Haloperidol-ratiopharm (Drops) Instructions for Use

Marketing Authorization Holder

Ratiopharm, GmbH (Germany)

Manufactured By

Merckle, GmbH (Germany)

ATC Code

N05AD01 (Haloperidol)

Active Substance

Haloperidol (Rec.INN registered by WHO)

Dosage Form

Haloperidol-ratiopharm

Oral drops 2 mg/1 ml: 30 ml or 100 ml bottle

Dosage Form, Packaging, and Composition

Oral drops in the form of a transparent, colorless solution.

Excipients: methylparahydroxybenzoate – 0.9 mg, propylparahydroxybenzoate – 0.1 mg, lactic acid – 1.7 mg, purified water – 997 mg.

30 ml – dark glass bottles (1) with a dropper cap – cardboard packs^×.
100 ml – dark glass bottles (1) with a pipette – cardboard packs^×.

^× protective stickers may additionally be applied.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psychotropic agents, antipsychotic agents, butyrophenone derivatives

Pharmacological Action

Antipsychotic agent (neuroleptic), a butyrophenone derivative. It has a pronounced antipsychotic effect, blocking postsynaptic dopamine receptors in the mesolimbic and mesocortical structures of the brain. It inhibits the release of neurotransmitters, reducing the permeability of presynaptic membranes. 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 and practically has no anticholinergic action.

The sedative effect is due to the blockade of α-adrenergic receptors of the brainstem reticular formation; the antiemetic effect is due to the blockade of dopamine D2 receptors of the trigger zone of the vomiting center; the hypothermic effect and galactorrhea are due to the blockade of dopamine receptors in the hypothalamus. Long-term use is accompanied by a change in endocrine status: in the anterior pituitary lobe, the production of prolactin increases and the production of gonadotropic hormones decreases.

It eliminates persistent personality changes, delusions, hallucinations, manias, and enhances interest in the environment.

Pharmacokinetics

Absorption after oral administration is 60%. C_max in plasma is reached after oral administration in 3 hours, after IM administration – in 10-20 minutes. V_d – 15-35 l/kg. Binding to plasma proteins is 92%. It easily passes through histohematic barriers, including the blood-brain barrier. Penetrates into breast milk.

It is metabolized in the liver and undergoes the first-pass effect through the liver. The metabolism of haloperidol is accelerated by enzyme-inducing substances (phenobarbital, phenytoin and carbamazepine). Isoenzymes CYP2D6, CYP3A3, CYP3A5, CYP3A7 are involved in the metabolism of haloperidol. It is an inhibitor of CYP2D6. There are no active metabolites.

T_1/2 after oral administration is 24 hours (12-37 hours). It is excreted with bile and urine: after oral administration, 15% is excreted with bile, 40% with urine (including 1% unchanged).

Due to the large V_d and low plasma concentration, only a very small amount of haloperidol is removed by dialysis.

Indications

• Acute psychotic syndromes accompanied by delusions, hallucinations, thought and consciousness disorders, catatonic syndromes, delirious and other exogenous psychotic syndromes;
• Chronic endogenous and exogenous psychoses (symptom suppression and relapse prevention);
• Psychomotor agitation;
• Vomiting, stuttering, when other therapy is impossible or there is resistance to treatment.

ICD codes

Dosage Regimen

1 ml of 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, characteristics of the disease course, age and tolerance of the drug. The daily dose should be divided into 1-3 doses; with high doses, more frequent administration of individual doses is possible. If the doctor has not determined an individual dose for the patient, the following treatment regimens are usually used.

Oral drops are taken with meals, dosed using a teaspoon, added to drinks or food, or on a piece of sugar (except for patients with diabetes mellitus).

Adults. Initial dose – 0.5-1.5 mg 2-3 times/day. Then the dose is gradually increased by 0.5-2 mg/day (in resistant cases by 2-4 mg/day) until the necessary therapeutic effect is achieved. For relief of acute symptoms in inpatient settings, initial daily doses 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, for chronic forms of schizophrenia – 20-40 mg/day, in resistant cases – up to 50-60 mg/day. Maintenance doses (outside exacerbation) in outpatient settings can range from 0.5-5 mg/day.

