Proserin

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

Composition:

Active substance: neostigmine;

1 ml of solution contains 0.5 mg of proserin calculated as 100% substance;

Excipients: water for injections.

Pharmaceutical form. Solution for injection.
Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.
Anticholinesterase agents. ATC code N07AA01.

Pharmacological Properties.

Pharmacodynamics.

Proserin is a synthetic reversible cholinesterase inhibitor. It has high affinity for acetylcholinesterase due to its structural similarity to acetylcholine. Like acetylcholine, proserin initially interacts with the catalytic site of cholinesterase; however, unlike acetylcholine, it subsequently forms, via its carbamoyl group, a stable complex with the enzyme. The enzyme temporarily (from several minutes to several hours) loses its specific activity. After this period, due to the slow hydrolysis of proserin, cholinesterase is released from the inhibitor and regains its activity. This action of proserin leads to accumulation and potentiation of acetylcholine effects at cholinergic synapses. Proserin exerts pronounced muscarinic and nicotinic effects and is capable of directly stimulating skeletal muscles. It causes a decrease in heart rate, increases secretion of exocrine glands (salivary, bronchial, sweat, and gastrointestinal tract), promotes hypersalivation, bronchorrhea, increases gastric juice acidity, constricts the pupil, induces accommodation spasm, reduces intraocular pressure, enhances smooth muscle tone of the intestine (increases peristalsis and relaxes sphincters) and bladder, provokes bronchial spasm, and strengthens skeletal muscle tone.

Pharmacokinetics.

Bioavailability after parenteral administration is high: 0.5 mg of proserin administered parenterally is equivalent to 15 mg given orally. When the dose of the drug is increased, bioavailability rises. After intramuscular administration, the time to reach maximum plasma concentration is 30 minutes. Protein binding (to albumin) in plasma is 15–25%. The elimination half-life (T_1/2) after intramuscular administration is 51–90 minutes, and after intravenous administration, it is 53 minutes. Proserin is metabolized via two pathways: hydrolysis at the site of binding to cholinesterase and by hepatic microsomal enzymes. In the liver, inactive metabolites are formed. Approximately 80% of the administered dose is excreted by the kidneys within 24 hours (of which 50% is excreted unchanged and 30% as metabolites).

Clinical characteristics.

Indications.

Myasthenia, acute myasthenic crisis. Motor disorders following brain injury. Paralysis. Recovery period after meningitis, poliomyelitis, encephalitis. Neuritis, optic nerve atrophy. Intestinal atony, bladder atony. Elimination of residual effects after blockade of neuromuscular transmission by non-depolarizing muscle relaxants.

Contraindications.

Hypersensitivity to the active substance or to other components of the drug. Epilepsy, hyperkinesia, vagotomy, ischemic heart disease, angina pectoris, arrhythmias, bradycardia, bronchial asthma, severe atherosclerosis, thyrotoxicosis, peptic ulcer of the stomach and duodenum, peritonitis, mechanical obstruction of the gastrointestinal tract and urinary tract, prostate hypertrophy accompanied by difficulty in urination, acute phase of infectious disease, intoxications in severely weakened children. Concomitant use with depolarizing muscle relaxants.

Interaction with other medicinal products and other types of interactions.

Possible interactions when using the drug concomitantly with other medicinal products:

with local anesthetics and certain general anesthetics, antiarrhythmic agents, organic nitrates, tricyclic antidepressants, anticonvulsants, antiparkinsonian agents, guanethidine – reduced efficacy of proserin;

with m-cholinoblockers – weakening of m-cholinomimetic effects of proserin;

with depolarizing muscle relaxants – prolonged and enhanced action of the latter;

with non-depolarizing muscle relaxants – reduced effect of the latter. Proserin is used as an antidote in case of overdose of non-depolarizing muscle relaxants;

with other anticholinesterase agents – increased toxicity;

with m-cholinomimetics – gastrointestinal dysfunction, toxic effects on the nervous system;

with β-adrenoblockers – enhanced bradycardia;

with ephedrine – potentiation of proserin's effect.

Use with caution concomitantly with neomycin, streptomycin, kanamycin.

In myasthenia, the drug is prescribed in combination with aldosterone antagonists, glucocorticosteroids, and anabolic hormones.

Special precautions for use.

Dosage of the drug should be carefully determined, taking into account the possibility of high individual sensitivity to it.

Use with caution in patients with arterial hypotension, cardiac arrhythmias (especially bradycardia), increased vagus nerve (n. vagus) tone, hyperthyroidism, Addison's disease, peptic ulcer of the stomach and duodenum when using anticholinergic agents, in children with myasthenia gravis who are receiving antibacterial drugs with depolarizing blocking effects (neomycin, streptomycin, kanamycin), local and general anesthetics, antiarrhythmic drugs that interfere with cholinergic transmission.

When administering large doses parenterally, atropine should be given (concurrently or prior to administration).

The drug should be used with caution in elderly patients.

If a myasthenic crisis (due to insufficient therapeutic dose) or cholinergic crisis (due to overdose) occurs during treatment, further use of the drug requires careful differential diagnosis due to similar clinical manifestations.

Before any medical or dental treatment or surgical intervention, the physician must be informed about the use of Proserin.

The drug should be prescribed with particular caution to patients after intestinal or bladder surgery and in patients with Parkinsonism.

Use during pregnancy or breastfeeding.

Well-controlled studies on the use of the drug in pregnant women have not been conducted. The drug may be used only if the expected benefit to the mother outweighs the potential risk to the fetus. If Proserin must be used, breastfeeding should be discontinued.

