Haloperidol decanoate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HALOPERIDOL DECANOATE

Composition:

Active substance: haloperidol;

1 ml of solution contains haloperidol 50 mg (as haloperidol decanoate 70.52 mg);

Excipients: benzyl alcohol, sesame oil.

Pharmaceutical form. Injection solution.

Main physicochemical properties: yellow or yellowish-green clear solution, practically free from particles.

Pharmacotherapeutic group. Antipsychotic agents. Butyrophenone derivatives.

ATC code N05AD01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Haloperidol decanoate is an ester of haloperidol and decanoic acid, a long-acting antipsychotic agent belonging to the butyrophenone derivatives. After intramuscular injection, haloperidol decanoate is gradually released from muscle tissue and slowly hydrolyzed into free haloperidol, which enters systemic circulation.

Haloperidol is a potent central dopamine D2 receptor antagonist. At recommended doses, it has low alpha-1-adrenergic antagonistic activity and lacks antihistaminic or anticholinergic effects.

Pharmacodynamic effects

Haloperidol suppresses delusions and hallucinations by blocking dopaminergic pathways in mesolimbic structures. Central antidopaminergic effects occur in the basal ganglia (nigrostriatal pathways). Haloperidol effectively reduces psychomotor agitation, explaining its beneficial effect in mania and other syndromes associated with agitation.

Effects on the basal ganglia likely underlie the occurrence of extrapyramidal movement disorders (dystonia, akathisia, parkinsonism).

Antidopaminergic action of haloperidol on lactotroph cells in the anterior pituitary leads to hyperprolactinemia, resulting from removal of dopamine-mediated tonic inhibition of prolactin secretion.

Clinical studies

In clinical trials, patients were reported to have received prior treatment with oral haloperidol before switching to haloperidol decanoate. In some cases, patients had previously received another oral antipsychotic agent.

Pharmacokinetics.

Absorption

After intramuscular injection of haloperidol decanoate, free haloperidol is slowly and continuously released from the depot site. Plasma haloperidol concentrations increase gradually, typically reaching peak levels within 3–9 days after injection.

With regular monthly administration, steady-state plasma concentrations are achieved within 2–4 months.

Distribution.

Plasma protein binding in adult patients averages approximately 88–92%. The extent of plasma protein binding shows high inter-individual variability. Haloperidol rapidly distributes into various tissues and organs, as evidenced by its large volume of distribution (mean values ranging from 8 to 21 L/kg after intravenous administration). Haloperidol readily crosses the blood-brain barrier. It also crosses the placenta and is excreted in breast milk.

Biotransformation

Haloperidol undergoes extensive hepatic metabolism. The main metabolic pathways in humans include glucuronidation, reduction of ketones, oxidative N-dealkylation, and formation of pyridinium metabolites. Metabolites of haloperidol are considered to have negligible pharmacological activity; however, approximately 23% of the drug undergoes reductive metabolism, and a complete reversal of the reduced metabolite back to haloperidol cannot be entirely ruled out. The cytochrome P450 isoenzymes CYP3A4 and CYP2D6 are involved in haloperidol metabolism. Inhibition or induction of CYP3A4, or inhibition of CYP2D6, may affect haloperidol metabolism. Reduced CYP2D6 isoenzyme activity may lead to increased haloperidol concentrations.

Elimination.

The terminal elimination half-life of haloperidol after intramuscular administration of haloperidol decanoate averages 3 weeks. This is longer than with other dosage forms, where the elimination half-life of haloperidol averages 24 hours after oral administration and 21 hours after intramuscular injection.

Apparent clearance of haloperidol after extravascular administration ranges from 0.9 to 1.5 L/h/kg and is reduced in CYP2D6 poor metabolizers. Reduced CYP2D6 isoenzyme activity may lead to increased haloperidol concentrations. Inter-individual variability (coefficient of variation, %) in haloperidol clearance among patients with schizophrenia was 44% in a population pharmacokinetic analysis. After intravenous administration of haloperidol, 21% of the dose is excreted in feces and 33% in urine. Less than 3% of the dose is excreted unchanged in urine.

Linearity/non-linearity

The pharmacokinetics of haloperidol after intramuscular injections of haloperidol decanoate are dose-dependent. With doses below 450 mg, there is an almost linear relationship between dose and plasma haloperidol concentration.

Special patient populations

Elderly patients

Plasma haloperidol concentrations in elderly patients are higher than in younger adults when the same dose is administered. Results from small clinical studies indicate lower clearance and a longer elimination half-life of haloperidol in elderly patients. These findings fall within the range of observed pharmacokinetic variability of haloperidol. Dose adjustment of haloperidol is recommended in elderly patients (see section "Dosage and administration").

