidated, antagonism of dopamine-mediated synaptic neurotransmission appears to be an important action of haloperidol and may be the primary action through which the antipsychotic and extra-pyramidal neurologic effects are mediated.

Within the autonomic nervous system, haloperidol displays less a-adrenergic antagonism than chlorpromazine and shows little anti-adrenergic activity in treated patients. The cholinergic blocking effects of anti-psychotic drugs are relatively weak and anti-cholinergic effects are infrequent with haloperidol, relative to other neuroleptic agents.

Orthostatic hypotension, seen with chlorpromazine and resulting from a combination of cental actions and peripheral a-adrenergic blockade, occurs much less frequently during therapy with haloperidol.

ATC Code: B05A D01 (antipsychotics, butyrophenone derivatives).

Pharmacokinetic properties

Haloperidol is readily absorbed from the gastro-intestinal tract. It is metabolised in the liver and is excreted in the urine and faeces. There is wide inter-subject variation in plasma concentrations of haloperidol. The drug is very extensively bound to plasma proteins. It is widely distributed in the body and it crosses the blood-brain barrier. The plasma half-life of haloperidol is reported to range from about 13 to nearly 40 hours.

5.3 Preclinical safety data

Preclinical information has not been included because the safety profile of haloperidol has been established after many years of clinical use. Please refer to section 4.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose (See section 4.3), Povidone,

Maize Starch,

Magnesium Stearate (E572), Stearic Acid (E570).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store below 25 °C. Protect from light.

6.5 Nature and contents of container

Blister pack, or HDPE or polypropylene tablet containers with caps or child resistant closures in packs of 25, 28, 50, 56, 84, 100, 250, 500 or 1000 tablets.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited,

Brampton Road Hampden Park Eastbourne BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 0289/0305

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

20/12/2006

10 DATE OF REVISION OF THE TEXT

29/06/2015