Haloperidol, 5 mg/ml 1 ml 10 pcs

Pharmacotherapeutic group

Antipsychotic drug (neuroleptic)

ATX code: N05AD01

Pharmacodynamics:

Haloperidol is an antipsychotic (neuroleptic) butyrophenone derivative. It has a pronounced antipsychotic effect blocks postsynaptic dopamine receptors in mesolimbic and mesocortical structures of the brain. High antipsychotic activity is combined with a moderate sedative effect (in small doses it has an activating effect) and a pronounced antiemetic effect. It causes extrapyramidal disorders practically does not have m-cholinoblocking action.

Sedative action is caused by blockade of alpha-adrenoreceptors of reticular formation in brain stem; antiemetic action – by blockade of dopamine D2-receptors of trigger zone of vomiting center; hypothermic action and galactorrhea – by blockade of dopamine receptors of hypothalamus. Prolonged use is accompanied by changes in endocrine status in the anterior pituitary gland lobe; prolactin production increases and gonadotropic hormones production decreases.

Pharmacokinetics:

When administered intravenously the bioavailability is 100%. With intramuscular injection maximum concentration (Cmax) is reached in 20 minutes. Ratio
of concentration in erythrocytes to plasma concentration 1:12. Protein binding is approximately 92%. The concentration of haloperidol in tissues is higher than in blood The drug tends to cumulate in tissues. Easily penetrates through histohematic barriers including placental and blood-brain barriers and penetrates into breast milk.

Hapoperidol is metabolized in liver metabolite is not active. The CYPZase and/or CYP2D6 isoenzyme has been found to be involved in the metabolism of haloperidol. Haloperidol also undergoes oxidative N-dealkylation and glucuronidation. The plasma elimination half-life after intramuscular administration is 21 hours (17-25 hours). Haloperidol is excreted as metabolites in the feces – 60% (including 15% in the bile) and in the urine – 40% (including 1% unchanged).

Indications

Treatment and management of acute psychotic disorders accompanied by psychomotor agitation.

Behavioral disorders such as aggression hyperactivity tendency to self-harm in the mentally retarded and in patients with organic brain lesions.

Treatment of nausea and vomiting.

Active ingredient

Haloperidol

Composition

Per 1 ml:

Active ingredient: haloperidol – 5.0 mg

Excipients: lactic acid – 5.0 mg, water for injection – up to 1.0 ml.

How to take, the dosage

Intramuscularly intravenously.The dose of the drug for all indications is set individually under the supervision of a physician. To determine the initial dose, the patient’s age, severity of symptoms, and previous response to neuroleptics should be considered. Older patients who are weakened and have previously identified adverse reactions to neuroleptics may require a lower dose of haloperidol The initial dose for such patients should be half the usual dose for adults and then gradually adjusted to achieve an optimal response to therapy.

For hepatic impairment, the dose should be reduced. Haloperidol should be administered at the lowest clinically effective dose.

Schizophrenia psychosis mania hypomania psychiatric disorders or behavior disorders psychomotor agitation violent or dangerous impulsive behavior organic brain damage: dose of 5 mg administered until symptoms are controlled every hour or up to a maximum dose of 20 mg/day.

For treatment of nausea and vomiting: 1-2 mg.

Parenteral administration should be as short as possible followed by transition to oral administration.

Interaction

Concomitant use of drugs that cause electrolyte imbalance requires increased caution – the risk of ventricular arrhythmias may increase. It is recommended to avoid using diuretics causing hypokalemia and to prefer potassium-saving diuretics.

Haloperidol potentiates the suppressive effect on the central nervous system of hypotensive drugs narcotic analgesics sleeping pills tricyclic antidepressants means for general anesthesia of alcohol. Concomitant use of haloperidol with these drugs may lead to respiratory depression. Concomitant use with antiparkinsonian drugs (levodopa etc) may decrease therapeutic effect of these drugs due to antagonistic effect on dopaminergic structures.

When used with methyldopa disorientation and slowing down of thought processes may occur.

Haloperidol may decrease the intensity of action of epinephrine and other sympathomimetics causing “paradoxical” reduction of blood pressure and tachycardia when used together.

It increases action of peripheral m-cholinoblockers and most hypotensive agents (reduces action of guanethidine due to its displacement from alpha-adrenergic neurons and suppression of its capture by these neurons). When combined administration with anticonvulsants (including barbiturates and other inducers of microsomal oxidation) the doses of the latter should be increased as haloperidol reduces the threshold of seizure activity. In particular, the simultaneous use of tea or coffee may weaken the effect of haloperidol.

Haloperidol may decrease the effectiveness of indirect anticoagulants therefore the dose of the latter should be corrected when combined.
Haloperidol slows down metabolism of tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) and therefore their plasma concentrations and toxicity increase.