Renal impairment

The effect of renal impairment on haloperidol pharmacokinetics has not been studied. Approximately one-third of the haloperidol dose is excreted in urine, primarily as metabolites. Less than 3% of the dose is excreted unchanged in urine.

Haloperidol metabolites are considered to have negligible pharmacological activity, although a complete reversal of the reduced metabolite back to haloperidol cannot be entirely excluded. Although renal impairment is not expected to significantly affect haloperidol elimination clinically, caution is recommended when treating patients with renal dysfunction, especially in cases of severe renal impairment, due to the long elimination half-life of haloperidol and its reduced metabolite and the potential for accumulation (see section "Dosage and administration").

Due to the large volume of distribution and high plasma protein binding of haloperidol, only a minimal amount of the drug can be removed by dialysis.

Hepatic impairment

The effect of hepatic impairment on haloperidol pharmacokinetics has not been studied. However, liver dysfunction may significantly affect haloperidol pharmacokinetics, as the drug undergoes extensive hepatic metabolism. Dose adjustment and safety precautions are recommended for patients with hepatic impairment (see sections "Dosage and administration" and "Special precautions for use").

Pharmacokinetic/pharmacodynamic relationship

Therapeutic concentrations

According to published data from numerous clinical studies, therapeutic effect in most patients with acute or chronic schizophrenia is achieved at plasma haloperidol concentrations between 1 and 10 ng/mL. Some patients may require higher concentrations due to high inter-individual variability in haloperidol pharmacokinetics.

In patients experiencing a first episode of schizophrenia and treated with immediate-release haloperidol formulations, therapeutic response may be achieved at concentrations of at least 0.6 to 3.2 ng/mL. Occupancy of 60–80% of D2 receptors best ensures therapeutic response with minimal extrapyramidal symptoms. On average, plasma haloperidol concentrations within this range are achieved with daily doses of 1 to 4 mg.

Due to high inter-individual variability in haloperidol pharmacokinetics and concentration-dependent effects, individualized dosing of haloperidol decanoate is recommended based on the patient's response to treatment. Adequate time should be allowed after a dose adjustment to reach a new steady-state plasma concentration and additional time for the therapeutic response to manifest. In individual cases, measurement of haloperidol plasma concentration may be advisable.

Cardiovascular effects

The risk of QTc interval prolongation increases with increasing haloperidol dose and plasma concentration.

Extrapyramidal symptoms

Extrapyramidal symptoms may occur during treatment within the therapeutic dose range, although their frequency generally increases with doses exceeding the therapeutic range.

Clinical characteristics.

Indications. Maintenance therapy of schizophrenia and schizoaffective disorders in adult patients whose condition has stabilized on oral haloperidol.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Comatose state;
• Central nervous system (CNS) depression;
• Parkinson's disease;
• Dementia with Lewy bodies (DLB);
• Progressive supranuclear palsy;
• Prolonged QTc interval or congenital long QT syndrome;
• Recent acute myocardial infarction;
• Uncompensated heart failure;
• History of ventricular arrhythmia or torsades de pointes;
• Uncorrected hypokalemia;
• Concomitant treatment with medicinal products that prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Effects on the cardiovascular system

Haloperidol decanoate is contraindicated in combination with medicinal products that prolong the QTc interval (see section "Contraindications").

Examples of such medicinal products include:

• Class IA antiarrhythmics: (disopyramide, quinidine);
• Class III antiarrhythmics (amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
• Some antidepressants (citalopram, escitalopram);
• Some antibiotics (azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, telithromycin);
• Other antipsychotics (phenothiazine derivatives, sertindole, pimozide, ziprasidone);
• Some antifungal agents (pentamidine);
• Some antimalarial drugs (halofantrine);
• Some gastrointestinal agents (dolasetron);
• Some anticancer drugs (toremifene, vandetanib);
• Some other medicinal products (bepridil, methadone).

This list is not exhaustive.

Concomitant use of medicinal products that may cause electrolyte imbalance requires caution (see section "Special warnings and precautions for use").

