Chlorpromazine hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CHLORPROMAZINE HYDROCHLORIDE (Chlorpromazine hydrochloride)

Composition:

Active substance: chlorpromazine;

1 ml of solution contains chlorpromazine hydrochloride, recalculated to 100% substance, 25 mg;

Excipients: sodium sulfite anhydrous (E 221), sodium metabisulfite (E 223), ascorbic acid, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish-green liquid.

Pharmacotherapeutic group. Antipsychotic agents. Phenothiazine derivatives with aliphatic side chain. ATC code N05A A01.

Pharmacological properties.

Pharmacodynamics.

A neuroleptic of the phenothiazine derivatives group. Exhibits pronounced antipsychotic, sedative, and antiemetic effects. Reduces or completely eliminates delusions and hallucinations, suppresses psychomotor agitation, decreases affective reactions, anxiety, restlessness, and reduces motor activity. The mechanism of antipsychotic action is associated with blockade of postsynaptic dopaminergic receptors in the mesolimbic structures of the brain. It also exerts blocking effects on α-adrenergic receptors and suppresses hormone release from the pituitary and hypothalamus. However, blockade of dopamine receptors increases prolactin secretion by the pituitary gland. Central antiemetic action is due to inhibition or blockade of dopamine D2-receptors in the chemoreceptor trigger zone of the medulla oblongata; peripheral antiemetic action results from blockade of the vagus nerve in the gastrointestinal tract. Sedative effects are mediated by blockade of central adrenergic receptors. Exhibits moderate or weak effects on extrapyramidal structures.

Pharmacokinetics.

Chlorpromazine is detectable in the blood in small amounts within 15 minutes after administration of a therapeutic dose and circulates for about 2 hours. It has high plasma protein binding (95–98%), is widely distributed throughout the body, and penetrates the blood-brain barrier, achieving higher concentrations in the brain than in blood plasma. The elimination half-life of the drug is approximately 30 hours. It is extensively metabolized in the liver, forming several active and inactive metabolites. It is excreted in urine, feces, and bile.

Clinical Characteristics.

Indications.

Chronic paranoid and hallucinatory-paranoid states; psychomotor agitation in patients with schizophrenia (hallucinatory-delusional, hebephrenic, catatonic syndromes); alcoholic psychosis; manic excitement in patients with manic-depressive psychosis; mental disorders in patients with epilepsy; agitated depression in patients with presenile and manic-depressive psychosis, as well as in other conditions accompanied by excitement and tension. Neurotic disorders associated with increased muscle tone. Persistent pain, including causalgia (in combination with analgesics), and persistent sleep disturbances (in combination with hypnotics and tranquilizers). Ménière’s disease; treatment and prevention of vomiting during anticancer therapy and radiation therapy. Dermatological pruritus. Component of lytic mixtures in anesthesiology.

Contraindications.

Hypersensitivity to chlorpromazine or other components of the drug. Liver disorders (cirrhosis, hepatitis, hemolytic jaundice, cholelithiasis), kidney disorders (nephritis, acute pyelitis, amyloidosis of the kidneys, urolithiasis), blood disorders, progressive systemic diseases of the central nervous system (slow neuroinfections, e.g., multiple sclerosis), decompensated heart failure, severe cardiovascular diseases, peptic ulcer of the stomach and duodenum during exacerbation, decompensated heart defects, marked arterial hypotension, stroke, thromboembolic disease, severe myocardiodystrophy, late-stage rheumatic carditis, myxedema, late stage of bronchiectasis, closed-angle glaucoma, urinary retention due to prostatic hyperplasia, pronounced central nervous system depression, comatose state, brain injuries, acute infectious diseases. Do not administer concurrently with barbiturates, alcohol, or narcotics.

Interaction with other medicinal products and other forms of interactions.

The sedative effect of chlorpromazine is enhanced when used concomitantly with zolpidem or zopiclone; the neuroleptic effect is enhanced with estrogens. Plasma concentrations of chlorpromazine are reduced by antacids containing aluminum and magnesium hydroxide (which impair absorption from the gastrointestinal tract) and by barbiturates (which enhance hepatic metabolism of chlorpromazine). Plasma concentrations of chlorpromazine are increased by chloroquine and sulfadoxine/pyrimethamine. Cimetidine may either decrease or increase chlorpromazine plasma levels. Chlorpromazine may reduce or completely suppress the antihypertensive effect of guanethidine, increase blood concentrations of imipramine, inhibit the effects of levodopa, increase or decrease blood levels of phenytoin, and reduce the efficacy of cardiac glycosides.

