HALKID 200MICROGRAMS / ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Halkid 200micrograms/ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 200micrograms haloperidol.

Excipients with known effect:

Each ml of oral solution contains 0.8mg methyl parahydroxybenzoate (E218).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral Solution

Clear, colourless solution

4.1 Therapeutic indications

Halkid 200micrograms/ml Oral Solution is indicated for use in children when low doses of haloperidol need to be administered for the treatment of the following conditions:

Schizophrenia in adolescents aged 13 to 17 years when other pharmacological treatments have failed or are not tolerated.

Persistent, severe aggression in children and adolescents aged 6 to 17 years with autism or pervasive developmental disorders, when other treatments have failed or are not tolerated.

Tic disorders, including Tourette’s syn­drome, in children and adolescents aged 10 to 17 years with severe impairment after educational, psychological and other pharmacological treatments have failed.

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 patient’s age, severity of symptoms and previous response to other neuroleptic drugs.

Halkid Oral Solution should be used at the minimum dose that is clinically effective.

Treatment of schizophrenia in adolescents aged 13 to 17 years when other pharmacological treatments have failed or are not tolerated

The recommended dose is 0.5 to 3mg/day, administered orally in divided doses (2 to 3 times a day).

It is recommended to assess the individual benefit-risk when considering doses above 3mg/day.

The maximum recommended dose is 5mg/day.

The treatment duration must be individually evaluated.

Treatment of persistent, severe aggression in children and adolescents aged 6 to 17 years with autism or pervasive developmental disorders, when other treatments have failed or are not tolerated

The recommended doses are 0.5 to 3mg/day in children aged 6 to 11 years and 0.5 to 5mg/day in adolescents aged 12 to 17 years, administered orally in divided doses (2 to 3 times a day).

The need for continued treatment must be reassessed after 6 weeks.

Treatment of tic disorders, including Tourette’s syn­drome, in children and adolescents aged 10 to 17 years with severe impairment after educational, psychological and other pharmacological treatments have failed

The recommended doses are 0.5 to 3mg/day in children and adolescents aged 10 to 17 years, administered orally in divided doses (2 to 3 times a day).

The need for continued treatment must be reassessed every 6 to 12 months.

The quantity in millilitres (ml) required to achieve a given single dose using Halkid 200 micrograms/ml oral solution is presented in Table 1.

Table 1: Conversion table for Halkid 200micrograms/ml (0.2miligrams/ml) oral solution

Any dosage greater than 2mg (equivalent to more than 10ml of the

200micrograms/ml oral solution) should be given using the 1mg/ml oral solution.

The safety and efficacy of Halkid oral solution in children below the ages defined in the indications have not been established. Data are not available for children aged less than 3 years.

Treatment withdrawal

Gradual withdrawal of haloperidol is advisable (see section 4.4).

Missed dose

If patients miss a dose, it is recommended that they take the next dose as usual, and do not take a double dose.

Special populations

Renal impairment

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 subsequent adjustments at smaller increments and at longer intervals than in patients without renal impairment (see section 5.2).

Hepatic impairment

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, and adjust the dose with smaller increments and at longer intervals than in patients without hepatic impairment (see sections 4.4 and 5.2).

The box containing this medicine also contains a 10ml dosing syringe, with graduation marks of 0.25ml and a syringe adaptor.

Method of administration

For oral administration only.

Haloperidol oral solution is for oral use. It may be mixed with water to facilitate dose administration, but it must not be mixed with any other liquid. The diluted solution must be taken immediately.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Comatose state.

Central nervous system (CNS) depression.

Parkinson’s di­sease.

Dementia with Lewy bodies.

Progressive supranuclear palsy.

Known QTc interval prolongation or congenital long QT syndrome.

Recent acute myocardial infarction.

Uncompensated heart failure.

History of ventricular arrhythmia or torsades de pointes.

Uncorrected hypokalaemia.

Concomitant treatment with medicinal products that prolong the QT interval (see section 4.5).

4.4 Special warnings and precautions for use

Increased mortality in elderly people with dementia

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 antipsychotics are at an increased risk of death. Analyses of seventeen placebo-controlled studies (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in 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.

Cardiovascular effects

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.

Cerebrovascular events

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. Halkid must be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

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

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 Halkid, must be considered.

Extrapyramidal symptoms

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 Halkid, 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 Halkid 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 Halkid.

Seizures/convul­sions

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).

Hepatobiliary concerns

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).

Endocrine system concerns

Thyroxine 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 oligomenorrhea 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. Halkid 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).

Venous thromboembolism

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 Halkid and preventive measures undertaken.

Treatment response and withdrawal

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.

Patients with depression

It is recommended that Halkid 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).

Switch from mania to depression

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.

