Proserin-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROZERIN-DARNITSA (PROZERIN-DARNITSA)

Composition:

Active substance: neostigminum methylsulphate;

1 ml of solution contains 0.5 mg of prozerin;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Anticholinesterase agents. ATC code N07A A01.

Pharmacological properties.

Pharmacodynamics.

Proserin-Darnytsia is a synthetic reversible cholinesterase inhibitor. It has high affinity for acetylcholinesterase, due to its structural similarity with acetylcholine. Like acetylcholine, proserin initially interacts with the catalytic site of cholinesterase, but subsequently, unlike acetylcholine, it forms a stable complex with the enzyme via its carbamoyl group. 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 its activity is restored. This action leads to accumulation and enhancement of acetylcholine effects at cholinergic synapses. Proserin has pronounced muscarinic and nicotinic effects and exerts a direct stimulatory effect on skeletal muscles.

It causes a reduction in heart rate, increases secretion of exocrine glands (salivary, bronchial, sweat, and gastrointestinal tract), promotes development of hypersalivation, bronchorrhea, increased gastric juice acidity, constricts pupils, induces accommodation spasm, reduces intraocular pressure, enhances smooth muscle tone of the intestine (increases peristalsis and relaxes sphincters) and urinary bladder, causes bronchospasm, and increases skeletal muscle tone.

Pharmacokinetics.

The bioavailability of proserin after parenteral administration is high – 0.5 mg of proserin administered parenterally is equivalent to 15 mg administered orally. Bioavailability increases with increasing dose of the drug. Time to reach maximum plasma concentration after intramuscular administration is 30 minutes. Protein binding (to albumin) in blood plasma is 15–25%. The drug poorly penetrates the blood-brain barrier and has no central effects. It 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. 80% of the administered dose is excreted by the kidneys within 24 hours (of which 50% is excreted unchanged and 30% as metabolites). The elimination half-life (T1/2) after intramuscular administration is 51–90 minutes, and after intravenous administration is 53 minutes.

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; pronounced atherosclerosis; thyrotoxicosis; peptic ulcer of the stomach and duodenum; peritonitis; mechanical obstruction of the gastrointestinal tract and urinary tract; prostatic hyperplasia accompanied by dysuria; acute phase of infectious disease; intoxications in severely weakened children; simultaneous use with depolarizing muscle relaxants.

Interaction with other medicinal products and other forms of interaction.

Possible interactions when the drug is used concomitantly with other medicinal products:

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

with M-cholinolytics – weakening of M-cholinomimetic effects of neostigmine;

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

with non-depolarizing muscle relaxants – reduced effect of the latter. Neostigmine should be used as an antidote in cases of overdose of non-depolarizing muscle relaxants;

with other anticholinesterase drugs – increased toxicity;

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

with β-adrenoblockers – enhanced bradycardia;

with ephedrine – potentiation of neostigmine's effect.

Use with caution when administered simultaneously with neomycin, streptomycin, kanamycin.

In myasthenia, administer in combination with aldosterone antagonists, glucocorticoids, and anabolic hormones.

Special precautions for use

When administering large doses parenterally, it is necessary to prescribe atropine (prior to or concurrently).

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 the similarity of clinical symptoms.

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 to patients with parkinsonism.

Use during pregnancy or breastfeeding

There have been no adequate and well-controlled studies on the use of the drug in pregnant women. Use during pregnancy is possible 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 influence reaction rate when driving or operating machinery

During treatment with this drug, driving vehicles and engaging in other potentially hazardous activities requiring increased attention and rapid psychomotor reactions is contraindicated.

Method of Administration and Dosage.

Adults.

The medicinal product should be administered 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, and the maximum daily dose is 6 mg. The duration of treatment course (except for myasthenia, myasthenic crisis, postoperative intestinal and bladder atony, and overdose of myorelaxants) is 25–30 days. If necessary, a repeated course may be prescribed after 3–4 weeks. The larger part of the total daily dose should be administered during daytime, when the patient is most fatigued.

Myasthenia: the medicinal product should be administered 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): the medicinal product should be administered intravenously at a dose of 0.25–0.5 mg (0.5–1 mL), followed by subcutaneous administration at short intervals.

Postoperative intestinal and bladder atony, prevention of postoperative urinary retention, including: the medicinal product should be administered subcutaneously or intramuscularly at a dose of 0.25 mg (0.5 mL), as early as possible after surgery, and repeated every 4–6 hours for 3–4 days.

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

Children (only under inpatient conditions).

Myasthenia gravis:

Newborns: at the initial stage, the medicinal product should be administered at a dose of 0.1 mg via intramuscular injection. Subsequently, the dose should be individually adjusted, usually 0.05–0.25 mg or 0.03 mg/kg body weight of the medicinal product intramuscularly every 2–4 hours. Due to the specific nature of the disease in newborns, the daily dose of the medicinal product may be gradually reduced, even to complete discontinuation.

Children under 12 years of age: the medicinal product should be administered at a dose of 0.2–0.5 mg via injection, as needed. Dosage should be adjusted according to the patient's response.

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

Other indications: the medicinal product should be administered at a dose of 0.125–1 mg via injection. Doses may be adjusted according to individual patient needs.

Children.

The medicinal product may be used in children only under inpatient conditions.

Overdose.

Symptoms: related to overstimulation of cholinergic receptors (cholinergic crisis): tachycardia, bradycardia, hypersalivation, dysphagia, miosis, bronchospasm, dyspnea, nausea, vomiting, increased peristalsis, diarrhea, increased urinary frequency, 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 mild, which complicates differential diagnosis between overdose and myasthenic crisis.

Treatment: reduction of dose or discontinuation of the medicinal product. If necessary, atropine (1 mL of 0.1% solution) or metacin should be administered. Further treatment is symptomatic.

Adverse reactions.

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 contraction and increased intestinal peristalsis, nausea, vomiting, flatulence, diarrhea, involuntary defecation.

Renal and urinary disorders: increased frequency of urination, involuntary urination.

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

Cardiovascular disorders: arrhythmia, brady- or tachycardia, atrioventricular block, atrioventricular nodal rhythm, nonspecific ECG changes, cardiac arrest, decreased arterial pressure (mainly after parenteral administration).

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

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

Shelf life. 4 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

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

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; 5 ampoules in a blister pack; 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspylska Street, Kyiv, 02093, Ukraine.