Haloperidol-Ratiofarm, drops 2 mg/ml 30 ml

Pharmacotherapeutic group: antipsychotic (neuroleptic).

ATX code: N05AD01

Pharmacological action

Pharmacodynamics

Antipsychotic (neuroleptic), butyrophenone derivative. It has strong antipsychotic effect, blocks postsynaptic dopamine receptors in mesolimbic and mesocortical structures of the brain. Inhibits mediator release by reducing the permeability of presynaptic membranes. High antipsychotic activity is combined with a moderate sedative effect (in small doses has an activating effect) and a pronounced antiemetic effect. It causes extrapyramidal disorders and has practically no choline-blocking effect.

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

Removes persistent changes in personality, delirium, hallucinations, delusions, and increases interest in the environment.

Pharmacokinetics

Absorption when taken orally is 60%. Binding with blood plasma proteins – 92%. Maximal concentration in plasma is reached when administered orally after 3 hours, after intramuscular injection – after 10-20 minutes. The volume of distribution is 15-35 l/kg, the binding to plasma proteins is 92%. It easily passes through histohematic barriers, including the blood-brain barrier.

Metabolized in the liver, subjected to the effect of “first passage” through the liver. Excreted with bile and urine: after per oral administration 15% is excreted with bile, 40% – with urine (including 1% – in unchanged form). Metabolism of haloperidol is accelerated by enzyme-inducing substances (phenobarbital, phenytoin and carbamazepine).

Because of the large volume of distribution and low plasma concentration, only a very small amount of haloperidol is removed by dialysis. It penetrates into breast milk. CYP2D6, CYP3A3, CYP3A5, CYP3A7 isoenzymes are involved in metabolism of haloperidol. It is an inhibitor of CYP2D6. There are no active metabolites. The elimination half-life when taken orally averages 24 hours (15 to 37 hours).

Indications

Active ingredient

Composition

How to take, the dosage

1 ml of the solution (20 drops) contains 2 mg of haloperidol; 10 drops contain 1 mg of haloperidol.

The individual dose is determined by the attending physician and depends on the clinical picture, the characteristics of the course of the disease, age and tolerance of the drug.

The daily dose should be divided into 1-3 doses; at high doses, more frequent individual doses are possible. If the doctor has not determined an individual dose for the patient, the following treatment regimens are usually used:

The oral drops are taken with meals, dosed with a teaspoon, added to drinks or food, or on a piece of sugar (except in patients with diabetes).

Adults. The initial dose is 0.5-1.5 mg 2-3 times daily. Then the dose is gradually increased by 0.5-2 mg/day (in resistant cases by 2-4 mg/day) to achieve the desired therapeutic effect. If acute symptoms are relieved in hospital conditions, the initial daily dose may be increased to 15 mg/day, in therapeutically resistant cases – higher. The maximum daily dose should not exceed 100 mg/day. The average therapeutic dose is 10-15 mg/day, in chronic forms of schizophrenia – 20-40 mg/day, in resistant cases – up to 50-60 mg/day. Maintenance doses (out of exacerbation) in outpatient conditions may vary from 0.5 to 5 mg/day.

Children over 3 years of age. Treatment begins with a dose of 0.025 to 0.05 mg/kg body weight, divided into 2-3 doses. Increasing the dose is possible up to 0.2 mg/kg of body weight.

Patients of advanced age and physically weakened patients. Treatment is started with a single dose not exceeding 0.5-1.5 mg. The daily dose is not recommended to increase more than 5 mg/day.

In children, elderly and frail patients, the dose is increased no more frequently than once every 3 to 5 days.

Interaction

Concomitant use with drugs that prolong the QT interval (quinidine, disopyramide, amiodarone, dronedarone, sotalol, azithromycin, clarithromycin, erythromycin, levofloxacin, phenothiazine, methadone) is contraindicated.

The simultaneous use of alcohol and haloperidol may increase the effect of alcohol and lead to arterial hypotension.

It increases the severity of the CNS depressant effects of ethanol, tricyclic antidepressants, opioid analgesics, barbiturates and other sleeping pills, means for general anesthesia.

It potentiates the effect of peripheral m-cholinoblockers and most hypotensive drugs (reduces the effect of guanethidine due to its displacement from alpha-adrenergic neurons and suppression of its uptake by these neurons).

Inhibits the metabolism of tricyclic antidepressants and monoamine oxidase inhibitors, while increasing (mutually) their sedative effect and toxicity.

When used concomitantly with bupropion, it reduces the epileptic threshold and increases the risk of large epileptic seizures.

Decreases the effect of anticonvulsants (decreased seizure threshold with haloperidol).

Limits the vasoconstrictor effect of dopamine, phenylephrine, norepinephrine, ephedrine and epinephrine (blockade of alpha-adrenoreceptors by haloperidol, may lead to perversion of epinephrine action and to paradoxical reduction of blood pressure). Reduces the effect of antiparkinsonian drugs (antagonistic effect on dopaminergic structures of the CNS).

Changes (may increase or decrease) the effect of anticoagulants.

Decreases the effect of bromocriptine (dose adjustment may be necessary).