Concomitant use with other medicinal products may result in:

• With anticholinergic agents – enhanced anticholinergic effects;
• With anticholinesterase agents – muscle weakness, worsening of myasthenia gravis;
• With epinephrine – reversal of its effects, leading to further reduction in blood pressure and development of severe arterial hypotension and tachycardia;
• With amitriptyline – increased risk of tardive dyskinesia, possible development of paralytic ileus;
• With diazoxide – pronounced hyperglycemia;
• With doxepin – potentiation of hyperpyrexia;
• With lithium carbonate – severe extrapyramidal symptoms, neurotoxic effects;
• With morphine – development of myoclonus;
• With cisapride – additive prolongation of the QT interval on ECG;
• With nortriptyline in patients with schizophrenia – possible worsening of clinical condition despite increased chlorpromazine blood levels;
• With tricyclic antidepressants, maprotiline, and monoamine oxidase inhibitors – prolonged and enhanced sedative and anticholinergic effects, increased risk of neuroleptic malignant syndrome;
• With antithyroid drugs – increased risk of agranulocytosis;
• With other drugs causing extrapyramidal reactions – possible increase in frequency and severity of extrapyramidal disorders;
• With other drugs causing arterial hypotension – possible pronounced orthostatic hypotension;
• With ephedrine – possible weakening of ephedrine’s vasoconstrictive effect;
• With other central nervous system (CNS) depressants: morphine derivatives (analgesics, antitussives, substitution therapy), barbiturates, benzodiazepines, other anxiolytics, antihypertensives, ethanol, and ethanol-containing products – increased CNS depression. Respiratory depression may occur. Reduced alertness may make driving or operating machinery hazardous.

In neurotic disorders associated with increased muscle tone, and in persistent pain (including causalgia), chlorpromazine may be combined with analgesics; in persistent insomnia – with hypnotics and tranquilizers.

When used concomitantly with anticonvulsant drugs, the effects of the latter may be enhanced, and the seizure threshold may be lowered. Combined use with other agents that depress the central nervous system, as well as with ethanol and ethanol-containing products, may lead to enhanced CNS depression and respiratory depression.

Barbiturates enhance the metabolism of chlorpromazine by inducing hepatic microsomal enzymes, thereby reducing its plasma concentrations and, consequently, its therapeutic effect.

Chlorpromazine may inhibit the effects of amphetamines, levodopa, clonidine, guanethidine, and adrenaline.

Special precautions for use.

The medicinal product is not recommended for patients with hypothyroidism, pheochromocytoma, or myasthenia gravis.

Use with particular caution and under close medical supervision in patients with pathological changes in blood parameters, rheumatism, rheumatic carditis, alcohol intoxication, Reye's syndrome, as well as in patients with breast cancer, severe arterial hypertension, predisposition to glaucoma, Parkinson's disease, chronic respiratory diseases (especially in children), epileptic seizures, moderate cardiovascular diseases, and diabetes mellitus.

Exercise caution when prescribing to elderly patients (increased risk of excessive sedative and hypotensive effects) and to debilitated or weakened patients.

In case of hyperthermia, which is one of the symptoms of neuroleptic malignant syndrome, the drug should be discontinued immediately.

In children, especially those with acute illnesses, there is an increased risk of developing extrapyramidal symptoms when using the drug.

During prolonged treatment, blood counts, prothrombin index, and liver and kidney function should be monitored regularly. After administration of the drug, patients should remain lying down for 1–1.5 hours (sudden transition to an upright position may cause orthostatic collapse).

To reduce neuroleptic depression, antidepressants and central nervous system stimulants may be used. During therapy, due to the possibility of photosensitization of the skin, prolonged exposure to sunlight should be avoided. The drug does not exhibit antiemetic effects when nausea results from vestibular stimulation or local irritation of the gastrointestinal tract. In patients with gastrointestinal atony and achylia, administration of gastric juice or hydrochloric acid is recommended concurrently (due to chlorpromazine's inhibitory effect on gastric motility and secretion), along with careful monitoring of diet and intestinal function.

Patients receiving this drug may develop an increased need for riboflavin.

Neuroleptic phenothiazines may potentiate QT interval prolongation, increasing the risk of ventricular arrhythmias, including torsade de pointes, which may potentially lead to sudden death. Prior to initiating treatment, patients should be evaluated (biochemical profile, ECG) to exclude potential risk factors (e.g., cardiac diseases, history of QT prolongation; metabolic disturbances such as hypokalemia, hypocalcemia, hypomagnesemia; starvation, alcohol abuse, concomitant therapy with other drugs that prolong the QT interval). ECG monitoring is required at the beginning of treatment and as needed during therapy.

This medicinal product contains less than 1 mmol (23 mg)/ml of sodium, i.e., it is practically sodium-free.

This medicinal product contains anhydrous sodium sulfite (E 221) and sodium metabisulfite (E 223), which may rarely cause hypersensitivity reactions and bronchospasm.

When procaine is used as a solvent, the safety information regarding procaine should be taken into account.

Use during pregnancy or breastfeeding.

The medicinal product is not recommended during pregnancy. In cases of acute necessity for use during pregnancy, treatment duration should be limited, and toward the end of the third trimester, the dose should be reduced if possible. Chlorpromazine prolongs labor.

Newborns whose mothers used antipsychotic agents (including chlorpromazine hydrochloride) during the third trimester of pregnancy are at risk of developing extrapyramidal symptoms and/or withdrawal symptoms after delivery. Symptoms in newborns may include agitation, increased or decreased muscle tone, tremor, somnolence, respiratory distress, and feeding difficulties. In some newborns, these symptoms resolve within a few hours or days and do not require specific treatment. Other newborns may require prolonged hospitalization.