Medicinal products that may increase haloperidol plasma concentration

Haloperidol metabolism occurs via several pathways (see section "Pharmacological properties"). The main pathways are glucuronidation and reduction to ketones. The cytochrome P450 enzyme system, particularly CYP3A4 and to a lesser extent CYP2D6, is also involved in metabolism. Inhibition of these metabolic pathways by another medicinal product or reduced activity of the CYP2D6 isoenzyme may lead to increased haloperidol concentration. An additive effect of CYP3A4 inhibition and reduced CYP2D6 isoenzyme activity is possible. Due to limited and sometimes conflicting data, the potential increase in haloperidol plasma concentration when co-administered with a CYP3A4 and/or CYP2D6 isoenzyme inhibitor may range from 20% to 40%, although increases up to 100% have been reported in some cases. Examples of medicinal products that may increase haloperidol plasma concentration (based on clinical experience or mechanisms of drug interactions) include:

• CYP3A4 isoenzyme inhibitors: alprazolam, fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, posaconazole, saquinavir, verapamil, voriconazole;
• CYP2D6 isoenzyme inhibitors: bupropion, chlorpromazine, duloxetine, paroxetine, promethazine, sertraline, venlafaxine;
• Combined CYP3A4 and CYP2D6 isoenzyme inhibitors: fluoxetine, ritonavir;
• Medicinal products with an undefined mechanism of action: buspirone.

This list is not exhaustive.

Increased haloperidol plasma concentration may increase the risk of adverse effects, including QTc interval prolongation (see section "Special warnings and precautions for use"). QTc prolongation has been observed when haloperidol was used in combination with metabolism inhibitors – ketoconazole (400 mg/day) and paroxetine (20 mg/day).

Patients receiving haloperidol in combination with such medicinal products should be monitored for symptoms of enhanced or prolonged pharmacological effect of haloperidol, and the dose of Haloperidol Decanoate should be reduced if necessary.

Medicinal products that may decrease haloperidol plasma concentration

Concomitant use of haloperidol with strong inducers of the CYP3A4 isoenzyme may gradually lead to decreased haloperidol plasma concentration to such an extent that haloperidol efficacy may be reduced. Examples include: carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort (Hypericum perforatum).

The list is not exhaustive.

Enzyme induction may be observed within a few days of treatment. Maximum enzyme induction is usually observed approximately 2 weeks after initiation and may persist for about the same duration after discontinuation of the inducing agent. When CYP3A4 inducers are used concomitantly, patients should be monitored and the dose of Haloperidol Decanoate may need to be increased. After discontinuation of a CYP3A4 inducer, haloperidol concentration may gradually increase, thus requiring a potential dose reduction of Haloperidol Decanoate.

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

Effect of haloperidol on other medicinal products

Haloperidol may potentiate the effects of agents that depress the central nervous system (CNS), including alcohol, hypnotics, sedatives, and strong analgesics. Enhanced CNS effects have also been reported when used concomitantly with methyldopa.

Haloperidol may exhibit antagonism toward the effects of epinephrine (adrenaline) and other sympathomimetic medicinal products (e.g., stimulants such as amphetamines) and may alter the antihypertensive effects of agents such as guanethidine.

Haloperidol may reduce the efficacy of levodopa and other dopamine agonists.

Haloperidol is an inhibitor of CYP2D6. Haloperidol decanoate inhibits the metabolism of tricyclic antidepressants (e.g., imipramine, desipramine), thereby increasing their plasma concentrations.

Other forms of interaction

In rare cases, when lithium and haloperidol are used concomitantly, symptoms such as encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, acute brain syndrome, and coma have been observed. Most of these symptoms are reversible. Whether these symptoms represent a distinct nosological entity remains unclear.

However, therapy with lithium and haloperidol decanoate should be discontinued immediately if such symptoms occur.

Antagonism of haloperidol toward the anticoagulant phenindione has been reported.

Special precautions for use.

Increased mortality in elderly patients with dementia

In patients with psychiatric disorders receiving antipsychotic agents, including haloperidol, isolated cases of sudden death have been reported (see section "Adverse reactions").

Elderly patients with psychosis associated with dementia who receive antipsychotic drugs have an increased risk of death. Analysis of 17 placebo-controlled studies (modal duration of 10 weeks) involving patients treated with atypical antipsychotics showed that the risk of death in patients receiving treatment was 1.6–1.7 times higher than in patients receiving placebo. In a 10-week controlled study, the mortality rate in treated patients was approximately 4.5%, compared to approximately 2.6% in the placebo group. Although causes of death varied, most fatal events were cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia). Observational studies suggest that the use of haloperidol in elderly patients is also associated with increased mortality. This association may be more pronounced with haloperidol than with atypical antipsychotics and is most evident during the first 30 days after initiation of treatment, persisting for at least 6 months. The extent to which this risk is attributable to the drug versus patient characteristics has not yet been established.