Children over 3 years old. Treatment starts with a dose of 0.025-0.05 mg/kg of body weight, divided into 2-3 doses. The dose can be increased to 0.2 mg/kg of body weight.

Elderly patients and physically debilitated patients. Treatment starts with single doses not exceeding 0.5-1.5 mg. The daily dose is not recommended to be increased by more than 5 mg/day.

For children, elderly patients and debilitated patients, doses are increased no more than once every 3-5 days.

Adverse Reactions

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

From the nervous system headache, dizziness, insomnia or drowsiness (especially at the beginning of treatment), feeling of restlessness, anxiety, agitation, fear, akathisia, euphoria, depression, lethargy, epileptic seizures, development of a paradoxical reaction – exacerbation of psychosis and hallucinations; with long-term treatment – extrapyramidal disorders, including tardive dyskinesia (smacking and puckering of lips, puffing of cheeks, rapid and worm-like movements of the tongue, uncontrolled chewing movements, uncontrolled movements of arms and legs), tardive dystonia (frequent blinking or spasms of eyelids, unusual facial expression, unusual body position, uncontrolled writhing movements of the neck, torso, arms and legs), malignant neuroleptic syndrome (difficult or rapid breathing, tachycardia, arrhythmia, hyperthermia, increase or decrease in BP, increased sweating, urinary incontinence, muscle rigidity, epileptic seizures, loss of consciousness).

From the cardiovascular system when used in high doses – decreased BP, orthostatic hypotension, arrhythmia, tachycardia, ECG changes (prolongation of QT interval, ventricular flutter and fibrillation).

From the respiratory system respiratory rhythm disturbance, shortness of breath, pneumonia (bronchopneumonia).

From the digestive system when used in high doses – decreased appetite, dryness of the oral mucosa, hyposalivation, nausea, vomiting, diarrhea, constipation, impaired liver function, jaundice.

From the hematopoietic organs transient leukopenia or leukocytosis, agranulocytosis, erythrocytopenia, monocytosis.

From the genitourinary system urinary retention (with prostate hyperplasia), peripheral edema, breast pain, gynecomastia, hyperprolactinemia, menstrual cycle disorder, decreased potency, increased libido, priapism.

From the sensory organs cataract, retinopathy, blurred vision.

Allergic reactions maculopapular skin changes, acne, photosensitivity reactions, bronchospasm, laryngospasm, hyperpyrexia.

Laboratory parameters hyponatremia, hyperglycemia, hypoglycemia.

Other alopecia, heat stroke, increased body weight.

Contraindications

• Coma of various origins;
• Children under 3 years of age;
• Pregnancy;
• Lactation period;
• Severe depression of the central nervous system function due to xenobiotic intoxication;
• Diseases of the central nervous system accompanied by pyramidal or extrapyramidal symptoms (including Parkinson’s disease);
• Hypersensitivity to haloperidol and/or other butyrophenone derivatives or other excipients of the drug.

With caution

Acute intoxication with alcohol, opioid analgesics, hypnotics or psychotropic drugs that depress the central nervous system; hepatic and renal failure; hypokalemia; bradycardia; prolonged QT interval (including congenital long QT syndrome) or predisposition to it – simultaneous use of drugs that may contribute to the development of hypokalemia; other clinically significant cardiac disorders (in particular, intracardiac conduction disorders, arrhythmias); prolactin-dependent tumors (e.g., breast tumors); severe arterial hypotension or orthostatic dysregulation; endogenous depression; diseases of the hematopoietic system; history of malignant neuroleptic syndrome; organic brain diseases and epilepsy; hyperthyroidism.

Special caution is required in patients with neurological symptoms of damage to the subcortical structures of the brain and a lowered seizure threshold (in history or against the background of alcohol withdrawal), because Haloperidol lowers the seizure threshold, so seizures of the “grand mal” type may be observed. Patients with epilepsy should be treated with haloperidol only if anticonvulsant therapy is continued.