When chlorpromazine is used in high doses during pregnancy, newborns may occasionally experience digestive disturbances related to its atropine-like effects, as well as extrapyramidal syndrome.

If use of the drug is necessary, breastfeeding should be discontinued.

Chlorpromazine hydrochloride and its metabolites cross the placental barrier and are excreted in breast milk.

Ability to affect reaction speed when driving or operating machinery.

During treatment with chlorpromazine hydrochloride, patients should refrain from driving or operating machinery.

Administration and Dosage.

The medicinal product should be administered intramuscularly and intravenously. The physician determines the dosage and treatment regimen individually, depending on the indications and patient's condition. For intramuscular administration, the maximum single dose is 150 mg and the daily dose is 600 mg. Typically, 1–5 mL of solution should be administered intramuscularly no more than 3 times daily. The treatment course lasts several months; when using high doses—up to 1.5 months, after which therapy should be switched to maintenance doses, gradually reducing the dose by 25–75 mg per day. In acute mental agitation, administer 100–150 mg (4–6 mL of solution) intramuscularly or 25–50 mg (1–2 mL of Chlorpromazine hydrochloride solution diluted in 20 mL of 5% or 40% glucose solution) intravenously; if necessary, 100 mg (4 mL of solution diluted in 40 mL of glucose solution). Administer slowly. For intravenous administration, the maximum single dose is 100 mg and the maximum daily dose is 250 mg.

For children aged 1 year and older, the single dose for intramuscular and intravenous administration is 250–500 mcg/kg body weight. For children aged 5 years (body weight up to 23 kg), the daily dose is 40 mg; for children aged 5–12 years (body weight 23–46 kg), the daily dose is 75 mg.

For debilitated patients and elderly patients, the recommended dose is up to 300 mg daily intramuscularly or up to 150 mg daily intravenously.

Children. The drug is not recommended for children under 1 year of age.

Overdose.

Symptoms: slurred speech, unsteady gait, bradycardia, labored breathing, marked weakness, confusion, diminished reflexes, drowsiness, seizures, persistent hypotension, hypothermia, prolonged depression, and later— toxic hepatitis.

Treatment: symptomatic therapy. There is no specific antidote. The drug is not removed by hemodialysis. In case of collapse-like conditions, administration of cordiamine, caffeine, or mesaton is recommended. If dermatitis develops, chlorpromazine treatment should be discontinued and antihistamines prescribed. Neurological complications usually diminish with dose reduction and can also be reduced by a single administration of cyclodol or other antiparkinsonian agents.

After prolonged use of high doses of the drug (0.5–1.5 g daily), jaundice, accelerated blood coagulation, lymphopenia and leukopenia, anemia, agranulocytosis, skin pigmentation, and lens and corneal opacities may be observed in isolated cases.

Adverse Reactions.

Central nervous system: with prolonged use, neuroleptic syndrome may develop: parkinsonism, akathisia, psychic indifference and other mental changes, delayed response to external stimuli, blurred vision; dystonic extrapyramidal reactions, tardive dyskinesia, neuroleptic depression, disturbances of thermoregulation, malignant neuroleptic syndrome; seizures, insomnia, excitement, delirium, drowsiness, nightmares, depression.

Cardiovascular system: arterial hypotension (especially with intravenous administration), tachycardia; ECG changes (prolongation of QT interval, ST-segment depression, changes in T and U waves, arrhythmia).

Gastrointestinal system: cholestatic jaundice, nausea, vomiting; dry mouth, constipation.

Hematopoietic system: leukopenia, agranulocytosis, hematological changes, eosinophilia.

Urinary system: difficulty in urination; priapism.

Endocrine system: menstrual cycle disturbances, impotence, gynecomastia, weight gain; galactorrhea, hyperprolactinemia, hyperglycemia, impaired glucose tolerance, hypercholesterolemia.

Immune system: hypersensitivity reactions, including skin rashes, pruritus, bronchospasm, urticaria, angioneurotic edema, erythema multiforme, exfoliative dermatitis, systemic lupus erythematosus, and other allergic reactions.

Skin and mucous membranes: when solutions come into contact with mucous membranes, skin or subcutaneous tissue – tissue irritation: injection site reactions, including painful infiltrates, endothelial damage and others. Skin pigmentation, photosensitization. To prevent these effects, chlorpromazine solution should be diluted with novocaine solution, glucose solution, or 0.9% sodium chloride solution.

Eye organs: with prolonged use at high doses, chlorpromazine may deposit in the anterior eye structures (cornea and lens), potentially accelerating the natural aging process of the lens, miosis.

Respiratory system: nasal congestion.

General: isolated reports of sudden death during drug use.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibility.

Do not mix with other medicinal products in the same syringe.

Packaging.

2 ml in an ampoule; 10 ampoules per box.

2 ml in an ampoule; 5 ampoules per blister, 2 blisters per box.

2 ml in an ampoule; 10 ampoules per blister; 1 blister per box.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu"".

Manufacturer's address and location of business activity.

41 Kuilikivska Street, Kharkiv, Kharkiv Region, 61002, Ukraine.