Poor metabolisers of CYP2D6

Halkid should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor.

Paediatric population

Available safety data in the paediatric population indicate a risk of developing extrapyramidal symptoms, including tardive dyskinesia, and sedation. Limited longterm safety data are available.

Excipient warnings:

This product contains methyl parahydroxybenzoate (E218) which may cause allergic reactions (possibly delayed).

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Cardiovascular effects

Halkid is contraindicated in combination with medicinal products known to prolong the QTc interval (see section 4.3). Examples include:

Class IA antiarrhythmics (e.g. disopyramide, quinidine).

Class III antiarrhythmics (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol).

Certain antidepressants (e.g. citalopram, escitalopram).

Certain antibiotics (e.g. azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, telithromycin).

Other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide, ziprasidone)

Certain antifungals (e.g. pentamidine).

Certain antimalarials (e.g. halofantrine).

Certain gastrointestinal medicinal products (e.g. dolasetron).

Certain medicinal products used in cancer (e.g. toremifene, vandetanib).

Certain other medicinal products (e.g. bepridil, methadone).

This list is not exhaustive.

Caution is advised when Halkid is used in combination with medicinal products known to cause electrolyte imbalance (see section 4.4).

Medicinal products that may increase haloperidol plasma concentrations

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:

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 (see section 4.4). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400mg/day) and paroxetine (20mg/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 Halkid dose be decreased as deemed necessary.

Medicinal products that may decrease haloperidol plasma concentrations

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 Halkid 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 Halkid dose.

Sodium valproate is known to inhibit glucuronidation, but does not affect haloperidol plasma concentrations.

Effect of haloperidol on other medicinal products

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.

Other forms of interaction

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 Halkid, therapy must be stopped immediately if such symptoms occur.

Antagonism of the effect of the anticoagulant phenindione has been reported.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 Halkid 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.

Breastfeeding

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 breastfed infants. A decision must be made whether to discontinue breastfeeding or to discontinue Halkid 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 (see section 4.4).

4.7 Effects on ability to drive and use machines

Halkid 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.

4.8 Undesirable effects

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 16 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 formulation to oral haloperidol), 9 open label studies and 1 dose response study.

Table 2 lists adverse reactions 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.

Table 2: Adverse reactions

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.

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 directly 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.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psycholeptics; antipsychotics; butyrophenone derivatives, ATC code: N05AD01.

Mechanism of action

Haloperidol is an antipsychotic belonging to the butyrophenones group. It is a potent central dopamine type 2 receptor antagonist, and at recommended doses, has low alpha-1 antiadrenergic activity and no antihistaminergic or anticholinergic activity.

Pharmacodynamic effects

Haloperidol suppresses delusions and hallucinations as a direct consequence of blocking dopaminergic signalling in the mesolimbic pathway. The central dopamine blocking effect has activity on the basal ganglia (nigrostriatal bundles). Haloperidol causes efficient psychomotor sedation, which explains the favourable effect on mania and other agitation syndromes.

The activity on the basal ganglia probably underlies the undesirable extrapyramidal motor effects (dystonia, akathisia and parkinsonism).

The antidopaminergic effects of haloperidol on lactotropes in the anterior pituitary explain hyperprolactinaemia due to inhibition of dopamine-mediated tonic inhibition of prolactin secretion.

5.2 Pharmacokinetic properties

Absorption

The average bioavailability of haloperidol after administration of the tablet or oral solution is 60 to 70%. Peak plasma levels of haloperidol are generally attained within 2 to 6 hours of oral dosing. A high inter-subject variability in plasma concentrations was observed. Steady state is reached within 1 week of treatment initiation.

Distribution

Mean haloperidol plasma protein binding in adults is approximately 88 to 92%. There is a high inter-subject variability for plasma protein binding. Haloperidol is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (mean values 8 to 21 l/kg after intravenous dosing). Haloperidol crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.

Biotransformation

Haloperidol is extensively metabolised in the liver. The main metabolic pathways of haloperidol in humans include glucuronidation, ketone reduction, oxidative N-dealkylation and formation of pyridinium metabolites. The metabolites of haloperidol are not considered to make a significant contribution to its activity; however, the reduction pathway accounts approximately for 23% of the biotransformation, and back-conversion of the reduced metabolite of haloperidol to haloperidol cannot be fully ruled out. The cytochrome P450 enzymes CYP3A4 and CYP2D6 are involved in haloperidol metabolism. Inhibition or induction of CYP3A4, or inhibition of CYP2D6, may affect haloperidol metabolism. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations.

