1. Name Of The Medicinal Product
Dozic 5mg/5ml Oral Solution
Serenace Liquid 1mg/1ml
Haloperidol Oral Solution BP 5mg/5ml
2. Qualitative And Quantitative Composition
Haloperidol 5mg/5ml
3. Pharmaceutical Form
Oral Solution
4. Clinical Particulars
4.1 Therapeutic Indications
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.
- Nausea and vomiting.
Children
-Childhood behavioural disorders especially when associated with hyperactivity and aggression.
- Gilles de la Tourette Syndrome.
4.2 Posology And Method Of Administration
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 patients age, severity of symptoms and previous response to other neuroleptics.
Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less haloperidol. The normal starting dose should be halved, followed by a gradual titration to achieve optimal response.
For Oral Administration Only
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 - 3.0mg b.d. or t.d.s.
Severe symptomatology/resistant patients 3.0 - 5.0mg b.d. or t.d.s.
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 10mg/day. Too rapid a dosage reduction should be avoided.
Restlessness or agitation in the elderly: Initial dose 1.5 - 3.0mg b.d or t.d.s titrated as required, to attain an effective maintenance dose (1.5 - 30mg daily).
Gilles de la Tourette Syndrome, severe tics, intractable hiccup:
Starting dose 1.5mg t.d.s 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 30mg.
Children
Childhood behavioural disorders/schizophrenia: Total daily maintenance dose of 0.025 - 0.05mg/Kg/day. Half the total dose should be given in the morning and the other half in the evening, up to a maximum of 10mg daily.
Gilles de la Tourette Syndrome: Oral maintenance doses of up to 10mg/day in most patients.
4.3 Contraindications
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, uncomepensated heart failure, arrhythmias treated with class IA and III, antiarrhythmic medicinal products), QTc interval prolongation, history of ventricular arrhythmia or Torsades de pointes, uncorrected hypokalaemia and use of other QT prolonging drugs.
4.4 Special Warnings And Precautions For Use
Please also refer to 'Drug Interactions' section. Caution is advised in patients with liver disease, renal failure, phaeochromocytoma, epilepsy and conditions pre-disposing to epilepsy (eg alcohol withdrawal and brain damage) or convulsions. Haloperidol should only be used with great caution in patients with disturbed thyroid function. Antipsychotic therapy in those patients must always be accompanied by adequate management of the underlying thyroid dysfunction.
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, 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 (see section 4.5), 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 (See section 4.3). 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 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 Dozic 5mg/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.
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.
Dozic 5mg/5ml Oral Solution is not licensed for the treatment of dementia-related behavioural disturbances.
Excipient Warnings
This product contains parahydroxybenzoates which may cause allergic reactions (possibly delayed)
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, 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 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.
Haloperidol may impair the metabolism of tricyclic antidepressants (clinical significance unknown) and the anti-parkinson effects of levodopa.
Antagonism of the effect of phenindione has been reported.
Neurotoxic reactions during combined treatment with lithium and haloperidol have been reported, although there is no known mechanism for this effect. One report showing symptomless EEG abnormalities on the combination has suggested that EEG monitoring might be advisable. It is recommended that lithium levels should always be maintained below 1mmol/Lwhen combined with haloperidol. If unexplained pyrexia occurs in the presence of extrapyramidal side effects both lithium and haloperidol should be stopped immediately.
There is an increased risk of arrhythmias when haloperidol is used with drugs that prolong the QT interval (e.g. ClassIA and III antiarrhythmics, arsenic trioxide, halofantrine, thioridazine, pimozide, moxifloxacin, dolasetron mesilate, mefloquine, sertindole or cisapride), Drugs causing electrolyte imbalance. Concomitant use of haloperidol and amiodarone is not recommended.
Increased haloperidol levels have been reported in patients given haloperidol with fluoxetine, fluvoxetine, quinidine and buspirone.
Metabolic inhibitors of cytochrome P450 and specifically CYP2D6 may increase haloperidol levels.
4.6 Pregnancy And Lactation
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 causal relationship has not been established.
Haloperidol is excreted in breast milk. If the use of haloperidol is considered essential, breast feeding should be discontinued.
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
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.
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 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.
Gastrointestinal system: Gastrointestinal 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. 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.
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, weight changes may occur.
The following have been reported very rarely: blood dyscrasias, including agranulocytosis, thrombocytopenia and transient leucopenia, hypersensitivity reactions including anaphylaxis.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs – Frequency unknown
4.9 Overdose
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 cases of severe extrapyramidal symptoms, appropriate anti-parkinson medication should be administered.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
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.
5.3 Preclinical Safety Data
There is no further information not included on other sections of this Summary of Product Characteristics.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Propylene glycol, methyl hydroxybenzoate, propyl hydroxybenzoate, lactic acid and purified water
6.2 Incompatibilities
None known.
6.3 Shelf Life
36 Months
6.4 Special Precautions For Storage
Store below 25°C, protected from light.
6.5 Nature And Contents Of Container
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6.6 Special Precautions For Disposal And Other Handling
Not Applicable
Administrative Data
7. Marketing Authorisation Holder
Rosemont Pharmaceuticals Ltd
Rosemont House
Yorkdale Industrial Park
Braithwaite Street
Leeds
LS11 9XE
UK
8. Marketing Authorisation Number(S)
PL 0427/0069
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of First Authorisation: 21.02.84
Date of Renewal: 15.12.95
10. Date Of Revision Of The Text
27/01/2010
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