Simultaneous use with bupropion reduces epileptic threshold and increases the risk of epileptic seizures.

Simultaneous use of haloperidol with fluoxetine quinidine buspirone increases the risk of adverse effects on the central nervous system especially extrapyramidal reactions. If concomitant use is necessary, the dose of haloperidol should be reduced. Inhibitors or substrates of CYPCA4 and CYP2D6 isoenzymes, such as itraconazole buspirone venlafaxine alprazolam fluvoxamine quinidine fluoxetine sertraline chlorpromazine promethazine may increase the plasma concentration of haloperidol. Decrease of activity of CYP2D6 isoenzyme may lead to increased concentration of haloperidol. Cases of prolonged QT interval and extrapyramidal symptoms have been reported in case of concomitant use of haloperidol with ketoconazole (400 mg/day) and paroxetine (20 mg/day). Dose adjustment of haloperidol may be required.

Concomitant use of haloperidol with drugs prolonging QT interval such as antiarrhythmic drugs IA (incl. quinidine disopyramide procainamide) and III (including amiodarone sotalol dofetilide) class some antimicrobials (sparfloxacin moxifloxacin erythromycin intravenously) tricyclic antidepressants (including amitriptyline and ametriptyline).some tetracyclic antidepressants (including amitriptyline) other neuroleptics (including phenothiazines pimozide sertindol) some antihistamines (including terfenadine) cisapride bretilium tozilate some antimalarials (including quinine mefloquine) increases the risk of ventricular arrhythmias including “pirouette” arrhythmias. Therefore, their combined use is not recommended (this list is not exhaustive).

Long-term concomitant use of haloperidol with drugs that are inducers of liver enzymes (carbamazepine rifampicin phenobarbital, etc.) leads to a decrease in the blood plasma concentration of haloperidol. If it is necessary to combine them, the dose of haloperidol may need to be increased, but after withdrawal of the liver enzyme inducer, the dose of haloperidol should be decreased.

Simultaneous use with lithium salts, especially in high doses, may cause irreversible neurointoxication and increase extrapyramidal symptomatology. In case of the above-mentioned condition in patients receiving lithium and haloperidol simultaneously the therapy should be stopped immediately.

Simultaneous use with amphetamines decreases antipsychotic effect of haloperidol and psychostimulant effect of amphetamines due to blockade of alpha-adrenergic receptors by haloperidol.

Haloperidol may decrease the effect of bromocriptine. Anticholinergic antihistamines (1st generation) antiparkinsonian drugs may increase anticholinergic side effects and decrease the antipsychotic effect of haloperidol.

Thyroxine may increase the toxicity of haloperidol. In hyperthyroidism, haloperidol may be administered only with simultaneous appropriate thyreostatic therapy.

Simultaneous use with anticholinergic drugs may increase intraocular pressure.

Special Instructions

Malignant neuroleptic syndrome: malignant neuroleptic syndrome (characterized by hyperthermia generalized muscle rigidity vegetative lability impaired patient consciousness and elevated plasma CPK levels) has been reported with antipsychotic drugs. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If these symptoms occur, antipsychotic treatment should be discontinued immediately and appropriate supportive therapy (e.g., intravenous infusions of dantrolene) initiated.

Extrapyramidal symptoms: with long-term use, signs characteristic of neuroleptics – muscle tremor rigidity bradykinesia akathisia acute muscular dystonia or laryngeal dystonia may be noted. In these cases, anticolinergic drugs may be prescribed but not as preventive therapy since their use reduces the effectiveness of haloperidol.

Late dyskinesia: as with other antipsychotic drugs, long-term use of haloperidol or its withdrawal may cause late dyskinesia. This syndrome is characterized by involuntary rhythmic twitching of the facial tongue of the mouth or jaw. These signs are constantly noted in some patients. The syndrome may masquerade when therapy is resumed by increasing the dose of haloperidol or prescribing another antipsychotic. If signs of tardive dyskinesia appear, it is advisable to interrupt the course of therapy as early as possible. Rhythmic occasional tongue twitches may be an early sign of tardive dyskinesia. Withdrawal of treatment at this early stage may prevent this syndrome from developing.In psychiatric practice, cases of sudden death have been reported in

patients treated with antipsychotics including haloperidol. Since during the treatment with haloperidol possible prolongation of the QT interval on ECG it is necessary to evaluate the benefit/risk ratio while using the drug in patients with circulatory system disease, presence of cases of sudden lethal outcome and/or prolongation of the QT interval in family history especially in parenteral use of haloperidol. ECG monitoring should be performed before the start of therapy (see section “Contraindications”).

