Halopril

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HALOPRIL (HALOPRIL)

Composition:

Active substance: haloperidol;

One tablet contains 1.5 mg of haloperidol;

Excipients: sodium croscarmellose; microcrystalline cellulose; lactose monohydrate; maize starch; colloidal anhydrous silicon dioxide; magnesium stearate; macrogol 4000.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets with a flat surface and bevelled edges.

Pharmacotherapeutic group.

Antipsychotic agents. Butyrophenone derivatives. ATC code N05AD01.

Pharmacological properties.

Haloperidol is a highly effective neuroleptic belonging to the butyrophenone derivatives. It exerts a pronounced antipsychotic and antiemetic effect.

The action of haloperidol is associated with blockade of central dopaminergic (D2) and alpha-adrenergic receptors in the mesocortical and limbic structures of the brain. Blockade of hypothalamic (D2) receptors leads to decreased body temperature and galactorrhea due to increased prolactin production. Inhibition of dopaminergic receptors in the trigger zone of the vomiting center underlies the antiemetic and antinausea effects. Interaction with dopaminergic structures of the extrapyramidal system (basal ganglia) leads to extrapyramidal disorders. The drug exhibits a moderate sedative effect by influencing the limbic system and also acts as an adjuvant in the treatment of chronic pain.

Haloperidol does not exert antihistaminic or anticholinergic effects.

Pharmacokinetics.

Absorption.

Maximum blood concentration is reached within 2–6 hours. The bioavailability of haloperidol is 60–70%. Haloperidol is 92% bound to plasma proteins. For a therapeutic effect, the drug concentration in plasma should be within the range of 4 to 20–25 μg/L.

Haloperidol is metabolized in the liver; the metabolite is inactive. Haloperidol is excreted in urine (40%) and feces (60%). Approximately 1% of haloperidol is excreted unchanged in urine. The volume of distribution at steady state is large (7.9 ± 2.5 L/kg). The elimination half-life from plasma after oral administration averages 24 hours (12–38 hours).

Haloperidol readily penetrates the blood-brain barrier.

Clinical characteristics.

Indications.

In adults:

• schizophrenia: treatment of symptoms and prevention of relapses;
• other psychoses: especially paranoid;
• mania and hypomania;
• mental and behavioral problems such as aggression, hyperactivity, tendency to self-mutilation in mentally retarded patients and patients with organic brain damage;
• as an adjunctive agent for short-term treatment of psychomotor agitation (from moderate to severe), anxiety, violent or dangerously impulsive behavior;
• intractable hiccups;
• anxiety and agitation in elderly patients;
• Gilles de la Tourette syndrome and severe tics.

Contraindications.

Comatose state, severe central nervous system depression of toxic origin (alcoholic or drug-induced), endogenous depression without agitation, asthenia, neuroses, spastic states due to basal ganglia lesions (hemiplegia, multiple sclerosis), Parkinson's disease. Pathological processes localized in the area of the basal ganglia.

Hypersensitivity (allergy) to haloperidol or to excipients of the drug and other butyrophenone derivatives.

Clinically significant heart diseases (e.g., recent acute myocardial infarction; decompensated heart failure; arrhythmias treated with class IA or III antiarrhythmic drugs); QTc interval prolongation, history of ventricular arrhythmia or torsades de pointes-type ventricular arrhythmia, clinically significant bradycardia; second- or third-degree atrioventricular block and uncontrolled hypokalemia; concomitant use of drugs that prolong the QT interval.

Interaction with other medicinal products and other forms of interactions.

Concomitant use of drugs causing electrolyte imbalance requires increased caution, as the risk of developing ventricular arrhythmias may increase.

Haloperidol potentiates the central nervous system depressant effects of centrally-acting antihypertensives, opioid analgesics, hypnotics, antidepressants, anesthetic agents, and alcohol. Concurrent use of haloperidol with these drugs may lead to respiratory depression.

Combined use of haloperidol with methyldopa enhances the effect of haloperidol on the central nervous system.

When used concomitantly with antiparkinsonian agents (levodopa), the therapeutic effect of these agents may be reduced due to antagonistic effects on dopaminergic structures.

Haloperidol slows the metabolism of tricyclic antidepressants, resulting in increased plasma levels and increased toxicity.