Haloperidol decanoate is not indicated for the treatment of behavioral disorders associated with dementia.

Effects on the cardiovascular system

Isolated cases of QTc interval prolongation and/or ventricular arrhythmias, as well as rare reports of sudden death, have been reported with haloperidol use (see sections "Contraindications" and "Adverse reactions"). The risk of such disorders increases with high doses of the drug, high plasma concentrations, in patients predisposed to such conditions, and with intravenous administration.

Haloperidol decanoate must not be administered intravenously.

Caution is recommended when administering the drug to patients with bradycardia, cardiac disease, a family history of QTc prolongation, or a history of severe alcohol abuse. Caution is also required in patients who may have potentially high plasma concentrations of the drug (see section "Special precautions for use": CYP2D6 poor metabolizers).

An ECG is recommended before initiating haloperidol treatment. During treatment, regular ECG monitoring should be considered to detect QTc prolongation and ventricular arrhythmias in all patients. Dose reduction is recommended if QTc prolongation occurs during treatment. If QTc duration exceeds 500 ms, haloperidol should be discontinued.

Electrolyte imbalances such as hypokalemia and hypomagnesemia increase the risk of ventricular arrhythmias and should be corrected before starting haloperidol treatment. Therefore, baseline and periodic monitoring of electrolyte levels is recommended.

Tachycardia and arterial hypotension (including orthostatic hypotension) have also been reported (see section "Adverse reactions"). Caution is recommended when prescribing haloperidol to patients with arterial or orthostatic hypotension.

Cerebrovascular disorders

In randomized, placebo-controlled clinical trials in patients with dementia, treatment with certain atypical antipsychotics was associated with approximately a threefold increase in the risk of cerebrovascular adverse events.

Observational studies comparing stroke incidence in elderly patients receiving any antipsychotic medication versus those not receiving such drugs have shown an increased frequency of stroke in the first group. The risk of stroke increases with the use of all butyrophenones, including haloperidol. The mechanism of this increased risk is unknown. An increased risk cannot be ruled out in other patient groups. Haloperidol decanoate should be used with caution in patients with risk factors for stroke.

Malignant neuroleptic syndrome

Haloperidol use has been associated with the development of neuroleptic malignant syndrome—a rare idiosyncratic reaction characterized by hyperthermia, generalized muscle rigidity, autonomic instability, altered mental status, and elevated serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment must be discontinued immediately, and appropriate supportive therapy should be initiated under close observation.

Tardive dyskinesia

Tardive dyskinesia may occur in some patients during prolonged treatment or after discontinuation of the drug. This syndrome is primarily characterized by involuntary rhythmic movements of the tongue, face, mouth, or jaw. In some patients, these manifestations may become permanent. The syndrome may be masked by resuming therapy, increasing the dose, or switching to another antipsychotic agent. If signs of tardive dyskinesia appear, antipsychotic therapy, including haloperidol, should be discontinued as soon as possible.

Extrapyramidal symptoms

Extrapyramidal symptoms such as tremor, rigidity, hypersalivation, bradykinesia, akathisia, and acute dystonia may occur during antipsychotic treatment.

Haloperidol use has been associated with akathisia, characterized by subjective distress or anxiety and an urge to keep moving, often accompanied by an inability to sit or stand still. Akathisia most commonly develops within the first few weeks of treatment. Dose escalation may be harmful in patients with such symptoms.

Acute dystonia may occur within the first few days of haloperidol treatment, although later onset or development after dose increase has also been reported. Symptoms of dystonia may include torticollis, facial grimacing, masticatory muscle spasm (trismus), tongue protrusion, and abnormal eye movements, including oculogyric crisis. The risk of such reactions is higher in male patients and younger individuals. Acute dystonia may necessitate discontinuation of the drug.

Antiparkinsonian agents with anticholinergic activity may be prescribed if necessary; however, their routine use as prophylaxis is not recommended. If concomitant antiparkinsonian treatment is required, it should be continued after discontinuation of haloperidol decanoate, as antiparkinsonian agents are eliminated more rapidly than haloperidol decanoate, to avoid development or worsening of extrapyramidal symptoms. When anticholinergic agents, including antiparkinsonian drugs, are used concomitantly with haloperidol decanoate, possible elevation of intraocular pressure should be considered.

Seizures

Haloperidol use has been reported to provoke seizures. Caution is required when treating patients with epilepsy or those predisposed to seizures (e.g., alcohol withdrawal syndrome or traumatic brain injury).