In the course of treatment, the need for ECG monitoring should be determined individually. In patients with subarachnoid hemorrhage who abuse alcohol and have uncorrected electrolyte disturbances, ECG and potassium levels should be monitored closely especially during the initial phase of treatment until equilibrium plasma concentrations are reached. Electrolyte imbalance may increase the risk of ventricular arrhythmias so regular monitoring of electrolyte levels is recommended especially in patients taking diuretics. During the therapy, the dose should be decreased in case of prolonged QT interval and haloperidol should be immediately discontinued if the QT interval exceeds 500 ms. Haloperidol should be used with caution in patients who are “slow metabolizers” of CYP2D6 as well as when using cytochrome P450 inhibitors.

Concurrent use with other neuroleptics should be avoided.

Caution should be exercised when using haloperidol for hepatic impairment. Periodic monitoring of blood count and liver function is necessary during long-term use of the drug. Patients with epilepsy and patients with increased susceptibility to convulsive states (chronic intoxication of both alcohol and other genesis, craniocerebral trauma in anamnesis etc) should be prescribed with caution.

Caution should be exercised while using haloperidol in patients with renal insufficiency and pheochromocytoma.

Thyroxine increases the toxicity of haloperidol so patients with hyperthyroidism should use it only under cover of adequate thyreostatic therapy.

Patients with schizophrenia respond to antipsychotic therapy with a delay. After termination of haloperidol treatment, symptoms do not reappear until several weeks or months later. Abrupt termination of antipsychotic therapy, especially when administered in high doses may cause withdrawal symptoms (nausea, vomiting, insomnia) and relapse of the disease, therefore the drug should be withdrawn gradually reducing the doses.

Patients with psychopathological disorders with depression and psychosis should take haloperidol in combination with antidepressants.

If there is a need for simultaneous therapy with haloperidol and antiparkinsonian drugs after withdrawal of haloperidol, the antiparkinsonian drug should be continued to prevent increased severity of extrapyramidal symptoms especially if the antiparkinsonian drug excretion rate is higher. It should be taken into account that the combined use of haloperidol and anticholinergic drugs (including antiparkinsonian drugs) may lead to increased intraocular pressure.

Cases of venous thromboembolism have been reported with antipsychotic drugs. Since patients treated with antipsychotics often have acquired risk factors for venous thromboembolism that should be identified prior to treatment, preventive measures should be taken when treated with haloperidol.

An increased mortality in elderly persons with dementia has been noted. A slightly increased risk of death was noted in elderly people with dementia who received antipsychotics compared to those who did not receive treatment. There is insufficient data to provide an accurate measure of the magnitude of the risk and the reason for its increase. Haloperidol is not indicated for treatment of behavioral disorders against the background of dementia in the elderly.

Alcohol consumption should be avoided during therapy with the drug. At the beginning of therapy with haloperidol and especially when administered in high doses, sedation of varying degrees and impaired attention may occur, the severity of which increases with the use of alcoholic beverages.
Impact on the ability to drive vehicles and machines: During treatment, avoid driving vehicles and other potentially dangerous activities that require high concentration and rapid psychomotor reactions.

Contraindications

Hypersensitivity to haloperidol and other butyrophenone derivatives. Behavioral disorders associated with dementia in elderly patients central nervous system depression and coma of any etiology; central nervous system diseases accompanied by pyramidal and extrapyramidal disorders (Parkinson’s disease, etc.); clinically significant heart disease (including recent acute myocardial infarction; decompensated heart failure arrhythmias treated with class IA and III antiarrhythmic drugs QT interval prolongation ventricular arrhythmias in history or pirouette ventricular arrhythmias clinically significant bradycardia heart block of II or III degree and unrepaired hypokalemia) Prolactin-dependent tumors concomitant use with drugs prolonging the QT interval; children under 18 years of age. With caution: Epilepsy closed-angle glaucoma hepatic and/or renal failure hyperthyroidism (with thyrotoxicosis phenomena) pulmonary-cardiac and respiratory failure (including chronic obstructive pulmonary disease and acute infectious diseases) prostatic hyperplasia with urinary retention alcoholism pheochromocytoma.

Side effects

Frequency of side effects is presented in the following gradation: very common (≥1/10) common (≥1/100 to < 1/10) infrequent (≥1/1000 to < 1/100) rare (≥1/10000 to < 1/1000) frequency unknown (cannot be estimated from available data).Blood and lymphatic system: infrequent – leukopenia; frequency unknown – agranulocytosis neutropenia pancytopenia thrombocytopenia.

Immune system: infrequent hypersensitivity reactions; frequency unknown – anaphylactic reactions toxic epidermal necrolysis Stevens-Johnson syndrome.

Endocrine system: rare – hyperprolactinemia, the frequency is unknown – inadequate secretion of antidiuretic hormone.
Metabolic and nutritional disorders: frequency is unknown – hypoglycemia.

Mental disorders: very common – agitation insomnia; frequent depression psychotic disorders; infrequent – confusion decrease and loss of libido anxiety.

