Euphyllin-n 200

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUPHYLLINUM-N 200 (Euphyllinum-N 200)

Composition:

Active substance: theophylline;

1 ml of solution contains 20 mg of anhydrous theophylline, calculated as 100 % substance;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colourless or slightly yellowish liquid.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Euphyllin-N 200 is a bronchodilator and spasmolytic agent belonging to the methylxanthine group (a purine derivative).

The bronchodilator mechanism of 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 calcium release from intracellular stores. Theophylline inhibits the release of inflammatory mediators from mast cells, enhances mucociliary clearance, and stimulates diaphragmatic contraction, improving the function of respiratory and intercostal muscles.

It produces a pronounced bronchodilator effect due to direct relaxation of bronchial smooth muscle. The extent of the bronchospasmolytic effect depends on the serum theophylline concentration.

It normalizes respiratory function, promotes blood oxygenation, and reduces carbon dioxide concentration; stimulates the respiratory center. Enhances pulmonary ventilation under conditions of hypokalemia.

Inhibits platelet aggregation (by inhibiting platelet-activating factor and prostaglandin E2), increases erythrocyte resistance to deformation (improving blood rheological properties), reduces thrombosis, and normalizes microcirculation.

It exerts a stimulatory effect on the central nervous system and cardiac activity, increases the force and rate of heart contractions, enhances coronary blood flow, and raises myocardial oxygen demand. Reduces vascular tone (primarily in cerebral, skin, and renal vessels). Decreases pulmonary vascular resistance and reduces pressure in the pulmonary circulation. Increases renal blood flow and produces a moderate diuretic effect. Dilates extrahepatic bile ducts.

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

Pharmacokinetics

Bioavailability is 80–100%. Plasma protein binding is 40–60%; in neonates and adults with liver disease, protein binding is reduced.

Theophylline crosses the blood-brain barrier and placental barrier, and penetrates into cerebrospinal fluid, saliva, sputum, and other body secretions, as well as into 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. Caffeine is an active metabolite formed in small amounts, except in premature neonates and infants under 6 months of age, in whom significant accumulation occurs due to a prolonged elimination half-life. In children over 6 years and adults, caffeine accumulation does not occur.

It is excreted by the kidneys in the form of metabolites and unchanged (in adults – 7–13% of the administered dose, in children – 50%).

Due to significant individual differences in the rate of hepatic theophylline metabolism, its clearance, plasma concentration, and elimination half-life are highly variable. The rate of theophylline metabolism in the liver depends on age, tobacco smoking, diet, concomitant diseases, and concomitant drug therapy.

The elimination half-life (T1/2) in adult patients with bronchial asthma and no significant pathology in other organs and systems who do not smoke is 6–12 hours; in smokers, it is 4–5 hours. T1/2 is prolonged in patients with alcoholism, heart failure, cor pulmonale, pulmonary heart disease, hepatic or renal dysfunction, pulmonary edema, chronic obstructive bronchitis, and in elderly patients. Total clearance is reduced in children under 1 year of age, patients with sepsis, severe respiratory insufficiency, hepatic or cardiac failure, viral infections, and in patients aged 55 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, therapeutic effects are weak; at higher concentrations, there is no significant increase in therapeutic efficacy, 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 medicinal product, including other xanthine derivatives (caffeine, pentoxifylline, theobromine), pulmonary edema, severe arterial hypertension or hypotension, generalized atherosclerosis, acute heart failure, acute myocardial infarction, decompensated chronic heart failure, angina pectoris, paroxysmal tachycardia, extrasystoles, epilepsy, increased seizure susceptibility, glaucoma, gastroesophageal reflux, peptic ulcer of the stomach and duodenum in the stage of exacerbation, severe hepatic and/or renal insufficiency, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, sepsis, porphyria, history of bleeding, hemorrhagic stroke, retinal hemorrhage, concomitant use with ephedrine in children.

Interaction with other medicinal products and other forms of interaction.

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 central nervous system.

The effect of theophylline may be enhanced when used concomitantly with fluconazole, methotrexate, ranitidine, allopurinol, acyclovir, carbimazole, zafirlukast, cimetidine, disulfiram, phenylbutazone, fluvoxamine, fluoroquinolones, furosemide, imipenem, isoprenaline, interferon alpha, 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 concurrently receiving theophylline and 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 ciprofloxacin is taken concomitantly, the dose of theophylline should be reduced by at least 60%, and when enoxacin is taken concomitantly, 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 who are taking 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 use of theophylline with ketamine may reduce the seizure threshold, and with doxapram may cause stimulation of the central nervous system.

