Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Pinewood Laboratories Limited, Ballymacarbry, Clonmel, Co. Tipperary, Ireland
Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotics, including haloperidol (see section 4.8).
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 study, the rate of death in patients treated with antipsychotics 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 treatment of elderly patients with haloperidol is also associated with increased mortality. This association may be stronger for haloperidol than for atypical antipsychotic medicinal products, is most pronounced in the first 30 days after the start of treatment, and persists for at least 6 months. The extent to which this association is attributable to the medicinal product, as opposed to being confounded by patient characteristics, has not yet been elucidated.
QTc prolongation and/or ventricular arrhythmias, in addition to sudden death, have been reported with haloperidol (see sections 4.3 and 4.8). The risk of these events appears to increase with high doses, high plasma concentrations, in predisposed patients or with parenteral use, particularly intravenous administration.
Caution is advised in patients with bradycardia, cardiac disease, family history of QTc prolongation or history of heavy alcohol exposure. Caution is also required in patients with potentially high plasma concentrations (see section 4.4, Poor metabolisers of CYP2D6).
A baseline ECG is recommended before treatment. During therapy, the need for ECG monitoring for QTc interval prolongation and for ventricular arrhythmias must be assessed in all patients. Whilst on therapy, it is recommended to reduce the dose if QTc is prolonged, but haloperidol must be discontinued if the QTc exceeds 500 ms.
Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for ventricular arrhythmias and must be corrected before treatment with haloperidol is started. Therefore, baseline and periodic electrolyte monitoring is recommended.
Tachycardia and hypotension (including orthostatic hypotension) have also been reported (see section 4.8). Caution is recommended when haloperidol is administered to patients manifesting hypotension or orthostatic hypotension.
In randomised, placebo-controlled clinical studies in the dementia population, there was an approximately 3-fold increased risk of cerebrovascular adverse events with some atypical antipsychotics. Observational studies comparing the stroke rate in elderly patients exposed to any antipsychotic to the stroke rate in those not exposed to such medicinal products found an increased stroke rate among exposed patients. This increase may be higher with all butyrophenones, including haloperidol. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. Haloperidol must be used with caution in patients with risk factors for stroke.
Haloperidol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterized by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.
Tardive dyskinesia may appear in some patients on long-term therapy or after discontinuation of the medicinal product.
The syndrome is mainly characterized 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 dose is increased or when a switch is made to a different antipsychotic. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including haloperidol, must be considered.
Extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia). The use of haloperidol has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Acute dystonia may occur during the first few days of treatment with haloperidol, but later onset as well as onset after dose increases has been reported. Dystonic symptoms can include, but are not limited to, torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis. Males and younger age groups are at higher risk of experiencing such reactions. Acute dystonia may necessitate stopping the medicinal product.
Antiparkinson medicinal products of the anticholinergic type may be prescribed as required to manage extrapyramidal symptoms, but it is recommended that they are not prescribed routinely as a preventive measure. If concomitant treatment with an antiparkinson medicinal product 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 possible increase in intraocular pressure must be considered when anticholinergic medicinal products, including antiparkinson medicinal products, are administered concomitantly with haloperidol.
It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to seizures (e.g. alcohol withdrawal and brain damage).
As Haloperidol is metabolised by the liver, dose adjustment and caution is advised in patients with hepatic impairment (see sections 4.2 and 5.2). Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported (see section 4.8).
Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism must be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.
Hormonal effects of antipsychotics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhoea or amenorrhoea (see section 4.8). Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics and human breast tumours has been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Haloperidol must be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours (see section 5.3).
Hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported with haloperidol (see section 4.8).
Cases of venous thromboembolism (VTE) have been reported with antipsychotics. 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.
In schizophrenia, the response to antipsychotic treatment may be delayed.
If antipsychotics are withdrawn, recurrence of symptoms related to the underlying condition may not become apparent for several weeks or months.
There have been very rare reports of acute withdrawal symptoms (including nausea, vomiting and insomnia) after abrupt withdrawal of high doses of antipsychotics. Gradual withdrawal is advisable as a precautionary measure.
