Atropine sulfate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATROPINE SULFATE (Atropine sulfate)

Composition:

Active substance: atropine;

1 ml of solution contains 1 mg of atropine sulfate calculated as 100% substance;

Excipients: diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Belladonna alkaloids, tertiary amines. Atropine. ATC code A03BA01.

Pharmacological properties.

Pharmacodynamics. The mechanism of action is due to atropine's selective blockade of M-cholinoreceptors (it affects N-cholinoreceptors to a lesser extent), rendering M-cholinoreceptors insensitive to acetylcholine formed at the endings of postganglionic parasympathetic neurons. Atropine's ability to bind to cholinoreceptors is explained by the presence in its molecule of a fragment that confers affinity for the endogenous ligand—acetylcholine. Atropine sulfate reduces secretion of salivary, bronchial, gastric, and sweat glands, increases the viscosity of bronchial secretions, suppresses the activity of ciliated epithelium in the bronchi, thereby reducing mucociliary transport, accelerates heart rate, enhances atrioventricular conduction, reduces tone of smooth-muscle organs, decreases both volume and total acidity of gastric juice (especially when cholinergic regulation of secretion predominates), reduces basal and nocturnal gastric secretion, has a weaker effect on stimulated secretion, and markedly dilates the pupil (which may lead to increased intraocular pressure). By crossing the blood-brain barrier, atropine exerts a stimulatory effect on the respiratory center at therapeutic doses.

Pharmacokinetics. After intravenous administration, maximum effect develops within 2–4 minutes. Atropine sulfate is rapidly absorbed into the bloodstream from the site of administration. It quickly distributes throughout the body and crosses the blood-brain barrier, placental barrier, and is excreted into breast milk. In the blood, atropine is approximately 50% protein-bound; its volume of distribution is about 3 L/kg. After intravenous administration, plasma concentration of atropine declines in two phases. The first phase is rapid, with a half-life of 2 hours. During this phase, approximately 80% of the administered dose is excreted in urine. The second phase involves elimination of the remaining portion of the drug via urine, with a half-life of 13–36 hours. Atropine is metabolized in the liver via enzymatic hydrolysis; approximately 50% of the dose is excreted unchanged by the kidneys.

Clinical Characteristics.

Indications. As a symptomatic agent in gastric and duodenal ulcers, pylorospasm, acute pancreatitis, cholelithiasis, cholecystitis, intestinal spasms, urinary tract spasms, bronchial asthma, bradycardia due to increased vagus nerve tone, to reduce secretions of salivary, gastric, bronchial, and sometimes sweat glands, and for radiographic examination of the gastrointestinal tract (to reduce organ tone and motility).

The drug is also used before anesthesia, surgery, and during surgical procedures as a means to prevent bronchospasm and laryngospasm, reduce glandular secretions, and minimize reflex responses and adverse effects caused by vagus nerve stimulation. As a specific antidote in poisoning with cholinomimetic compounds and anticholinesterase agents (including organophosphorus compounds).

Contraindications. Hypersensitivity to the components of the drug. Cardiovascular disorders in which an increase in heart rate may be undesirable: atrial fibrillation, tachycardia, chronic heart failure, ischemic heart disease (IHD), mitral stenosis, severe arterial hypertension. Acute bleeding. Thyrotoxicosis. Hyperthermic syndrome. Gastrointestinal disorders associated with obstruction (esophageal achalasia, pyloric stenosis, intestinal atony, and toxic megacolon). Glaucoma. Hepatic and renal insufficiency. Myasthenia gravis. Urinary retention or predisposition to it (e.g., due to prostate or urethral disease). Brain injury.

When atropine is used for life-threatening indications in poisoning with cholinomimetic compounds and anticholinesterase agents (including organophosphorus compounds), there are no contraindications.

Interaction with other medicinal products and other types of interactions. When atropine sulfate is used with monoamine oxidase inhibitors, cardiac arrhythmias may occur. With quinidine and procainamide, a summation of the anticholinergic effect is observed. When administered orally together with convallaria preparations or tannins, a physicochemical interaction occurs, resulting in mutual weakening of effects.