Quinidine, buspirone, and fluoxetine moderately increase haloperidol blood concentration; therefore, when concomitant use is necessary, the dose of haloperidol should be reduced. Inhibitors of cytochrome P450 and CYP2D6 enzyme systems may increase haloperidol plasma levels.

Concomitant use of haloperidol with drugs known to prolong the QT interval (antiarrhythmic agents of classes IA and III, arsenic trioxide, halofantrine, levomethadyl acetate, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron mesylate, mefloquine, sertindole, or cisapride) is contraindicated (see section "Contraindications").

Prolonged concomitant use of haloperidol with drugs that are hepatic enzyme inducers (carbamazepine, rifampicin, phenobarbital) leads to decreased serum concentration of haloperidol. When combination is necessary, an increase in haloperidol dose may be required; however, after discontinuation of the hepatic enzyme inducer, haloperidol dose must be reduced.

Rare cases of the following symptoms have been reported with concomitant use of haloperidol and lithium salts: encephalopathy, extrapyramidal reactions, tardive dyskinesia, neuroleptic malignant syndrome, brainstem dysfunction, acute cerebral syndrome, and coma. Most of these symptoms were reversible. It is unknown whether they belong to a distinct nosological entity. If any of the above symptoms occur in patients receiving lithium and haloperidol concomitantly, therapy must be discontinued immediately.

Haloperidol affects the activity of indirect anticoagulants (phenindione); therefore, when used concomitantly, the dose of the latter must be adjusted. An antagonistic effect on the anticoagulant effect of phenindione is observed. Haloperidol may reduce the effectiveness of adrenaline and other sympathomimetics and may cause a decrease in blood pressure when alpha-blockers (guanethidine) are used.

Haloperidol may interfere with the effect of anticonvulsant drugs when used concomitantly, reducing their plasma levels. Dose adjustment of anticonvulsants may become necessary.

Sodium valproate, a known inhibitor of glucuronidation, does not affect haloperidol plasma levels.

Special precautions for use.

Since QT interval prolongation on ECG may occur during haloperidol treatment, the benefit/risk ratio should be assessed before administering the drug to patients with cardiovascular disorders, a family history of sudden death and/or a personal history of QT prolongation. ECG monitoring should be performed prior to initiating therapy (see section "Contraindications"). The need for ECG monitoring during treatment should be determined individually.

Careful ECG and potassium level monitoring is required in patients with subarachnoid hemorrhage, starvation, alcohol abuse, or uncorrected electrolyte disturbances, especially during the initial phase of treatment until steady-state plasma concentrations of the drug are achieved. Electrolyte imbalance may increase the risk of ventricular arrhythmias; therefore, regular electrolyte monitoring is recommended, particularly in patients receiving diuretics. The dose should be reduced if QT prolongation occurs, and haloperidol should be discontinued immediately if the QT interval exceeds 500 ms.

Concomitant use with other neuroleptic agents should be avoided.

In psychiatric practice, cases of sudden death have been reported in patients receiving antipsychotic drugs, including haloperidol. Analyses of seventeen placebo-controlled clinical trials (median duration 10 weeks), primarily involving atypical antipsychotics, showed a 1.6 to 1.7 times higher risk of death in patients receiving antipsychotics compared to those receiving placebo. In a 10-week controlled clinical trial with typical antipsychotics, mortality rates were approximately 4.5% in patients receiving the drug compared to about 2.6% in the placebo group. Although causes of death varied, most were due to cardiovascular events (e.g., heart failure, sudden death) or infections (e.g., pneumonia).

Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional antipsychotics may also increase mortality. Therefore, it remains unclear whether the increased mortality observed in these studies is due to the effects of neuroleptics or to specific patient characteristics.

Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic drugs. Since patients receiving antipsychotic therapy often have acquired risk factors for VTE, which should be identified before initiating treatment, preventive measures should be taken during haloperidol therapy.

Cases of tachycardia and hypotension have been observed in some patients.

Malignant neuroleptic syndrome (MNS). Like other drugs, haloperidol is associated with malignant neuroleptic syndrome—a rare and idiosyncratic condition. Cases of malignant neuroleptic syndrome have been reported with antipsychotic drugs (characterized by hyperthermia, generalized muscle rigidity, autonomic instability, impaired consciousness, and elevated plasma creatine phosphokinase levels). Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If these symptoms occur, antipsychotic treatment should be discontinued immediately and appropriate supportive therapy initiated (e.g., intravenous dantrolene infusions).