It is recommended that haloperidol is not used alone in patients in whom depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist (see section 4.5).
There is a risk in the treatment of manic episodes of bipolar disorder for patients to switch from mania to depression.
Monitoring of patients for the switch to a depressive episode with the accompanying risks such as suicidal behaviour is important in order to intervene when such switches occur.
Haloperidol should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.
Available safety data in the paediatric population indicate a risk of developing extrapyramidal symptoms, including tardive dyskinesia, and sedation. Limited long-term safety data are available.
Interaction studies have only been performed in adults.
Haloperidol is contraindicated in combination with medicinal products known to prolong the QTc interval (see section 4.3).
Examples include:
This list is not exhaustive.
Caution is advised when haloperidol is used in combination with medicinal products known to cause electrolyte imbalance (see section 4.4).
Haloperidol is metabolised by several routes (see section 5.2). The major pathways are glucuronidation and ketone reduction. The cytochrome P450 enzyme system is also involved, particularly CYP3A4 and, to a lesser extent, CYP2D6. Inhibition of these routes of metabolism by another medicinal product or a decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive (see section 5.2). Based on limited and sometimes conflicting information, the potential increase in haloperidol plasma concentrations when a CYP3A4 and/or CYP2D6 inhibitor is coadministered may range between 20 to 40%, although in some cases, increases of up to 100% have been reported. Examples of medicinal products that may increase haloperidol plasma concentrations (based on clinical experience or drug interaction mechanism) include:
This list is not exhaustive.
Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc prolongation (see section 4.4). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day).
It is recommended that patients who take haloperidol concomitantly with such medicinal products be monitored for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol, and the haloperidol dose be decreased as deemed necessary.
Coadministration of haloperidol with potent enzyme inducers of CYP3A4 may gradually decrease the plasma concentrations of haloperidol to such an extent that efficacy may be reduced. Examples include:
This list is not exhaustive.
Enzyme induction may be observed after a few days of treatment. Maximal enzyme induction is generally seen in about 2 weeks and may then be sustained for the same period of time after the cessation of therapy with the medicinal product.
During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the haloperidol dose increased as deemed necessary. After withdrawal of the CYP3A4 inducer, the concentration of haloperidol may gradually increase and therefore it may be necessary to reduce the haloperidol dose.
Sodium valproate is known to inhibit glucuronidation, but does not affect haloperidol plasma concentrations.
Haloperidol can increase the CNS depression produced by alcohol or CNS-depressant medicinal products, including hypnotics, sedatives or strong analgesics. An enhanced CNS effect, when combined with methyldopa, has also been reported.
Haloperidol may antagonise the action of adrenaline and other sympathomimetic medicinal products (e.g. stimulants like amphetamines) and reverse the blood pressure-lowering effects of adrenergic-blocking medicinal products such as guanethidine.
Haloperidol may antagonise the effect of levodopa and other dopamine agonists.
Haloperidol is an inhibitor of CYP2D6. Haloperidol inhibits the metabolism of tricyclic antidepressants (e.g. imipramine, desipramine), thereby increasing plasma concentrations of these medicinal products.
In rare cases the following symptoms were reported during the concomitant use of lithium and haloperidol: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, acute brain syndrome and coma. Most of these symptoms were reversible. It remains unclear whether this represents a distinct clinical entity.
Nonetheless, it is advised that in patients who are treated concomitantly with lithium and haloperidol, therapy must be stopped immediately if such symptoms occur.
Antagonism of the effect of the anticoagulant phenindione has been reported.
A moderate amount of data on pregnant women (more than 400 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of haloperidol. However, there have been isolated case reports of birth defects following foetal exposure to haloperidol, mostly in combination with other medicinal products. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of haloperidol during pregnancy.
Newborn infants 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, it is recommended that newborn infants be monitored carefully.
Haloperidol is excreted in human milk. Small amounts of haloperidol have been detected in plasma and urine of breastfed newborns of mothers treated with haloperidol. There is insufficient information on the effects of haloperidol in breastfed infants. A decision must be made whether to discontinue breastfeeding or to discontinue haloperidoltherapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Haloperidol elevates prolactin level. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients (see section 4.4).