Atropine sulfate reduces the duration and depth of action of narcotic agents and diminishes the analgesic effect of opioids.

Concomitant use with diphenhydramine or diprazine enhances the effect of atropine; with nitrates, haloperidol, and systemic corticosteroids – increases the likelihood of elevated intraocular pressure; with sertraline – enhances the depressive effect of both drugs; with spironolactone and minoxidil – reduces the effect of spironolactone and minoxidil; with penicillins – enhances the effect of both drugs; with nizatidine – enhances the effect of nizatidine; with ketoconazole – reduces ketoconazole absorption; with ascorbic acid and attapulgite – reduces the effect of atropine; with pilocarpine – reduces the effect of pilocarpine in glaucoma treatment; with oxprenolol – reduces the antihypertensive effect of the drug. Under the influence of octadine, a possible reduction in the antisecretory effect of atropine may occur, which weakens the action of M-cholinomimetics and anticholinesterase agents. Concomitant use with sulfonamide drugs increases the risk of kidney damage; with potassium-containing preparations – possible development of intestinal ulcers; with nonsteroidal anti-inflammatory drugs – increased risk of gastric ulcers and bleeding.

The effect of atropine sulfate may be enhanced, increasing the risk of atropine-related adverse effects (urinary retention, constipation, dry mouth), when used concomitantly with other drugs having antimuscarinic effects (M-cholinoblockers, spasmolytics, antiparkinsonian agents (amantadine), certain antihistamines, mequitazine, butyrophenone-group drugs, phenothiazines, disopyramides, quinidine, tricyclic antidepressants, nonselective inhibitors of neuronal monoamine reuptake). Reduced intestinal motility under the influence of atropine may alter the absorption of other medicinal products.

When atropine and pralidoxime are used together, signs of atropine overdose (flushing, mydriasis, tachycardia, dry mouth) are intensified, as pralidoxime may potentiate the effect of atropine.

Barbiturates should be used with caution in the treatment of seizures caused by atropine.

Special precautions for use

Use with caution in patients with prostatic hypertrophy without urinary tract obstruction, Down's syndrome, cerebral palsy in children, pyloric stenosis, reflux esophagitis (since atropine may delay gastric emptying, reduce gastric motility, and relax the esophageal sphincter), hiatal hernia associated with reflux esophagitis, intestinal atony in elderly patients, ulcerative colitis, megacolon, patients with xerostomia, elderly or debilitated patients, chronic lung diseases without reversible obstruction, chronic lung diseases characterized by low production of thick, difficult-to-expectorate mucus, especially in young children and debilitated patients, autonomic (vegetative) neuropathy, patients with heart failure, arrhythmias, conduction disorders, hyperthyroidism, during fever or in conditions of high ambient temperature.

Atropine should not be administered to patients with myasthenia gravis unless it is used concomitantly with anticholinesterase agents.

Use atropine with caution in patients with high-degree atrioventricular block (second-degree Mobitz type II or third-degree block).

Atropine should be used cautiously in patients with tachyarrhythmia, congestive heart failure, or ischemic heart disease, as blockade of vagal inhibition of the sinoatrial node pacemaker may occur.

Special considerations for the use of atropine in poisoning with cholinomimetic and anticholinesterase agents (including organophosphorus compounds)

Atropine should not be administered until cyanosis has been corrected, as atropine may induce ventricular fibrillation and possible seizures in the presence of hypoxia.

In patients with recent myocardial infarction and/or severe ischemic heart disease, atropine-induced tachycardia may precipitate myocardial ischemia, extend or initiate a new myocardial infarction, and promote ectopic activity and ventricular fibrillation.

In cases of severe respiratory distress, artificial ventilation may be required in addition to atropine, since atropine is not sufficiently effective in treating weakness or paralysis of respiratory muscles.

Anhidrosis may lead to heat intolerance and impaired thermoregulation, particularly in hot environments.