Increased mortality in elderly patients with dementia.

Elderly patients with dementia treated with antipsychotics have shown a slightly increased risk of death compared to untreated patients. Data on the exact magnitude and causes of this increased risk are insufficient. Haloperidol is not indicated for the treatment of behavioral disorders associated with dementia.

Cases of tachycardia and hypotension have been observed in some patients.

In some patients on long-term therapy or after discontinuation of treatment, tardive dyskinesia may develop. This syndrome is characterized by rhythmic involuntary movements of the tongue, face, mouth, or jaw. Symptoms may be persistent or may be masked by resumption of treatment, dose increase, or switching to another antipsychotic agent. Treatment should be discontinued immediately. Safety data in elderly patients indicate a risk of extrapyramidal symptoms, including tardive dyskinesia and sedation. Long-term safety data are lacking.

As with all neuroleptics, extrapyramidal symptoms may occur: tremor, rigidity, hypersalivation, bradykinesia, akathisia, and acute dystonia.

Haloperidol should be administered with caution to patients with epilepsy and those with an increased predisposition to seizures (e.g., chronic intoxication of alcoholic or other origin, history of head trauma).

Patients with schizophrenia respond to antipsychotic therapy with a delay. After discontinuation of haloperidol treatment, symptoms may reappear only after several weeks or months. Sudden discontinuation of antipsychotic therapy, especially after high-dose treatment, may lead to withdrawal symptoms (nausea, vomiting, insomnia) and disease relapse. Therefore, the drug should be tapered gradually by reducing the dose.

Patients with depressive and psychotic symptoms associated with psychopathological disorders should receive haloperidol in combination with antidepressants.

If concomitant therapy with haloperidol and antiparkinsonian agents is required, antiparkinsonian treatment should be continued after discontinuation of haloperidol to prevent worsening of extrapyramidal symptoms, especially if the antiparkinsonian agent is eliminated more rapidly. It should be noted that concomitant use of haloperidol and anticholinergic drugs (including antiparkinsonian agents) may increase intraocular pressure.

Haloperidol should be used with particular caution in patients who are "poor metabolizers" of CYP2D6, as well as when inhibitors of cytochrome P450 are co-administered.

Caution is required when using haloperidol in patients with hepatic impairment. With prolonged use, periodic monitoring of blood counts and liver function is necessary.

Caution is advised when administering haloperidol to patients with renal insufficiency or pheochromocytoma.

Thyroxine increases the toxicity of haloperidol; therefore, in patients with hyperthyroidism, haloperidol should only be used under adequate antithyroid therapy.

Hormonal effects of antipsychotic neuroleptics include hyperprolactinemia, which may cause galactorrhea, gynecomastia, and oligo- or amenorrhea. Rare cases of hypoglycemia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported.

Alcohol consumption is contraindicated during treatment. At the beginning of haloperidol therapy, and especially when high doses are used, sedation of varying degrees and reduced attention may occur, which may be intensified by alcohol consumption.

In patients with lactose intolerance, it should be noted that Halopryl tablets contain lactose as an excipient; therefore, the drug should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Corn starch is included as an excipient in the formulation; therefore, patients with increased sensitivity or gluten intolerance should not take this dosage form.

Use during pregnancy or breastfeeding.

The use of haloperidol during pregnancy is possible only if the expected benefit outweighs the potential teratogenic risk. During the third trimester, newborns are at risk of adverse effects, including extrapyramidal symptoms or withdrawal syndrome, which may vary in severity and duration after birth. Cases of agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress, and feeding difficulties have also been reported. Therefore, newborns should be closely monitored. Haloperidol is contraindicated in confirmed or suspected pregnancy. Haloperidol passes into breast milk. If haloperidol treatment is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Haloperidol may cause sedative effects and reduced attention, particularly at higher doses and at the beginning of treatment; this effect may be enhanced by alcohol. Patients should be warned against driving vehicles or operating machinery during treatment until their individual response to the drug is established.

Method of Administration and Dosage

Take orally during or after meals, swallowing with a full glass of water.