Haloperidol has a moderate influence on the 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. It is recommended that patients be advised not to drive or operate machines during treatment, until their susceptibility is known.
The safety of Haloperidol was evaluated in 284 haloperidol-treated subjects who participated in 3 placebo-controlled clinical studies and in 1295 haloperidol-treated patients who participated in sixteen double blind active comparator-controlled clinical studies.
Based on pooled safety data from these clinical studies, the most commonly reported adverse reactions were: Extrapyramidal disorder (34%), Insomnia (19%), Agitation (15%), Hyperkinesia (13%), Headache (12%), Psychotic disorder (9%), Depression (8%), Weight increased (8%), Tremor (8%), Hypertonia (7%), Orthostatic hypotension (7%), dystonia (6%) and Somnolence (5).
In addition, the safety of haloperidol decanoate was evaluated in 410 patients who participated in 3 comparator studies (1 comparing haloperidol decanoate versus fluphenazine and 2 comparing the decanoate formula to oral haloperidol), 9 open label studies and 1 dose response study.
Table 5 lists adverse reactions as follows:
Adverse reaction frequencies are based on (or estimated from) clinical trials or epidemiology studies with haloperidol, and classified using 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.
The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.
Table 5. Adverse reactions:
Uncommon: Leukopenia
Not Known: Pancytopenia, Agranulocytosis, Thrombocytopenia, Neutropenia
Uncommon: Hypersensitivity
Not Known: Anaphylactic reaction
Rare: Hyperprolactinaemia
Not Known: Inappropriate antidiuretic hormone secretion
Not Known: Hypoglycaemia
Very Common: Agitation, Insomnia
Common: Psychotic disorder, Depression
Uncommon: Confusional state, Loss of libido, Libido decreased, Restlessness
Very Common: Extrapyramidal disorder, Hyperkinesia, Headache
Common: Tardive dyskinesia, Akathisia, Bradykinesia, Dyskinesia, Dystonia, Hypokinesia, Hypertonia, Dizziness, Somnolence, Tremor
Uncommon: Convulsion, Parkinsonism, Sedation, Muscle contractions involuntary
Rare: Neuroleptic malignant syndrome, Motor dysfunction, Nystagmus
Not Known: Akinesia, Cogwheel rigidity, Masked facies
Common: Oculogyric crisis, Visual disturbance
Uncommon: Vision blurred
Uncommon: Tachycardia
Not Known: Ventricular fibrillation, Torsade de pointes, Ventricular tachycardia, Extrasystoles
Common: Hypotension, Orthostatic hypotension
Uncommon: Dyspnoea
Rare: Bronchospasm
Not Known: Laryngeal oedema, Laryngospasm
Common: Vomiting, Nausea, Constipation, Dry mouth, Salivary hypersectretion
Common: Liver function test abnormal
Uncommon: Hepatitis, Jaundice
Not Known: Acute hepatic failure, Cholestasis
Common: Rash
Uncommon: Photosensitivity reaction, Urticaria, Pruritis, Hyperhidrosis
Not Known: Angioedema, Dermatitis exfoliative, Leukocytoclastic vasculitis
Uncommon: Torticollis, Muscle rigidity, Muscle Spasms, Musculoskeletal stiffness
Rare: Trismus, Muscle twitching
Rhabdomyolysis
Common: Urinary retention
Not Known: Drug withdrawal syndrome neonatal (see section 4.6)
Common: Erectile dysfunction
Uncommon: Amenorrhoea, Galactorrhoea, Dysmenorrhoea, Breast pain, Breast discomfort
Rare: Menorrhagia, Menstrual disorder, Sexual Dysfunction
Not Known: Priapism, Gynaecomastiaa
Uncommon: Hyperthermia, Oedema, Gait disturbance
Not Known: Sudden death, Face oedema, Hypothermia
Common: Weight increased, Weight decreased
Rare: Electrocardiogram QT prolonged
Electrocardiogram QT prolonged, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), torsade de pointes and sudden death have been reported with haloperidol.
Cardiac arrest has been reported with antipsychotics.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotics. The frequency is unknown.
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
None known.
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