Hepatic and biliary disorders

Since the drug is metabolized in the liver, dose adjustment and precautionary measures are recommended in patients with hepatic impairment (see sections "Dosage and administration" and "Pharmacological properties"). Isolated cases of impaired liver function or hepatitis, mostly cholestatic, have been reported (see section "Adverse reactions").

Endocrine system disorders

Thyroxine enhances the toxicity of haloperidol. Antipsychotics should be used with caution in patients with hyperthyroidism and only in combination with therapy aimed at achieving an euthyroid state.

Hormonal effects of antipsychotics include hyperprolactinemia, which may cause galactorrhea, gynecomastia, and oligo- or amenorrhea (see section "Adverse reactions").

Tissue culture studies indicate that prolactin may stimulate the growth of human breast tumor cells. Although a clear association between antipsychotic use and breast cancer has not been established in clinical and epidemiological studies, caution is recommended when treating patients with relevant medical history. Haloperidol decanoate should be used with caution in patients with pre-existing hyperprolactinemia and in those with possible prolactin-dependent tumors.

Very rare cases of hypoglycemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported (see section "Adverse reactions").

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported during antipsychotic treatment. Since patients receiving antipsychotic therapy often have acquired VTE risk factors, all possible risk factors should be identified before and during haloperidol treatment, and preventive measures should be taken.

Initiation of treatment

Patients planned to receive haloperidol decanoate should first be treated with oral haloperidol to reduce the likelihood of unpredictable adverse sensitivity to haloperidol.

Patients with depression

Haloperidol decanoate is not recommended as monotherapy for patients with predominant depressive symptoms. It may be combined with antidepressants for the treatment of conditions characterized by a combination of depression and psychosis (see section "Interaction with other medicinal products and other forms of interaction").

Poor metabolizers of CYP2D6 isoenzyme

Haloperidol decanoate should be used with caution in patients who are poor metabolizers of cytochrome P450 (CYP) 2D6 and during concomitant use of CYP3A4 inhibitors.

Excipients in haloperidol decanoate

Haloperidol decanoate injection solution contains 15 mg/mL of benzyl alcohol, which may cause anaphylactoid reactions.

Haloperidol decanoate injection solution contains sesame oil. Sesame oil has very rarely caused severe allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

According to data on haloperidol use in pregnant women (over 400 pregnancies with known outcomes), there is no confirmed evidence of teratogenic effects or fetal/neonatal toxicity. However, isolated reports of congenital malformations have been associated with haloperidol use in combination with other drugs during pregnancy. Toxic effects on reproductive function have been demonstrated in animal studies. Haloperidol decanoate use during pregnancy is not recommended.

Newborns whose mothers received antipsychotics (including haloperidol) during the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms after delivery, which may vary in severity and duration. Agitation, hypertonia, hypotonia (increased or decreased muscle tone), tremor, somnolence, respiratory distress, or feeding difficulties have been reported. Therefore, newborns should be closely monitored.

Breastfeeding

Haloperidol decanoate passes into breast milk. Small amounts of haloperidol have been detected in the plasma and urine of newborns whose mothers received haloperidol. Information on the effects of haloperidol in breastfed infants is limited. The decision to discontinue breastfeeding or to discontinue haloperidol decanoate therapy should be made considering the benefits of breastfeeding for the child and the benefits of treatment for the mother.

Fertility

Haloperidol increases prolactin levels. Hyperprolactinemia may suppress the synthesis of gonadotropin-releasing hormone (GnRH) in the hypothalamus, leading to reduced gonadotropin secretion. This may impair reproductive function by inhibiting sex steroid synthesis in the gonads of both women and men (see section "Special precautions for use").

Ability to affect reaction speed when driving or operating machinery
Haloperidol decanoate has a moderate effect on the ability to drive or operate machinery. Sedation or impaired concentration may occur, especially with high doses and at the beginning of treatment. These effects may be intensified by alcohol consumption. Patients are advised to refrain from driving or performing work involving a high risk of injury during haloperidol treatment until their individual response to the drug is known.

Dosage and administration.

Initiation of treatment and dose titration should be performed under close medical supervision.

Dosage

The individual dose will depend on both the severity of symptoms and the current dose of oral haloperidol. The lowest effective dose should always be used.

The initial dose of haloperidol decanoate should be determined based on a multiple of the daily dose of oral haloperidol. Specific recommendations for switching from other antipsychotics have not been established (see section "Pharmacological properties").