When used with methyldopa, increases the risk of psychiatric disorders (including disorientation in space, slowing down and difficulty in thinking processes).

Amphetamines decrease the antipsychotic effect of haloperidol, which, in turn, reduces their psychostimulant effect (blockade of alpha-adrenoreceptors by haloperidol).

Mcholine-blocking drugs, first-generation H1-histamine receptor blockers and antidyskinetic drugs may increase the m-choline-blocking effect of haloperidol and decrease its antipsychotic effects (dose adjustment may be required).

Long-term use of carbamazepine, barbiturates and other inducers of microsomal oxidation decreases the plasma concentration of haloperidol.

Concomitant use with lithium preparations (especially in high doses) may lead to encephalopathy (may cause irreversible neurointoxication) and increased extrapyramidal symptoms.

Concomitant use with fluoxetine increases the risk of CNS adverse effects, particularly extrapyramidal reactions.

Concomitant use with drugs that cause extrapyramidal reactions increases the frequency and severity of extrapyramidal disorders.

The consumption of strong tea or coffee (especially in large quantities) reduces the effects of haloperidol.

Special Instructions

In rare cases, sudden death has been reported in patients with psychiatric disorders who received antipsychotic medications, including haloperidol (see section “Side effects”).

In case of fever, especially in the first three months of treatment, gingivitis and stomatitis, pharyngitis, purulent angina, and flu-like symptoms, the attending physician should be consulted immediately. Self-treatment with analgesics should be avoided.

Before treatment with haloperidol, patients should undergo a study of general blood count (including differential count of blood cells and platelet counts), ECG and electroencephalogram parameters. If deviations from the norm are detected, haloperidol may be used only for absolute indications and under the condition of obligatory control tests of general blood parameters. Monitoring of electrolyte balance and correction of hypokalemia, if necessary, is necessary before and during treatment.

In patients with organic brain damage, arteriosclerotic cerebrovascular disease and endogenous depression, special caution is required during therapy with haloperidol.

Haloperidol may provoke seizures in patients with epilepsy and other conditions with predisposition to seizures.

Malignant neuroleptic syndrome may be seen during treatment with haloperidol. Hyperthermia is often an early sign of this syndrome. If malignant neuroleptic syndrome is suspected, the drug should be withdrawn immediately and appropriate therapy administered.

With regard to the fact that in elderly patients and patients with concomitant cardiovascular diseases, abnormal intracardiac conduction may be observed, regular monitoring of cardiac activity during therapy is recommended. Patients with pheochromocytoma, renal insufficiency, heart failure or cerebral insufficiency may develop hypotensive reactions during therapy with haloperidol, therefore these patients require close monitoring.

Extrapy with the drug may cause extrapyramidal symptoms (e.g., tremor, rigidity, akathisia), and increasing the dose may worsen these symptoms.

While the prevalence of tardive dyskinesias is not well understood, elderly patients (especially elderly women) are prone to develop this condition. The risk of developing tardive dyskinesias, especially of the irreversible type, increases with the duration of treatment and with antipsychotic doses. Late dyskinesias may also develop after short-term, low-dose treatment. Initial antipsychotic treatment may mask symptoms of primary tardive dyskinesia. If symptoms of tardive dyskinesia appear, all antipsychotic medications, including haloperidol, should be evaluated for withdrawal.

In patients with psychosis with predominant depression, concomitant use with antidepressants is recommended.

In patients with bipolar disorder with manic episodes, there is a possibility of switching manic episodes to depressive episodes. These patients should be monitored, as depressive behaviors, such as suicidal behaviors, may develop.

The symptoms may occur after discontinuation of the drug.

Please be careful when performing heavy physical work, taking a hot bath (heat stroke may develop due to suppression of central and peripheral thermoregulation in the hypothalamus).

Any over-the-counter cold medication should be avoided during treatment (increased m-cholin-blocking effects and risk of heat stroke are possible).

We should protect exposed skin from excessive sunlight because of the increased risk of photosensitization reactions.

The treatment is stopped gradually to avoid the occurrence of “withdrawal” syndrome. The antiemetic effect may mask the signs of drug toxicity and complicate the diagnosis of these conditions, the first symptom of which is nausea. Influence on driving and operating machinery

At the time of treatment it is necessary to avoid (especially in the first stages of treatment) or be careful when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions.

Synopsis

Contraindications

Side effects

When using a dose of 1-2 mg/day, adverse reactions are not pronounced and are transient in nature. When using higher doses, the incidence of adverse reactions increases.

Within the system-organ classes, the following categories are used according to the frequency of adverse reactions: Very common (≥ 1/10); common (≥ 1/100, < 1/10); infrequent (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (cannot be estimated based on available data).

Blood and lymphatic system disorders: infrequent – leukopenia; frequency unknown – pancytopenia, agranulocytosis, thrombocytopenia, neutropenia.

In immune system disorders: infrequent – hypersensitivity; frequency unknown – anaphylactic reactions.

From the endocrine system: rarely – hyperprolactinemia; frequency unknown – inadequate secretion of antidiuretic hormone.

Metabolic and nutritional disorders: frequency unknown – hypoglycemia.