Nervous system disorders: very common – extrapyramidal disorders hyperkinesia headache; tardive dyskinesia oculogyric crisis dystonia dyskinesia akathisia bradykinesia hypokinesia hypertonicity sleepiness masked face tremor dizziness; infrequent – convulsions parkinsonism akinesia rigidity in the “cog wheel” type sedation involuntary muscle contracture; rare – motor disorders malignant neuroleptic syndrome nystagmus.

Sight: often – visual impairment; infrequently – blurred vision.

Cardiovascular system: frequently – decreased arterial blood pressure – orthostatic hypotension; infrequent – tachycardia, ventricular fibrillation – “pirouette” type arrhythmia ventricular tachycardia extrasystole; frequency is unknown (while taking antipsychotic) – venous thromboembolism including pulmonary embolism – deep vein thrombosis.

Gastrointestinal tract: often – constipation dry mouth increased salivation; nausea vomiting.

Respiratory system: infrequent – dyspnea; rare – bronchospasm; frequency unknown – laryngeal edema.

Liver: frequent – abnormal “liver” enzymes; infrequent – hepatitis jaundice; frequency unknown – acute liver failure cholestasis.

Skin and subcutaneous tissue: frequently – skin rash; infrequent – photosensitization reactions urticaria itching hyperhidrosis; frequency unknown – leukocytoclastic vasculitis exfoliative vasculitis.

Musculoskeletal system: infrequent – torticollis muscle rigidity muscle spasm rigidity of the skeletal muscles, rarely – trismus muscle twitching.

Renal and urinary tract: common – urinary retention.

Reproductive system and mammary glands: often erectile dysfunction; infrequent – amenorrhea dysmenorrhea galactorrhea pain and discomfort in breasts/breasts; menorrhea menstrual disorders sexual dysfunction; frequency unknown – gynecomastia priapism.

General disorders and disorders at the place of administration: infrequent – gait disturbance hyperthermia edema; frequency unknown – sudden death facial edema hypothermia syndrome “withdrawal” in newborns.

Laboratory indicators: frequent – increase or decrease in body weight prolongation of QT interval on ECG.

Overdose

Symptoms: characterized by increased severity of known pharmacological and side effects. The most important signs of overdose: severe extrapyramidal disorders hypotension pronounced lethargy. Extrapyramidal disorders appear in the form of muscle stiffness general or local muscle tremor. Arterial hypertension may develop more frequently than hypotension. Coma with respiratory depression and marked arterial hypotension may occur in some cases. It may be so severe that it may lead to a state of shock. Consider the possibility of ventricular arrhythmia with prolongation of the QT interval.

Treatment: there is no specific antidote symptomatic therapy should be conducted. In comatose condition support of respiratory system function by orotracheal or endotracheal tube insertion is necessary. Respiratory depression may necessitate ventilatory support. Monitoring of ECG and vital hemodynamic parameters until ECG normalization is required. In severe arterial hypotension or circulatory insufficiency, intravenous administration of sufficient plasma fluid or concentrated albumin, as well as vasopressor agents (dopamine or norepinephrine) should be administered. Epinephrine should not be used as it may cause severe arterial hypotension in combination with haloperidol. In severe extrapyramidal disorders parenteral antiparkinsonian drugs (benztropine mesylate in adults at a dose of 1-2 mg intravenously or intramuscularly) are used. Withdrawal of these drugs should be done with caution, since abrupt cessation of their administration may lead to a relapse of the extrapyramidal disorders.

Pregnancy use

When administered in high doses during late pregnancy, butyrophenones may cause prolonged neurological disorders in the newborn. In animal studies the use of haloperidol during organogenesis was accompanied by the development of side effects including intrauterine fetal death by malformations such as “cleft palate” and neural tube development defects as well as decreased brain weight and body weight and behavioral disorders in the offspring.

The significance of these results in humans exposed to therapeutic doses of haloperidol is unknown. Newborns exposed to antipsychotics (including haloperidol) during the third trimester of pregnancy are at risk of developing extrapyramidal disorders and/or withdrawal symptoms after delivery. There have been post-marketing reports of cases of agitation hyper- and hypotonia tremor drowsiness respiratory distress and eating disorders in such neonates. These complications varied in severity and in some cases the symptoms resolved on their own and in others additional treatment or monitoring was required.

Haloperidol should be used during pregnancy only as a last resort if the expected benefit to the mother exceeds the potential risk to the fetus. The dose and duration of treatment should be as low and short as possible.

Haloperidol is excreted with the breast milk: In cases where intake of haloperidol is unavoidable, breastfeeding should be stopped. In some cases extrapyramidal symptoms have been observed in infants whose mothers took haloperidol during lactation.

Similarities

Haloperidol, Haloperidol, Haloperidol, Haloperidol, Haloperidol