Adults (aged 18 years and older)

Table 1. Recommended doses of haloperidol decanoate for adult patients (aged 18 years and older)

Special patient groups

Elderly patients

Table 2. Recommendations for haloperidol decanoate dosing in elderly patients.

Renal impairment

The effect of renal impairment on the pharmacokinetics of haloperidol has not been studied.

Dose adjustment is not recommended, but caution should be exercised when treating patients with renal impairment. Patients with severe renal impairment may require a lower initial dose, with subsequent dose increases in smaller increments and at longer intervals than in patients with normal renal function (see section "Pharmacological properties").

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of haloperidol has not been studied.

Since haloperidol undergoes active metabolism in the liver, it is recommended to reduce the initial dose by half and to increase it in smaller increments and at longer intervals than in patients with normal hepatic function (see sections "Special warnings and precautions for use" and "Pharmacological properties").

Use in children

The safety and efficacy of haloperidol decanoate in children and adolescents (under 18 years of age) have not been established. Data are lacking.

Method of administration

The product is intended for intramuscular use only! Intravenous administration is contraindicated!

Haloperidol decanoate is administered as a single deep intramuscular injection into the gluteal muscle. Alternating gluteal muscles is recommended. Administration of doses exceeding 3 mL in volume should be avoided to prevent uncomfortable distension at the injection site.

Children. Parenteral administration of haloperidol decanoate in children (under 18 years of age) is contraindicated!

Overdose

With parenteral administration of haloperidol, overdose occurs less frequently than with oral administration. The data below are based on oral haloperidol intake.

Symptoms

In general, manifestations of haloperidol overdose are an exaggerated expression of its known pharmacological effects and adverse reactions. The most prominent of these include severe extrapyramidal symptoms, arterial hypotension, and sedation. Extrapyramidal reactions manifest as muscular rigidity and generalized or localized tremor. Arterial hypertension may be observed more frequently than hypotension.

In rare cases, coma with respiratory depression and arterial hypotension may occur, which can be severe and lead to shock-like conditions.

The risk of ventricular arrhythmia, possibly associated with QTc interval prolongation, should be considered.

Treatment

There is no specific antidote. Treatment should be symptomatic.

Dialysis is not recommended for the treatment of overdose, as it removes only very small amounts of haloperidol (see section "Pharmacokinetic properties").

Airway patency in comatose patients should be maintained using an oropharyngeal or endotracheal tube; mechanical ventilation may be required in case of respiratory depression.

Monitoring of vital functions and ECG is recommended until complete normalization. Appropriate antiarrhythmic measures are recommended for the treatment of severe arrhythmias.

In case of reduced arterial pressure and circulatory insufficiency, intravenous administration of adequate amounts of fluids, plasma, or concentrated albumin, as well as vasopressor agents—dopamine or noradrenaline—is required. Adrenaline (epinephrine) should not be used, as its interaction with haloperidol may cause extreme hypotension.

In cases of severe extrapyramidal disorders, antiparkinsonian agents with prolonged duration of action (lasting several weeks) are recommended. Antiparkinsonian agents should be discontinued very cautiously, as extrapyramidal symptoms may recur.

Adverse reactions

Based on pooled safety data from clinical studies, the most commonly reported adverse events were: extrapyramidal disorders (14%), tremor (8%), parkinsonism (7%), muscle rigidity (6%), and somnolence (5%).

Table 3 lists the adverse reactions:

• identified in clinical studies of haloperidol decanoate;
• identified in clinical studies of haloperidol (in other dosage forms) and considered related to the active substance;
• identified during the post-marketing period of haloperidol decanoate and haloperidol use.

The frequency of adverse reactions was assessed in clinical trials or epidemiological studies of haloperidol decanoate according to the following classification:

Adverse reactions are listed by organ systems and in order of decreasing severity.

Table 3

Prolongation of the QT interval, torsades de pointes ventricular tachycardia; ventricular arrhythmias, including ventricular fibrillation, ventricular tachycardia, and sudden death have been reported in patients treated with haloperidol.

Specific effects of antipsychotic agents

Cases of cardiac arrest have been reported with the use of antipsychotic agents. Venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been observed with antipsychotic agents. The frequency of occurrence is unknown.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C, in the original packaging to protect from light. Keep the medicinal product out of the reach of children!

Packaging. 1 ml of solution in an amber glass ampoule with a break point;
5 ampoules in a plastic tray in a cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Gedeon Richter".
Address: 19-21, Dózsa György út, H-1103 Budapest, Hungary.