Symptoms: In general, the manifestations of Haloperidol-Apo 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-Apo. 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.
Comatose states; CNS depression; Parkinsons disease; known hypersensitivity to Haloperidol-Apo 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.
None known.
The safety of Haloperidol-Apo was evaluated in 284 Haloperidol-Apo-treated subjects who participated in 3 placebo-controlled, and in 1295 Haloperidol-Apo-treated subjects who participated in sixteen double blind active comparator-controlled clinical trials. The safety of Haloperidol-Apo decanoate was evaluated in 410 subjects who participated in 3 comparator trials (one comparing Haloperidol-Apo 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-Apo. 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).
| System Organ Class | Adverse Drug Reactions | ||||
| Frequency Category | |||||
| 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) | Not Known | |
| Blood and lymphatic System disorders | Leukopenia | Agranulocytosis; Neutropenia; Pancytopenia; Thrombocytopenia | |||
| Immune System disorders | Hypersensitivity | Anaphylactic reaction | |||
| Endocrine disorders | Hyperprolactinaemia | Inappropriate antidiuretic hormone secretion | |||
| Metabolism and Nutritional disorders | Hypoglycaemia | ||||
| Psychiatric disorders | Agitation; Insomnia | Depression; Psychotic disorder | Confusional state; Libido Decreased; Loss of libido; Restlessness | Apparent exacerbation of psychotic symptoms; | |
| Nervous System disorders | Extrapyramidal disorder; Hyperkinesia; Headache | Tardive dyskinesia; Oculogyric Crisis; Dystonia; Dyskinesia; Akathisia; Bradykinesia; Hypokinesia; Hypertonia; Somnolence; Masked Facies, Tremor; Dizziness | Convulsion; Parkinsonism; Akinesia; Cogwheel rigidity; Sedation; Muscle Contractions Involuntary | Motor dysfunction; Neuroleptic malignant syndrome; Nystagmus; | Drowsiness; Vertigo; Epileptic Seizure |
| Eye disorders | Visual disturbance | Vision blurred | |||
| Cardiac disorders | Tachycardia | Ventricular Fibrillation; Torsade de pointes; Ventricular Tachycardia; Extrasystoles | |||
| Vascular Disorders | Orthostatic Hypotension; Hypotension | Venous Thromboembolism; Deep Vein Thrombosis; Pulmonary Embolism | |||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Bronchospasm | Laryngeal Oedema; Laryngospasm | ||
| Gastrointestinal disorders | Constipation; Dry mouth; Salivary hypersecretion; Nausea; Vomiting | Loss of appetite; Dyspepsia | |||
| Hepatobiliary disorders | Liver function test abnormal | Hepatitis; Jaundice | Acute Hepatic Failure; Cholestasis | ||
| Skin and subcutaneous tissue disorders | Rash | Photosensitivity Reaction; Urticaria; Pruritis; Hyperhidrosis | Leukocytoclastic Vasculitis; Dermatitis Exfoliative; Toxic Epidermal Necrolysis; Stevens-Johnson Syndrome; Erythema Multiforme | ||
| Musculoskeletal and Connective Tissue disorders | Torticollis; Muscle rigidity; Muscle Spasms; Musculoskeletal stiffness | Trismus; Muscle Twitching | |||
| Renal and Urinary disorders | Urinary retention | ||||
| Pregnancy, Puerperium and Perinatal conditions | Drug withdrawal syndrome neonatal | ||||
| Reproductive System and Breast disorders | Erectile dysfunction | Amenorrhoea; Dysmenorrhoea; Galactorrhoea; Breast discomfort; Breast Pain | Menorrhagia; Menstrual disorder; Sexual Dysfunction | Gyanaecomastia, Priapism; Oligomenorrhoea | |
| General disorders and administration site conditions | Gait disturbance; Hyperthermia; Oedema | Sudden Death; Face Oedema; Hypothermia | |||
| Investigations | Weight increased; Weight decreased | Electrocardiogram QT prolonged | |||
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-Apo Oral Solution.
Tardive dyskinesia may occur during administration, particularly in patients over 50 years, or after withdrawal of neuroleptic drugs, including Haloperidol-Apo 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-Apo are used as recommended. However since its occurrence may be related to duration of treatment, as well as daily dose, Haloperidol-Apo 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-Apo 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-Apo, 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
There is no further information not included on other sections of this Summary of Product Characteristics.
Haloperidol-Apo 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.
Haloperidol-Apo is a neuroleptic of the butyrophenone class. The mechanism of the therapeutic effect is not clearly established, Haloperidol-Apo 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-Apo 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-Apo 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-Apo 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.
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-Apo 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-Apo. 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-Apo treatments, they may occur more frequently with high doses and in pre-disposed patients.
The risk-benefit of Haloperidol-Apo 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-Apo 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-Apo 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-Apo 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-Apo 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-Apo 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-Apo 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-Apo 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-Apo 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-Apo if its excretion is faster than that of Haloperidol-Apo 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-Apo.
Seizures/Convulsions
It has been reported that seizures can be triggered by Haloperidol-Apo. 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-Apo 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-Apo 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)
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.
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-Apo solution and half the normal starting dose may be sufficient for therapeutic response.
Haloperidol-Apo 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
Not applicable