Elimination

The terminal elimination half-life of haloperidol is on average 24 hours (range of means 15 to 37 hours) after oral administration. Haloperidol apparent clearance after extravascular administration ranges from 0.9 to 1.5 l/h/kg and is reduced in poor metabolisers of CYP2D6. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. After intravenous haloperidol administration, 21% of the dose was eliminated in the faeces and 33% in the urine. Less than 3% of the dose is excreted unchanged in the urine.

Linearity/non-linearity

A linear relationship exists between haloperidol dose and plasma concentrations in adults.

Special populations

Elderly

Haloperidol plasma concentrations in elderly patients were higher than in younger adults administered the same dose. Results from small clinical studies suggest a lower clearance and a longer elimination half-life of haloperidol in elderly patients. The results are within the observed variability in haloperidol pharmacokinetics. Dose adjustment is recommended in elderly patients (see section 4.2).

Renal impairment

The influence of renal impairment on the pharmacokinetics of haloperidol has not been evaluated. About one-third of a haloperidol dose is excreted in urine, mostly as metabolites. Less than 3% of administered haloperidol is eliminated unchanged in the urine. Haloperidol metabolites are not considered to make a significant contribution to its activity, although for the reduced metabolite of haloperidol, back-conversion to haloperidol cannot be fully ruled out. Even though impairment of renal function is not expected to affect haloperidol elimination to a clinically relevant extent, caution is advised in patients with renal impairment, and especially those with severe impairment, due to the long half-life of haloperidol and its reduced metabolite, and the possibility of accumulation (see section 4.2).

Because of the high haloperidol distribution volume and its high protein binding, only very small amounts are removed by dialysis.

Hepatic impairment

The influence of hepatic impairment on the pharmacokinetics of haloperidol has not been evaluated. However, hepatic impairment may have significant effects on the pharmacokinetics of haloperidol because it is extensively metabolised in the liver. Therefore, half the initial dose and caution is advised in patients with hepatic impairment (see sections 4.2 and 4.4).

Paediatric population

Limited plasma concentration data were established in paediatric studies including 78 patients with various disorders (schizophrenia, psychotic disorder, Tourette’s syn­drome, autism) who received oral haloperidol doses up to a maximum of 30 mg/day. These studies included mainly children and adolescents aged between 2 and

haloperidol in some animal models has caused significant QTc prolongation at doses around 0.3 mg/kg, producing Cmax plasma levels at least 7 to 14 times higher than the therapeutic plasma concentrations of 1 to 10 ng/ml that were effective in the majority of patients in clinical studies. These intravenous doses, which prolonged QTc, did not cause arrhythmias. In some animal studies, higher intravenous haloperidol doses of 1 mg/kg or greater caused QTc prolongation and/or ventricular arrhythmias at Cmax plasma levels at least 38 to 137 times higher than the therapeutic plasma concentrations that were effective in the majority of patients in clinical studies.

6.1 List of excipients

(S)-Lactic acid

Methyl parahydroxybenzoate (E218)

Purified water

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3

2 years

Discard 30 days after first opening.

6.4 Special precautions for storage

Do not store above 25°C.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Bottle: Ph. Eur Type III Amber glass.

Closure: Tamper evident, child resistant white plastic cap consists of polypropylene inner, polyethylene outer, expanded polyethylene (EPE) liner.

Dosing Device: A 10ml oral syringe with 0.25ml graduation marks and a syringe adaptor

Pack size: 100ml and 200ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Instructions for the use of syringe:

a) Open the bottle: press the cap and turn it anticlockwise (figure 1). Separate the adaptor from the syringe (figure 2).

b) Insert the adaptor into the bottle neck (figure 3). Ensure it is properly fixed. Take the syringe and put it in the adaptor opening (figure 4).

c) Turn the bottle upside down. Fill the syringe with a small amount of solution by pulling the piston down (figure 5A), then push the piston upwards in order to remove any possible bubble (figure 5B). Pull the piston down to the graduation mark corresponding to the quantity in millilitres (ml) prescribed by your doctor (figure 5C).

d) Turn the bottle the right way up (figure 6A). Remove the syringe from the adaptor (figure 6B).

e) During administration the oral syringe should be directed towards the cheek on the side of the mouth. Empty the content of the syringe by pushing the piston to the bottom of the syringe (figure 7). Close the bottle with the plastic screw cap. Wash the syringe with water (figure 8).

7. MARKETING AUTHORISATION HOLDER

Syri Limited

Unit 4, Bradfield Road,

Ruislip, Middlesex,

HA4 0NU, UK

Trading as:

Thame Laboratories, Unit 4, Bradfield Road, Ruislip, Middlesex, HA4 0NU, UK

OR

Trading as:

SyriMed,

Unit 4, Bradfield Road, Ruislip, Middlesex, HA4 0NU, UK.

8 MARKETING AUTHORISATION NUMBER(S)

PL 39307/0024

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/02/2022