The dosage of the drug for all indications should be individually determined under close medical supervision. The initial dose should be based on the patient's age, severity of symptoms, and previous response to neuroleptics.

Elderly or debilitated patients, especially those who have previously experienced adverse reactions to neuroleptics, may require a lower dose of haloperidol. The initial dose should be half the usual adult dose, then gradually adjusted to achieve the optimal therapeutic response. Hepatic function should be carefully considered; in the presence of hepatic impairment, the dose should be reduced.

Haloperidol should be administered at the lowest clinically effective dose.

Adults.

Schizophrenia, psychoses, mania, hypomania, mental or behavioral problems, psychomotor agitation, anxiety, aggressive or dangerously impulsive behavior, organic brain damage.

Initial dose:

Moderate symptoms: 1.5 – 3 mg/day, divided into 3 doses.

Severe symptoms/resistant patients: 3 – 5 mg/day, divided into 3 doses.

The initial dose may be used in adolescents and patients with resistant schizophrenia, who may require up to 30 mg/day.

Maintenance dose: After satisfactory symptom control is achieved, the dose should be gradually reduced to the lowest effective maintenance dose, usually 5 or 10 mg/day. Avoid overly rapid dose reduction.

Anxiety and agitation in elderly patients.

Initial dose: 1.5 – 3 mg/day, divided into 3 doses. Dose titration may be necessary to achieve an effective maintenance dose (1.5 – 30 mg/day).

Gilles de la Tourette syndrome, severe tics, intractable hiccups.

Initial dose: 1.5 mg/day, divided into 3 doses, adjusted according to therapeutic response. A daily maintenance dose of 10 mg may be required for Gilles de la Tourette syndrome.

Children. This formulation is not recommended for use in children.

Overdose.

Symptoms: Characterized by an intensification of known pharmacological and adverse effects. The most important signs of overdose include severe extrapyramidal disorders, arterial hypotension, and sedative effects. Extrapyramidal disorders manifest as muscle rigidity and generalized or localized muscle tremor. Arterial hypertension may occur more frequently than hypotension.

In extreme cases, coma with respiratory depression and profound hypotension may develop. This may be so severe as to lead to shock. Ventricular arrhythmias with QT interval prolongation should be considered as possible complications.

Treatment: There is no specific antidote. Symptomatic therapy should be administered. Activated charcoal may be used.

In cases of coma, respiratory support is required, including orotracheal or endotracheal intubation. Artificial ventilation of the lungs may be necessary in the presence of respiratory depression.

ECG and vital hemodynamic parameters must be monitored until ECG normalizes. For treatment of severe arterial hypotension or circulatory failure, intravenous administration of adequate amounts of fluids, plasma, or concentrated albumin, along with vasopressor agents (dopamine or noradrenaline), is required. Adrenaline (epinephrine) should not be used, as its combination with haloperidol may cause severe arterial hypotension. In cases of severe extrapyramidal symptoms, parenteral antiparkinsonian agents (benztropine mesylate) should be administered (1–2 mg intravenously or intramuscularly in adults). Discontinuation of these agents should be done cautiously, as abrupt withdrawal may lead to recurrence of extrapyramidal disorders.

Adverse Reactions

When haloperidol is used briefly and in low doses (1–2 mg per day), adverse effects are rare, mild, and transient. However, with prolonged use of higher doses, adverse effects occur more frequently. Neurological side effects are the most commonly observed.

Blood and lymphatic system disorders: There have been reports of mild and transient reduction in blood cell counts. Very rarely, agranulocytosis and thrombocytopenia may occur; transient leukopenia, usually when haloperidol is used in combination with other drugs; neutropenia, leukocytosis, and pancytopenia.

Immune system disorders: Rarely, anaphylactic reactions may occur.

Endocrine system disorders: Endocrine-related adverse effects of antipsychotic neuroleptics include the possibility of hyperprolactinemia, which may lead to inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: Decreased appetite; rarely, in exceptional cases, hypoglycemia and reduced antidiuretic hormone secretion may occur.

Psychiatric disorders: Depression, agitation, insomnia, confusion, exacerbation of psychotic symptoms, restlessness, and loss of libido.

Nervous system disorders: In individual cases, sedative effects, drowsiness, headache, dizziness, grand mal seizures, hyperkinesia, oculogyric crises, dyskinesia, bradykinesia, hypokinesia, akinesia, mask-like facies, nystagmus, hypertension, lethargy, dizziness, involuntary muscle contractions, parkinsonism, and cardiac neurosis may occur.

Neuroleptic Malignant Syndrome (NMS): The use of antipsychotic agents, including haloperidol, may lead to NMS. This rare idiosyncratic reaction is characterized by hyperthermia, generalized muscle rigidity, autonomic instability, altered consciousness, and elevated plasma creatine phosphokinase levels. Hyperthermia is often an early sign of NMS. If symptoms of NMS appear, neuroleptic therapy must be discontinued immediately, and supportive treatment should be initiated under close monitoring.

Extrapyramidal symptoms: With prolonged use, symptoms typical of neuroleptics may occur: tremor, muscle rigidity, bradykinesia, akathisia, acute muscle dystonia, or laryngeal dystonia. In such cases, antiparkinsonian agents with anticholinergic activity may be administered, but not as prophylactic therapy, since their use may reduce the efficacy of haloperidol.

Tardive dyskinesia: As with other antipsychotic agents, prolonged use of haloperidol or its discontinuation may lead to tardive dyskinesia. This syndrome is characterized by involuntary rhythmic movements of the tongue, face, mouth, or jaw. These symptoms may persist continuously in some patients. The syndrome may be masked when therapy is resumed, the dose of haloperidol is increased, or another antipsychotic agent is prescribed. Upon appearance of signs of tardive dyskinesia, it is advisable to discontinue therapy as early as possible.

Rhythmic, involuntary movements of the tongue may be an early sign of tardive dyskinesia. Discontinuation of treatment at this early stage may prevent the development of this syndrome.

Eye disorders: In elderly patients, acute angle-closure glaucoma attacks may occur. Periodically, blurred vision, eye movements, and hazy vision may also be observed.

Cardiac disorders: In some cases, tachycardia and hypotension may occur. Rarely, in exceptional cases, QT interval prolongation on ECG and/or ventricular arrhythmias, including ventricular fibrillation, ventricular tachycardia, torsades de pointes, and sudden cardiac arrest, may occur. Extrasystoles have also been reported. Cases of sudden fatal outcomes have been reported. These disorders may occur in patients receiving high doses of the drug or those predisposed to cardiovascular disorders.

Vascular disorders: Arterial hypotension has been reported periodically; arterial hypertension less frequently. With the use of antipsychotic drugs, cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported. The frequency of occurrence is unknown. Orthostatic hypotension may also occur.

Gastrointestinal disorders: Nausea, vomiting, and dyspeptic symptoms have been reported periodically. In some cases, constipation, dyspepsia, dry mouth, and increased salivation may occur.

Respiratory system disorders: Dyspnea, bronchospasm, laryngeal edema, and laryngospasm.

Hepatic disorders: Isolated cases of abnormal liver function tests have been reported, as well as acute liver failure, hepatitis (mostly cholestatic), and cholestasis. Jaundice may occur periodically.

Skin and subcutaneous tissue disorders: Increased sweating may occur periodically. Rarely, hypersensitivity reactions such as skin rashes, pruritus, peripheral edema, urticaria, exfoliative dermatitis, erythema multiforme, photosensitization, and leukocytoclastic vasculitis have been observed.

Musculoskeletal and connective tissue disorders: Torticollis, trismus, muscle twitching, muscle spasms, gait disturbances, muscle cramps, and musculoskeletal pain.

Renal and urinary disorders: Urinary retention may occur periodically.

Reproductive system and breast disorders: Very rarely, oligo- or amenorrhea, galactorrhea, gynecomastia, breast engorgement, discomfort, and breast pain may occur. Menstrual disorders such as menorrhagia and dysmenorrhea may also occur. Sexual dysfunction, including erectile dysfunction, ejaculation disorders, and priapism, may be observed.

Laboratory findings: Both weight gain and weight loss are possible.

General disorders and administration site conditions: Very rarely, gait disturbances, facial edema, hyponatremia, hyperthermia, and sudden death may occur.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 tablets in a blister; 5 or 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

Manufacturer's address and location of business activity.

41 Kułykivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.