Psychiatric disorders:very common – agitation, insomnia; common – psychotic disorders, depression; infrequent – confusion, loss of libido, decreased libido, feelings of anxiety.

Nervous system disorders: frequent – extrapyramidal disorders, headache, hyperkinesia; frequent – tardive dyskinesia, akathisia, bradykinesia, dyskinesia, dystonia, hypokinesia, hypertonicity, dizziness, somnolence, tremor; infrequent – seizures, parkinsonism, sedation, involuntary muscle contractions; rare – malignant neuroleptic syndrome, impaired motor function, nystagmus; frequency unknown – akinesia, “mask-like” face, “cogwheel” type rigidity, anxiety.

Heart: infrequent – tachycardia; frequency unknown – ventricular fibrillation, arrhythmia torsade de pointes, ventricular tachycardia, extrasystole.

Vascular disorders: often – arterial hypotension, orthostatic hypotension.

Respiratory system: infrequent – shortness of breath; rarely – bronchospasm, pharyngeal edema, laryngospasm.

The digestive system: often – dry mouth, hypersecretion of salivary glands, nausea, vomiting, constipation.

Hepatic and biliary tract disorders: frequently – changes of laboratory indexes of liver function; infrequent – hepatitis, jaundice; frequency unknown – acute liver failure, cholestasis.

Skin and subcutaneous tissue: common – rash, infrequent – photosensitivity reaction, urticaria, pruritus, hyperhidrosis; frequency unknown – angioedema, exfoliative dermatitis, leukocytoclastic vasculitis.

Skeletal-muscular system disorders: infrequent – torticollis, muscle stiffness, muscle spasm, musculoskeletal stiffness; rare – spasm of masticatory muscles (trismus), muscle twitching; frequency unknown – rhabdomyolysis.

Urogenital system disorders: often – urinary retention.

Pregnancy, postpartum, perinatal period: frequency unknown – withdrawal syndrome in the neonatal period in the newborn (see section “Use in pregnancy and during breastfeeding”).

Reproductive system disorders: often – erectile dysfunction; infrequent – pain in the breasts, breast discomfort, amenorrhea, galactorrhea, dysmenorrhea; rarely – menstrual irregularities, sexual dysfunction; frequency unknown – priapism, gynecomastia.

An organ of vision: often – oculogyric crisis, visual disturbance, blurred vision.

General disorders: infrequent – hyperthermia, edema, gait disturbances; frequency unknown – sudden death, facial edema, hypothermia.

Overdose

Because of the wide therapeutic index, intoxication usually develops only in cases of severe overdose.

Symptoms of overdose:

Treatment. There is no specific antidote. Treatment is symptomatic and supportive with observance of the general principles of treatment of overdose, the following circumstances should be taken into account.

Attempts to induce vomiting may be hampered by the antiemetic effects of antipsychotic drugs. Because of rapid absorption, gastric lavage is recommended only in cases of early diagnosis of overdose. Forced diuresis and dialysis are ineffective.

An analeptics are contraindicated, since against the background of haloperidol use due to decreased seizure threshold there is a tendency to develop epileptic seizures. If severe extrapyramidal symptoms develop, antiparkinsonian drugs such as biperiden intravenously should be used; it may be necessary to use antiparkinsonian drugs for several weeks. Patients in coma are intubated. Pharyngeal spasm may interfere with intubation; short-acting muscle relaxants may be used.

In symptomatic patients with intoxication, ECG and basic body function parameters should be monitored until they normalize.

In arterial hypotension due to increased paradoxical effects, adrenaline-type drugs (epinephrine (adrenaline)) that affect blood circulation should not be used; instead, drugs such as norepinephrine (norepinephrine) or angiotensinamide should be used. Beta-adrenomimetics should be avoided because they cause increased vasodilation.

Hypothermia is treated with slow warming. Infusion solutions for use in patients with hypothermia should be heated.

In case of severe fever, antipyretics should be used, and ice baths should be used if necessary.

M-cholin-blocking symptoms may be managed with physostigmine (1-2 mg IV) (repeat if necessary); use in standard daily practice is not recommended because of the severe adverse effects of this medication.

Anticonvulsants are used to treat recurrent epileptiform seizures, provided that artificial ventilation is possible, because there is a risk of respiratory depression.

Pregnancy use

Pregnancy

The use of the drug Haloperidol-rationfarm during pregnancy is contraindicated. A pregnancy test should be performed before starting treatment. Effective methods of contraception should be used during treatment with the drug.

Breastfeeding

Haloperidol is excreted with breast milk. Haloperidol has been detected in small amounts in the plasma and urine of breastfed infants of mothers treated with haloperidol. There is insufficient information about the effect of the drug on neonatal development. The use of the drug Haloperidol-ratiofarm during breastfeeding is contraindicated.

Fertility

Haloperidol increases prolactin levels. Hyperprolactinemia can inhibit hypothalamic gonadotropin-releasing hormone secretion, resulting in decreased pituitary gonadotropin secretion. This phenomenon may suppress reproductive function by disrupting the production of sex steroid hormones in both women and men (see “Special Indications”).

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