Hypokalemia may occur during theophylline treatment, especially during combination 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 must be warmed to body temperature before parenteral administration.

The drug should be used 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 medicinal product should be prescribed with caution and only in case of acute necessity in patients with renal impairment and in those with a history of peptic ulcer disease of the stomach and duodenum. Theophylline should be avoided in patients with a history of seizures; alternative treatment should be considered. Increased caution is required when administering the drug to patients suffering from insomnia.

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

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

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

This medicinal product contains 19.2 mg of sodium in a 5 ml vial, which is equivalent to 0.95% of the WHO recommended maximum daily intake of 2 g sodium for adults.

This medicinal product contains 38.2 mg of sodium in a 10 ml vial, which is equivalent to 1.9% of the WHO recommended maximum daily intake of 2 g sodium for adults.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy. If treatment is necessary, breastfeeding should be discontinued.

Ability to influence reaction speed when driving or operating machinery

Given that adverse reactions (e.g., dizziness and others) may occur in sensitive patients, patients should refrain from driving or operating machinery and from performing other tasks requiring concentration during treatment with this medicinal product.

Method of Administration and Dosage.

The dosage should be individually adjusted, taking into account possible variations in the rate of administration.

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

The patient should be in a lying position during administration; 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, pre-dilute a single dose of the drug in 100–150 mL of 0.9% sodium chloride solution.

Intravenous bolus injection should be administered slowly (over at least 5 minutes); intravenous infusion should be administered at a rate of 30–50 drops per minute.

The dosage is calculated based on the amount of theophylline in milligrams, considering that 1 mL of Euphyllin-N 200 contains 20 mg of theophylline.

Adults: Administer intravenously by bolus injection in 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, and during the first administration, do 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 intravenously by 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, 9–12 years – 20 mg/kg body weight, 12–16 years – 18 mg/kg body weight, patients aged 16 years and older – 13 mg/kg body weight (or 900 mg).

Maximum doses for adults: Intravenous: single dose – 250 mg, daily dose – 500 mg.

Maximum doses for children: Intravenous: single dose – 3 mg/kg body weight.

The duration of treatment depends on the severity and course of the disease, sensitivity to the drug, and ranges from several days to two weeks (but not longer than 14 days).

Do not use in patients with severe renal and/or hepatic insufficiency (see section "Contraindications").

Children.

The drug should not be used for intravenous administration in children under 3 years of age.

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

Overdose.

With rapid intravenous administration, seizures, arrhythmias, severe hypotension, and angina may occur. At plasma theophylline concentrations exceeding 20 mg/L (110 µmol/L), nausea, vomiting (repeated vomiting, sometimes with blood, which may lead to dehydration), diarrhea, excitation, tremor, arterial hypertension, hyperventilation, supraventricular and ventricular arrhythmias, arterial hypotension, coma, seizures, metabolic disturbances (hypokalemia, hypercalcemia, hypophosphatemia, hyperuricemia, hyperglycemia, metabolic acidosis, respiratory alkalosis) may be observed. Other toxic manifestations include dementia, toxic psychosis, symptoms of acute pancreatitis, rhabdomyolysis with renal failure.

Treatment: Depends on the severity of symptoms and includes discontinuation of the drug, correction of hemodynamics, stimulation of theophylline elimination from the body (forced diuresis, hemoadsorption, plasmapheresis, hemodialysis, peritoneal dialysis), administration of symptomatic agents, oxygen therapy, mechanical ventilation. To control seizures, administer diazepam intravenously. The use of barbiturates is inappropriate. Avoid using antiarrhythmic drugs with proconvulsant effects, such as lidocaine, in ventricular arrhythmias due to the risk of seizure exacerbation.

For efficacy and safety, serum drug concentration should be maintained within 10–15 mg/L. If monitoring of theophylline blood concentration is not possible, the daily dose should not exceed 10 mg/kg.

Adverse reactions.

Central 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, disturbances in blood acid-base balance, rhabdomyolysis.

Cardiovascular system: arrhythmias, palpitations, tachycardia, decreased arterial 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.

Local reactions at injection site: swelling, hyperemia, pain, induration.

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

Shelf life.

3 years.

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

Storage conditions.

Store in 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 medicinal product must not be used with glucose or fructose (levulose) solutions.

The pH of solutions used concomitantly with theophylline should be taken into account: the product is pharmaceutically incompatible with acidic solutions.

Packaging.

5 ml or 10 ml in an ampoule. 5 or 10 ampoules per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.