All patients who have received atropine require careful monitoring for at least 48–72 hours. This is particularly important for patients with a history of prior anaphylactic reactions to atropine and those requiring treatment for poisoning with cholinomimetic or anticholinesterase agents (including organophosphorus compounds).

Use during pregnancy or breastfeeding. The medicinal product is contraindicated during pregnancy.

Administration of atropine sulfate during breastfeeding is contraindicated due to the risk of toxic effects on the infant.

Ability to influence reaction speed when driving or operating machinery. Given the possible occurrence of adverse reactions such as dizziness, drowsiness, hallucinations, and accommodation disturbances, patients should refrain from driving or operating vehicles or machinery while receiving this medicinal product.

Administration and Dosage.

Atropine sulfate is administered subcutaneously, intramuscularly, or intravenously. For pre-anesthetic medication to reduce the risk of vagal-induced bradycardia and to decrease secretions from salivary and bronchial glands: 0.3–0.6 mg subcutaneously or intramuscularly 30–60 minutes before anesthesia; in combination with morphine (10 mg morphine sulfate) – 1 hour before anesthesia. In cases of poisoning with anticholinesterase agents, atropine sulfate should be administered at 2 mg intramuscularly every 20–30 minutes until signs of atropinization appear, such as skin flushing and dryness, pupil dilation, tachycardia, and normalization of respiration. In moderate to severe poisoning, atropine may be administered for up to two days (until signs of "over-atropinization" appear).

Maximum single doses for children are:

• under 6 months of age – 0.02 mg;
• 6 months to 1 year – 0.05 mg;
• 1 to 2 years – 0.2 mg;
• 3 to 4 years – 0.25 mg;
• 5 to 6 years – 0.3 mg;
• 7 to 9 years – 0.4 mg;
• 10 to 14 years – 0.5 mg.

Atropine sulfate should be used with caution in elderly patients.

Maximum doses for adults (subcutaneous): single dose – 1 mg, daily dose – 3 mg.

Children. Infants during the first 3 months of life are particularly sensitive to atropine.

The medicinal product should be administered to children in the doses specified in the section "Administration and Dosage."

Overdose.

Symptoms. With mild overdose: dry mouth, pupil dilation, accommodation disturbances, tachycardia, difficulty in urination, intestinal atony, dizziness, impaired heat dissipation, reduced sweating. In cases of poisoning: pupil dilation, increased intraocular pressure, dryness of mucous membranes and skin, elevated body temperature, urinary retention, tachycardia, headache, dizziness, hallucinations, complete disorientation, sudden psychomotor agitation; seizures may occur, accompanied by confusion or loss of consciousness, as well as decreased or increased arterial blood pressure.

Other possible symptoms: flushing, rash, dry and burning tongue, increased light sensitivity, difficulty swallowing, rapid breathing, nausea, vomiting, insomnia, drowsiness, irritability, restlessness, paranoid and psychotic reactions, delirium, tremor, and exacerbation of adverse reactions.

In severe overdose, drowsiness, stupor, depression of respiratory and vasomotor centers, central nervous system (CNS) depression, coma, circulatory and respiratory disturbances may occur; fatal outcome is possible.

Treatment. Administration of an antidote – proserin (1 ml of 0.05% solution subcutaneously) or physostigmine (0.5–1 ml of 0.1% solution subcutaneously). Ensure airway patency, perform gastric lavage, and administer cholinomimetics and anticholinesterase agents parenterally. For psychomotor agitation – administer aminazine intramuscularly (2 ml of 2.5% solution). For seizures – barbiturates (5–10 ml of 2.5% solution of sodium thiopental intravenously, or up to 10–15 ml of 2.5% solution of hexenal intravenously, administered in 3–4 ml portions with 30-second intervals). Diazepam may be used to control agitation and seizures, but the risk of CNS depression should be considered. In case of sudden marked hyperthermia – apply ice to the head and groin area, use wet wraps, and administer antipyretic agents. For tachycardia – propranolol. Antiarrhythmic drugs are not recommended in case of arrhythmia. In case of urinary retention – catheterization. For mydriasis – local application in the form of eye drops: phosphacol, physostigmine, pilocarpine. In case of an acute glaucoma attack, instill 1% pilocarpine solution into the conjunctival sac, 2 drops every hour, and administer proserin 0.05% solution 1 ml subcutaneously 3–4 times daily. In cases of severe intoxication – forced diuresis and blood alkalinization. Intravenous administration of glucose with ascorbic acid is indicated.

Adverse Reactions

The adverse effects of the drug are primarily associated with the M-cholinolytic action of atropine, and, when large doses are used, also with its N-cholinolytic action. Adverse effects are dose-dependent and usually reversible after discontinuation of therapy. The most common adverse reactions occurring with relatively small doses include visual disturbances, decreased bronchial secretion, dry mouth, constipation, reflux, flushing, difficulty in urination, and dry skin. Transient bradycardia followed by tachycardia, palpitations, and arrhythmia may also occur.

Gastrointestinal system: dry mouth, thirst, taste disturbances, dysphagia, reduced intestinal motility up to atony, decreased tone of bile ducts and gallbladder, constipation, reflux, suppressed gastric secretion, nausea, vomiting, bloating, pyloric stenosis, reduced absorption, abdominal pain, salivation.

Urinary system: difficulty and retention of urination, enuresis, imperative urges to urinate.

Cardiovascular system: tachycardia, transient exacerbation of bradycardia, arrhythmia (particularly of atria and ventricles), atrial/ventricular fibrillation, extrasystoles of various localizations, asystole, disturbances of cardiac conduction, cardiac dilation, myocardial ischemia, myocardial infarction, hypertensive crisis, palpitations, hypotension, loss of consciousness, increased or labile arterial pressure, facial flushing, sensation of hot flushes.

Nervous system: headache, dizziness, nervousness, insomnia, coordination disturbances, dysarthria, disturbances of consciousness and/or auditory or visual hallucinations (especially at higher doses), hyperthermia, psychiatric disorders (paranoia, mania, restlessness, anxiety, withdrawal, delirium, stupor, amnesia), seizures, drowsiness, pathological reflexes, muscle twitching, dysmetria, ataxia, coma.

Eye disorders: dilated pupils, photophobia, accommodation paralysis, increased intraocular pressure, visual disturbances, eye irritation, lacrimation, conjunctivitis, dry keratoconjunctivitis, blepharitis, strabismus, reduced contrast sensitivity and light sensitivity, angle-closure glaucoma, blindness.

Respiratory system: reduced secretory activity and bronchial tone, leading to formation of viscous sputum that is difficult to cough up, exacerbation of chronic lung disease, laryngitis, intercostal retractions, labored breathing, wheezing, slow breathing, shallow breathing, tachypnea, respiratory insufficiency, laryngospasm, pulmonary edema.

Skin: skin rashes, urticaria, exfoliative dermatitis, dryness of skin and/or mucous membranes, sweating, rashes, cyanosis of the skin.

Immune system: anaphylactic reactions, anaphylactic shock, hypersensitivity reactions.

Other: decreased sweating, injection site reactions, pain at injection site, chest pain, weakness, fatigue, dehydration.

Laboratory findings: hyponatremia, increased or decreased hemoglobin levels, erythrocytosis, increased blood nitrogen levels, changes in electroencephalogram.

Special patient populations.

Atropine may cause excitation, coordination disturbances, disturbances of consciousness and/or hallucinations, particularly in elderly patients. Similar epidemiological studies have reported cognitive decline in elderly patients receiving antimuscarinic drugs.

Patients with Down syndrome may be more sensitive to antimuscarinic effects.

Reporting of adverse reactions.

Reporting of adverse reactions following drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 5 years.

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

Keep out of reach of children.

Packaging. 1 ml in an ampoule; 10 ampoules per box.

1 ml in an ampoule; 5 ampoules per blister pack; 2 blister packs 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 Kulikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.