Haloperidol

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: carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s Wort (Hypericum perforatum). 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.

Haloperidol is metabolised by several routes. 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. 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:

• CYP3A4 inhibitors – alprazolam, fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, posaconazole, saquinavir, verapamil, voriconazole.
• CYP2D6 inhibitors – bupropion, chlorpromazine, duloxetine, paroxetine, promethazine, sertraline, venlafaxine.
• Combined CYP3A4 and CYP2D6 inhibitors: fluoxetine, ritonavir.
• Uncertain mechanism – buspirone.

This list is not exhaustive.

Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc prolongation. 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.

The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. Since haloperidol is extensively metabolised in the liver, it is recommended to halve the initial dose. Further doses may be administered and adjusted according to the patient’s response.

The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. No dose adjustment is recommended, but caution is advised when treating patients with renal impairment. However, patients with severe renal impairment may require a lower initial dose, with further doses administered and adjusted according to the patient’s response.

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.

Haloperidol can increase the CNS depression produced by alcohol or CNS-depressant medicinal products, including hypnotics, sedatives or strong analgesics.

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.

Haloperidol may antagonise the action of adrenaline and other sympathomimetic medicinal products (e.g. stimulants like amphetamines).

Haloperidol may 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.

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.

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.

An enhanced CNS effect, when haloperidol combined with methyldopa, has been reported.

Antagonism of the effect of the anticoagulant phenindione has been reported in co-administration with haloperidol.

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.

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.

Hormonal effects of antipsychotics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhoea or amenorrhoea. 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.

Hypoglycaemia has been reported with haloperidol.

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.

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.

Syndrome of inappropriate antidiuretic hormone secretion have been reported 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).

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. 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 breast-fed newborns of mothers treated with haloperidol. There is insufficient information on the effects of haloperidol in breast-fed infants. A decision must be made whether to discontinue breastfeeding or to discontinue haloperidol therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

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.

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.

Adverse reactions are listed as follows:

• Reported in clinical studies with haloperidol.
• Reported in clinical studies with haloperidol decanoate and relate to the active moiety.
• From postmarketing experience with haloperidol and haloperidol decanoate.

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.

Blood and lymphatic System disorders

Uncommon: Leukopenia

Not Known: Pancytopenia, Agranulocytosis, Thrombocytopenia, Neutropenia

Immune System disorders

Uncommon: Hypersensitivity

Not Known: Anaphylactic reaction

Endocrine disorders

Rare: Hyperprolactinaemia

Not Known: Inappropriate antidiuretic hormone secretion

Metabolism and Nutritional disorders

Not Known: Hypoglycaemia

Psychiatric disorders

Very Common: Agitation, Insomnia

Common: Psychotic disorder, Depression

Uncommon: Confusional state, Loss of libido, Libido decreased, Restlessness

Nervous System disorders

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

Eye disorders

Common: Oculogyric crisis, Visual disturbance

Uncommon: Vision blurred

Cardiac disorders

Uncommon: Tachycardia

Not Known: Ventricular fibrillation, Torsade de pointes, Ventricular tachycardia, Extrasystoles

Vascular Disorders

Common: Hypotension, Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Rare: Bronchospasm

Not Known: Laryngeal oedema, Laryngospasm

Gastrointestinal disorders

Common: Vomiting, Nausea, Constipation, Dry mouth, Salivary hypersectretion

Hepatobiliary disorders

Common: Liver function test abnormal

Uncommon: Hepatitis, Jaundice

Not Known: Acute hepatic failure, Cholestasis

Skin and subcutaneous tissue disorders

Common: Rash

Uncommon: Photosensitivity reaction, Urticaria, Pruritis, Hyperhidrosis

Not Known: Angioedema, Dermatitis exfoliative, Leukocytoclastic vasculitis

Musculoskeletal and Connective Tissue disorders

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

Rare: Trismus, Muscle twitching

Rhabdomyolysis

Renal and Urinary disorders

Common: Urinary retention

Pregnancy, Puerperium and Perinatal conditions

Not Known: Drug withdrawal syndrome neonatal

Reproductive System and Breast disorders

Common: Erectile dysfunction

Uncommon: Amenorrhoea, Galactorrhoea, Dysmenorrhoea, Breast pain, Breast discomfort

Rare: Menorrhagia, Menstrual disorder, Sexual Dysfunction

Not Known: Priapism, Gynaecomastiaa

General disorders and administration site conditions

Uncommon: Hyperthermia, Oedema, Gait disturbance

Not Known: Sudden death, Face oedema, Hypothermia

Investigations

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.

Class effects of antipsychotics

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.