Haloperidol should not be used in severe depressive states. For concomitant depression and psychosis, Haloperidol should be combined with antidepressants.

Since thyroxine may contribute to an increase in the frequency of adverse effects associated with haloperidol, patients with hyperthyroidism should not receive haloperidol treatment, except in cases where they are simultaneously undergoing adequate antithyroid therapy.

Use in Pregnancy and Lactation

The use of Haloperidol-ratiopharm 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. Haloperidol is excreted in breast milk. The use of Haloperidol-ratiopharm during breastfeeding is contraindicated.

Pediatric Use

Children over 3 years old. Treatment starts with a dose of 0.025-0.05 mg/kg of body weight, divided into 2-3 doses. The dose can be increased to 0.2 mg/kg of body weight.

The drug is contraindicated for children under 3 years of age.

Geriatric Use

Elderly patients and physically debilitated patients. Treatment starts with single doses not exceeding 0.5-1.5 mg. The daily dose is not recommended to be increased by more than 5 mg/day.

Special Precautions

If fever, gingivitis and stomatitis, pharyngitis, purulent tonsillitis and flu-like symptoms occur, especially in the first three months of treatment, it is necessary to immediately consult the attending physician.

Self-treatment with analgesics should be avoided.

Before starting treatment with haloperidol, patients need to have a complete blood count (including differential count of blood cells and platelet count), ECG and electroencephalogram parameters examined. If deviations from the norm are detected, Haloperidol can be used only for absolute indications and subject to mandatory control studies of general blood parameters. Hypokalemia must be corrected before starting treatment.

Special caution is required in patients with organic brain damage, arteriosclerotic cerebrovascular diseases and endogenous depression during therapy with haloperidol.

Since elderly patients and patients with concomitant cardiovascular diseases may experience intracardiac conduction disorders, regular monitoring of cardiac activity is recommended during therapy. In patients with pheochromocytoma, renal failure, heart failure or cerebral failure, hypotensive reactions may develop during therapy with haloperidol, so such patients require careful observation.

Although the prevalence of tardive dyskinesia has not been sufficiently studied, elderly patients (especially elderly women) are prone to developing this condition. The risk of developing tardive dyskinesia, especially of the irreversible type, increases with increasing duration of treatment and with the use of antipsychotic doses. Tardive dyskinesia can also develop after short-term treatment with low doses. Antipsychotic treatment may initially mask the symptoms of primary tardive dyskinesia. Symptoms may appear after drug withdrawal. Caution should be exercised when performing heavy physical work, taking a hot bath (heat stroke may develop due to suppression of central and peripheral thermoregulation in the hypothalamus).

During treatment, “cold” over-the-counter medications should not be taken (possible enhancement of anticholinergic effects and risk of heat stroke).

Open areas of the skin should be protected from excessive solar radiation due to an increased risk of photosensitivity reactions.

Treatment should be discontinued gradually to avoid the occurrence of “withdrawal” syndrome.

The antiemetic effect may mask signs of drug toxicity and complicate the diagnosis of these conditions, the first symptom of which is nausea.

Effect on the ability to drive vehicles and operate machinery

During the treatment period, it is necessary to avoid (especially in the initial stages of treatment) or exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Due to the wide therapeutic index, intoxication usually develops only in cases of significant overdose. Overdose symptoms

• Severe extrapyramidal disorders: acute dyskinetic or dystonic symptoms, glossopharyngeal syndrome, oculogyric crisis, laryngeal and pharyngeal spasms;
• Drowsiness, sometimes coma, agitation and confusion with delirium;
• Less commonly – epileptic seizures;
• Hyperthermia or hypothermia;
• Cardiovascular system: decrease or increase in BP, tachycardia or bradycardia, ECG changes such as prolongation of PQ and QT intervals, ventricular flutter and fibrillation, cardiovascular failure;
• Rarely – anticholinergic effects: blurred vision, acute attack of increased intraocular pressure, intestinal paresis, urinary retention;
• Rarely – respiratory complications: cyanosis, respiratory depression, respiratory failure, aspiration, pneumonia.