Ability to affect reaction rate when driving or operating machinery.

During treatment, driving and engaging in other potentially hazardous activities requiring increased concentration and rapid psychomotor reactions are prohibited.

Method of Administration and Dosage

Adults.

Administer the drug subcutaneously in a dose of 0.5–2 mg (1–4 mL) 1–2 times daily. The maximum single dose for adults is 2 mg; the maximum daily dose is 6 mg. The duration of treatment course (except for myasthenia, myasthenic crisis, postoperative intestinal and urinary bladder atony, and overdose of myorelaxants) is 25–30 days. If necessary, repeat the course after 3–4 weeks. The larger part of the total daily dose should be administered during daytime, when the patient is most fatigued.

Myasthenia. Administer the drug subcutaneously or intramuscularly at a dose of 0.5 mg (1 mL) daily. The treatment course is prolonged, with alternating routes of administration.

Myasthenic crisis (with impaired respiration and swallowing). Administer the drug intravenously at a dose of 0.25–0.5 mg (0.5–1 mL), followed by subcutaneous administration at short intervals.

Postoperative intestinal and urinary bladder atony, prophylaxis, including postoperative urinary retention. Administer the drug subcutaneously or intramuscularly at a dose of 0.25 mg (0.5 mL) as soon as possible after surgery, and repeat every 4–6 hours for 3–4 days.

As an antidote in case of myorelaxant overdose (after prior intravenous administration of atropine sulfate at a dose of 0.6–1.2 mg, until pulse rate increases to 80 beats/min). Administer the drug slowly intravenously at a dose of 0.5–2 mg every 0.5–2 minutes. If necessary, repeat injections (including atropine injections in case of bradycardia); total dose should not exceed 5–6 mg (10–12 mL) within 20–30 minutes. Artificial ventilation of the lungs must be ensured during the procedure.

Children (only under inpatient conditions).

Myasthenia gravis.

Newborns. Initially, administer the drug at a dose of 0.1 mg via intramuscular injection. Subsequently, individualize dosing, typically 0.05–0.25 mg or 0.03 mg/kg body weight intramuscularly every 2–4 hours. Due to the specific nature of the disease in newborns, the daily dose may be gradually reduced until complete discontinuation.

Children under 12 years of age. If necessary, administer the drug at a dose of 0.2–0.5 mg via injection. Dosage should be adjusted according to the patient's response.

As an antidote in case of myorelaxant overdose (after prior intravenous administration of atropine sulfate at a dose of 0.02–0.03 mg/kg body weight, until pulse rate increases to 80 beats/min). Administer the drug slowly intravenously at a dose of 0.05–0.07 mg/kg body weight over 1 minute. The maximum recommended dose for children is 2.5 mg.

Other indications. Administer the drug at a dose of 0.125–1 mg via injection. The dose may be adjusted according to individual patient needs.

Children.

The drug may be administered to children only under inpatient conditions.

Overdose.

Symptoms associated with overstimulation of cholinoreceptors (cholinergic crisis): tachycardia, bradycardia, hypersalivation, difficulty swallowing, miosis, bronchospasm, dyspnea, nausea, vomiting, increased peristalsis, diarrhea, increased frequency of urination, impaired coordination, twitching of tongue and skeletal muscles, cold sweat, progressive development of generalized weakness, paralysis, decreased arterial pressure, anxiety, panic. Very high doses may cause agitation and restlessness. Fatal outcome may result from cardiac arrest or respiratory paralysis, pulmonary edema. In patients with myasthenia gravis, in whom overdose is more likely, muscle twitching and parasympathomimetic effects may be absent or poorly expressed, complicating differential diagnosis between overdose and myasthenic crisis.

Treatment: reduce or discontinue the drug. If necessary, administer atropine (1 mL of 0.1% solution), metacine. Further treatment is symptomatic.

Adverse reactions.

Cardiovascular system: arrhythmia, bradycardia or tachycardia, atrioventricular block, nodal rhythm, non-specific ECG changes, cardiac arrest, decreased arterial pressure (mainly with parenteral administration).

Nervous system: headache, dizziness, fainting, weakness, drowsiness, tremor, seizures, spasms and twitching of skeletal muscles, including tongue and larynx muscles, numbness of legs, dysarthria.

Eye disorders: miosis, visual disturbances.

Respiratory, thoracic and mediastinal disorders: dyspnea, respiratory depression up to respiratory arrest, bronchospasm, increased bronchial secretion.

Gastrointestinal disorders: hypersalivation, spastic contractions and increased intestinal peristalsis, nausea, vomiting, flatulence, diarrhea, involuntary defecation.

Renal and urinary disorders: frequent urination, involuntary urination.

Immune system disorders: hypersensitivity reactions, including rash, pruritus, hyperemia, urticaria, allergic reactions, including anaphylactic shock.

General disorders and administration site conditions: increased sweating, feeling of warmth, lacrimation, arthralgia, injection site reactions including hyperemia, pruritus, skin swelling.

To manage adverse effects, the dose should be reduced or the drug discontinued. If necessary, administer atropine, metacin, or other anticholinergic agents.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibility. Proserin should not be mixed in the same syringe with alkaline solutions and oxidizing agents, as this leads to its degradation.

Packaging.

1 ml in an ampoule; 10 ampoules per box.

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

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

Prescription status.

Prescription only.

Manufacturer.

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

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVYA".

Manufacturer's address and place of business.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kuлиkivska Street, 41.

(Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVYA")