Euphyllin-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUPHYLLINE-ZDOROVYE (EUPHYLLINE-ZDOROVYE)

Composition:

active substance: theophylline;

1 ml of solution contains 20 mg of theophylline monohydrate calculated as theophylline;

excipients: sodium acetate trihydrate; sodium hydroxide; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly colored solution.

Pharmacotherapeutic group. Agents for systemic use in obstructive respiratory diseases. Xanthines. Theophylline. ATC code R03DA04.

Pharmacological properties.

Pharmacodynamics. Theophylline is a bronchodilator, spasmolytic, and vasodilating agent.

The mechanism of bronchodilatory action is due to the ability of theophylline to block adenosine receptors, non-selectively inhibit the enzyme phosphodiesterase, thereby increasing the concentration of cyclic 3',5'-AMP (cAMP) in tissues, inhibit calcium ion transport through "slow" channels of cell membranes, and reduce its release from intracellular stores. Theophylline inhibits the release of inflammatory mediators from mast cells, enhances mucociliary clearance, stimulates diaphragmatic contractions, and improves the function of respiratory and intercostal muscles.

It produces a pronounced bronchodilatory effect caused by direct relaxation of bronchial smooth muscle. The extent of the bronchospasmolytic effect depends on the concentration of theophylline in the blood. It also relaxes smooth muscle of the gastrointestinal tract, bile ducts, and uterus.

Theophylline normalizes respiratory function, promotes blood oxygenation and reduces carbon dioxide concentration; stimulates the respiratory center. It enhances pulmonary ventilation under conditions of hypokalemia. It inhibits platelet aggregation (by inhibiting platelet-activating factor and prostaglandin F2α), increases erythrocyte resistance to deformation (improving blood rheological properties), reduces thrombus formation, and normalizes microcirculation.

It exerts a stimulatory effect on the central nervous system (CNS) and cardiac activity, increases the force and rate of cardiac contractions, enhances coronary blood flow and myocardial oxygen demand. It reduces vascular tone (mainly in cerebral, skin, and renal vessels). It decreases perifocal and general cerebral edema, lowers cerebrospinal fluid and, consequently, intracranial pressure. It reduces pulmonary vascular resistance and pressure in the pulmonary circulation. It increases renal blood flow and exhibits a moderate diuretic effect.

Therapeutic effects develop within 5–15 minutes after intravenous injection.

Pharmacokinetics. Bioavailability is 80–100%. Plasma protein binding is approximately 60%.

Theophylline penetrates the blood-brain barrier and placental barrier, enters cerebrospinal fluid, saliva, sputum, and other body secretions, and is excreted in breast milk. It is metabolized in the liver (90%) with the involvement of several cytochrome P450 isoenzymes (the most important being CYP1A2). The main metabolites are 1,3-dimethyluric acid (which has pharmacological activity 2–5 times lower than theophylline) and 3-methylxanthine. It is excreted by the kidneys unchanged (in adults – 7–13% of the administered dose, in children – 50%) and as metabolites.

The half-life (T½) in adult patients with bronchial asthma without significant pathological changes in other organs and systems who do not smoke is 6–12 hours; in smokers – 4–5 hours, in children – 1–5 hours. T½ is prolonged in patients with alcoholism, heart failure, cor pulmonale, "pulmonary heart," and renal insufficiency. Total clearance is reduced in patients with severe sepsis, pronounced respiratory, hepatic, and cardiac insufficiency, viral infections, and in patients aged 60 years and older. Optimal therapeutic plasma concentrations of theophylline are: for bronchodilation – 10–20 mcg/mL, for stimulation of the respiratory center – 5–10 mcg/mL. At lower concentrations, the therapeutic effect is weak; at higher concentrations, there is no significant enhancement of therapeutic action, while the risk of adverse effects increases substantially.

Clinical characteristics.

Indications. Bronchoobstructive syndrome in bronchial asthma, bronchitis, pulmonary emphysema, respiratory center disorders (nocturnal paroxysmal apnea), "pulmonary heart".

Contraindications. Hypersensitivity to the components of the drug, to other xanthine derivatives (caffeine, pentoxifylline, theobromine); acute heart failure, decompensated chronic heart failure, angina pectoris, acute myocardial infarction, paroxysmal tachycardia, extrasystole, severe arterial hypertension or hypotension, widespread vascular atherosclerosis, pulmonary edema, hemorrhagic stroke, hemorrhage into the retina, history of bleeding, peptic ulcer of the stomach and duodenum in the stage of exacerbation, gastroesophageal reflux, epilepsy, glaucoma, increased seizure susceptibility, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, severe hepatic and/or renal insufficiency, porphyria, sepsis, concomitant use of ephedrine in children.

Interaction with other medicinal products and other types of interactions. During treatment, alcoholic beverages should not be consumed, nor large amounts of food and beverages containing methylxanthines (coffee, tea, cocoa, chocolate, Coca-Cola), or drugs related to theophylline (caffeine, theobromine, pentoxifylline), as these substances may enhance the stimulatory effect of theophylline on the CNS.

The action of theophylline may be enhanced when used concomitantly with fluconazole, methotrexate, nizatidine, allopurinol, acyclovir, carbimazole, zafirlukast, cimetidine, disulfiram, phenylbutazone, fluvoxamine, fluoroquinolones, furosemide, imipenem, isoprenaline, interferon α, isoniazid, calcium channel blockers (verapamil, diltiazem), lincomycin, macrolides, amiodarone, mexiletine, paracetamol, pentoxifylline, oral contraceptives, probenecid, propafenone, propranolol, ranitidine, tacrine, thiabendazole, ticlopidine, viloxazine, or influenza vaccine. In patients receiving theophylline concomitantly with one or more of the above-mentioned drugs, serum theophylline concentrations should be monitored and the dose reduced if necessary. Combination of theophylline with fluvoxamine should be avoided. If this combination cannot be avoided, patients should receive half the dose of theophylline and plasma concentrations of theophylline should be closely monitored.

When co-administered with ciprofloxacin, the dose of theophylline should be reduced by at least 60%, and when co-administered with enoxacin, by 30%.

The effect of theophylline may be reduced when taken concomitantly with antiepileptic agents (e.g., phenytoin, carbamazepine, primidone), barbiturates (especially phenobarbital and pentobarbital), aminoglutethimide, isoproterenol, magnesium hydroxide, moricizine, rifampicin, ritonavir, or sulfinpyrazone. The effect of theophylline may also be reduced in smokers. In patients receiving theophylline concomitantly with one or more of the above-mentioned drugs, serum theophylline concentrations should be monitored and the dose adjusted accordingly.

Concomitant use of theophylline with herbal products containing St. John's wort (Hypericum perforatum) should be avoided.

Ephedrine enhances the effect of theophylline.

Theophylline may enhance the effect of β-receptor agonists, diuretics, and reserpine. Theophylline may reduce the effectiveness of adenosine, lithium carbonate, and β-receptor antagonists. Concomitant use of theophylline and β-receptor antagonists should be avoided, as theophylline may lose its efficacy.

Combinations of theophylline with benzodiazepines, halothane, and lomustine should be used with particular caution. Halothane anesthesia may cause serious cardiac arrhythmias in patients receiving theophylline.

Concomitant administration of theophylline with ketamine may lower the seizure threshold, and with doxapram may cause CNS stimulation.

Hypokalemia may occur during treatment with theophylline, especially during combined therapy with α-receptor agonists, thiazide diuretics, furosemide, corticosteroids, and also in the presence of hypoxemia; therefore, periodic monitoring of serum potassium levels is recommended.

Special precautions for use.

The solution should be warmed to body temperature before administration.

Use with caution in patients with cardiovascular diseases, liver disorders, viral infections, prolonged hyperthermia, benign prostatic hyperplasia, severe hypoxia, diabetes mellitus, and in patients aged 60 years and older. The drug should be prescribed with caution only when urgently needed in patients with impaired renal function and in those with a history of peptic ulcer disease of the stomach and duodenum. In patients with a history of seizures, theophylline should be avoided and alternative treatments should be considered. Particular attention is required when administering the drug to patients suffering from insomnia.

Smoking and alcohol consumption may increase theophylline clearance, thereby reducing its therapeutic effect and potentially necessitating higher doses.

Fever, regardless of its cause, may reduce the elimination rate of theophylline.

Theophylline may alter certain laboratory parameters: it may increase levels of free fatty acids and catecholamines in urine.

This medicinal product contains 1.86 mmol (or 42.92 mg) of sodium per 250 mg theophylline dose. Caution is advised when administering this product to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding. The drug is contraindicated during pregnancy. If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery. Given that adverse reactions (such as dizziness and others) may occur in sensitive patients during treatment, patients should refrain from driving or operating machinery and from performing other tasks requiring mental concentration during therapy.

Dosage and Administration

The drug should be administered intravenously. The dose should be individually adjusted, taking into account possible variations in the rate of administration.

If the patient is taking oral theophylline preparations, the dose of theophylline for parenteral administration should be reduced.

During administration, the patient should be in a supine position; the physician must monitor arterial pressure, heart rate, respiratory rate, and the patient's general condition. The solution should be prepared immediately before use: for intravenous bolus injection, dilute a single dose of the drug in 10–20 mL of 0.9% sodium chloride solution; for intravenous infusion, dilute in 100–150 mL of 0.9% sodium chloride solution.

Intravenous bolus injection should be administered slowly (over no less than 5 minutes); intravenous infusion should be administered at a rate of 30–50 drops/minute.

The dose should be calculated based on theophylline content in milligrams, considering that 1 mL of the drug contains 20 mg of theophylline.

Adults: Administer intravenously by bolus injection at a daily dose of 10 mg/kg body weight (on average, 600–800 mg), divided into 3 doses. In patients with cachexia or low initial body weight, reduce the daily dose to 400–500 mg; in such cases, the first dose should not exceed 200–250 mg. If tachycardia, dizziness, or nausea occur, reduce the rate of administration or switch to intravenous infusion.

Children aged 14 years and older: administer by intravenous infusion at a dose of 2–3 mg/kg body weight. The maximum daily dose for children aged 14 years and older is 3 mg/kg body weight.

Maximum daily doses that can be used without monitoring plasma theophylline concentration: children aged 3–9 years – 24 mg/kg body weight; aged 9–12 years – 20 mg/kg; aged 12–16 years – 18 mg/kg; patients aged 16 years and older – 13 mg/kg body weight (or 900 mg).

Higher doses for adults: intravenously – single dose 250 mg, daily dose 500 mg.

Higher doses for children: intravenously – single dose 3 mg/kg body weight.

Duration of treatment depends on the severity and course of the disease and sensitivity to therapy, but should not exceed 14 days.

Children. The drug is contraindicated for intravenous administration in children under 3 years of age.

In children aged 3 years and older, the drug may be used under life-threatening indications, but not for longer than 14 days.

Overdose. Rapid intravenous administration may cause seizures, arrhythmias, severe hypotension, and angina. At plasma theophylline concentrations exceeding 20 mg/L (110 µmol/L), symptoms may include nausea, vomiting (sometimes recurrent and with blood, potentially leading to dehydration), diarrhea, restlessness, tremor, arterial hypertension, hyperventilation, supraventricular and ventricular arrhythmias, arterial hypotension, coma, seizures, and metabolic disturbances (hypokalemia, hypercalcemia, hypophosphatemia, hyperuricemia, hyperglycemia, metabolic acidosis, respiratory alkalosis). Other toxic manifestations include dementia, toxic psychosis, symptoms of acute pancreatitis, and rhabdomyolysis with renal failure.

Treatment: Depends on the severity of symptoms and includes discontinuation of the drug, hemodynamic correction, enhancement of theophylline elimination from the body (forced diuresis, hemoadsorption, plasmapheresis, hemodialysis, peritoneal dialysis), administration of symptomatic agents, oxygen therapy, and mechanical ventilation. To control seizures, administer diazepam intravenously. The use of barbiturates is not recommended. Avoid using antiarrhythmic agents with proconvulsant effects, such as lidocaine, in ventricular arrhythmias due to the risk of worsening seizures.

For optimal efficacy and safety, serum drug concentration should be maintained within 10–15 mg/L. In the absence of the ability to monitor blood theophylline concentration, the daily dose should not exceed 10 mg/kg.

Adverse reactions.

Nervous system: dizziness, headache, restlessness, anxiety, excitement, irritability, sleep disturbances, tremor, seizures, confusion/loss of consciousness, insomnia (especially in children), delirium, hallucinations, pre-syncopal condition.

Gastrointestinal tract: stomach pain, nausea, vomiting, gastroesophageal reflux, heartburn, exacerbation of peptic ulcer, stimulation of gastric acid secretion, intestinal atony, diarrhea; with prolonged use – decreased appetite.

Metabolic disorders: metabolic acidosis, hypokalemia, hypercalcemia, hyperuricemia, hyperglycemia, acid-base imbalance in blood, rhabdomyolysis.

Cardiovascular system: arrhythmias, palpitations, tachycardia, decreased blood pressure, shock, cardialgia, increased frequency of angina attacks, extrasystoles (ventricular, supraventricular), heart failure, collapse (with rapid intravenous administration).

Urinary system: increased diuresis (due to increased glomerular filtration), in elderly patients – difficulty in urination (due to detrusor relaxation).

Immune system: allergic reactions, including rash, pruritus, urticaria, exfoliative dermatitis, angioneurotic edema, bronchospasm, anaphylactic shock.

Injection site reactions: swelling, hyperemia, pain, induration.

General disorders: increased body temperature, sensation of warmth and facial hyperemia, excessive sweating, chills, weakness, dyspnea.

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. Do not use in the same syringe with other injectable medicinal products, except 0.9% sodium chloride solution, due to pharmaceutical incompatibility. The drug must not be used with glucose solutions, fructose (levulose) solutions.

Consider the pH of solutions used in combination with the drug: the drug is pharmaceutically incompatible with acidic solutions.

Packaging. 5 ml in ampoules, 10 ampoules per box; № 5, № 5×2 in blisters per box.

Prescription category. By prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address. 22 Shevchenko Street, Kharkiv, Kharkiv Region, 61013, Ukraine.