Treatment is symptomatic and supportive, following the general principles of overdose treatment, while the following circumstances must be taken into account.

Attempts to induce vomiting may be difficult due to the antiemetic effect of antipsychotic drugs. Due to rapid absorption, gastric lavage is recommended only in cases of early diagnosis of overdose. Forced diuresis and dialysis are not very effective.

Analeptics are contraindicated because when using haloperidol, due to a lowered seizure threshold, there is a tendency to develop epileptic seizures. If severe extrapyramidal symptoms develop, antiparkinsonian drugs should be used, for example, biperiden IV; the use of antiparkinsonian agents may be required for several weeks. Patients in a coma are intubated. Spasm of the pharyngeal muscles may complicate intubation; in this case, the use of short-acting muscle relaxants is possible.

In patients with symptoms of intoxication, ECG parameters and basic functional parameters of the body should be constantly monitored until they normalize. For arterial hypotension due to increased paradoxical effects, drugs of the adrenergic series (epinephrine (adrenaline)) that affect circulation should not be used; instead, drugs such as norepinephrine (for example, continuous drip infusions of norepinephrine (noradrenaline)) or angiotensinamide should be used. Beta-adrenergic agonists should be avoided because they cause increased vasodilation.

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

For severe fever, antipyretic agents should be used, if necessary – ice baths.

Anticholinergic symptoms can be relieved by the use of physostigmine (1-2 mg IV) (repeat if necessary); use in standard daily practice is not recommended due to the severe adverse effects of this drug.

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

Drug Interactions

Simultaneous use of ethanol and haloperidol may enhance the effect of alcohol and lead to arterial hypotension.

It increases the severity of the inhibitory effect on the central nervous system of ethanol, tricyclic antidepressants, opioid analgesics, barbiturates and other hypnotic drugs, and general anesthetics.

It potentiates the action of peripheral M-cholinoblocking agents and most antihypertensive drugs (it reduces the effect of guanethidine due to its displacement from alpha-adrenergic neurons and suppression of its uptake by these neurons).

It inhibits the metabolism of tricyclic antidepressants and MAO inhibitors, thereby mutually increasing their sedative effect and toxicity.

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

It reduces the effect of anticonvulsant drugs (due to the lowering of the convulsive activity threshold by haloperidol).

It weakens the vasoconstrictive action of dopamine, phenylephrine, norepinephrine, ephedrine, and epinephrine (blockade of α-adrenergic receptors by haloperidol may lead to an inversion of the effect of epinephrine and a paradoxical decrease in blood pressure).

It reduces the effect of antiparkinsonian drugs (antagonistic influence on dopaminergic structures of the CNS).

It alters (may increase or decrease) the effect of anticoagulants.

It reduces the effect of bromocriptine (dose adjustment may be required).

When used with methyldopa, it increases the risk of developing mental disorders (including disorientation in space, slowing and difficulty of thought processes).

Amphetamines reduce the antipsychotic action of haloperidol, which, in turn, reduces their psychostimulant effect (blockade of α-adrenergic receptors by haloperidol).

M-cholinoblocking drugs, first-generation histamine H₁-receptor blockers, and antidyskinetic drugs may enhance the M-cholinoblocking influence of haloperidol and reduce its antipsychotic action (dose adjustment may be required).

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

Concomitant use with lithium preparations (especially in high doses) may lead to the development of encephalopathy (which can cause irreversible neurotoxicity) and an increase in extrapyramidal symptoms.

Concomitant use with fluoxetine increases the risk of CNS side effects, especially extrapyramidal reactions.

When used concomitantly with drugs causing extrapyramidal reactions, it increases the frequency and severity of extrapyramidal disorders.

Consumption of strong tea or coffee (especially in large quantities) reduces the effect of haloperidol.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 5 years.

After opening the vial, the drug is suitable for use for 6 months. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.