Euphyllin-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUPHYLLIN-DARNITSA (EUPHYLLIN-DARNITSA)

Composition:

Active substance: theophylline;

1 ml of solution contains 20 mg of theophylline;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Systemic agents for obstructive respiratory diseases. Xanthines. Theophylline. ATC code R03DA04.

Pharmacological properties.

Pharmacodynamics.

Theophylline is a bronchodilator and spasmolytic agent.

The mechanism of bronchodilator 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 the “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, stimulates diaphragmatic contraction, and improves the function of respiratory and intercostal muscles.

It produces a pronounced bronchodilator effect caused by direct relaxation of bronchial smooth muscle. The extent of the bronchospasmolytic effect depends on the concentration of theophylline in blood serum.

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

Theophylline inhibits platelet aggregation (by inhibiting platelet-activating factor and prostaglandin E2), 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 frequency of heart contractions, enhances coronary blood flow, and raises myocardial oxygen demand. It reduces vascular tone (mainly in cerebral, skin, and renal vessels), decreases pulmonary vascular resistance, and lowers pressure in the pulmonary circulation. It increases renal blood flow, produces a moderate diuretic effect, and dilates extrahepatic bile ducts.

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

Pharmacokinetics.

The bioavailability of the drug is 80–100%. Plasma protein binding is approximately 60%. Theophylline crosses the placental barrier and is excreted into breast milk. It is metabolized in the liver (90%) with the involvement of several cytochrome P450 enzymes (the most important being CYP1A2). The main metabolites of the drug are 1,3-dimethyluric acid and 3-methylxanthine. Metabolites are excreted by the kidneys. Approximately 7–13% of the administered dose is excreted unchanged (in children, up to 50%). In infants, a significant portion is excreted as caffeine (due to immaturity of further metabolic pathways). The elimination half-life (T_1/2) in non-smoking patients is 6–12 hours; in smokers, it is significantly shorter – 4–5 hours; in children – 1–5 hours; in newborns and premature infants – 10–45 hours. T_1/2 is prolonged in patients with liver cirrhosis, renal insufficiency, and alcoholism. Total drug clearance is reduced in patients with influenza, severe respiratory, hepatic, or cardiac insufficiency, viral infections, and in patients aged 55 years and older.

Clinical characteristics.

Indications.

Broncho-obstructive syndrome in bronchial asthma, bronchitis, pulmonary emphysema, respiratory center disorders (nocturnal paroxysmal apnea), "pulmonary heart".

Contraindications.

Hypersensitivity to the components of the drug, as well as to other xanthine derivatives (caffeine, pentoxifylline, theobromine), acute heart failure, angina pectoris, acute myocardial infarction, acute cardiac arrhythmias, decompensated chronic heart failure, paroxysmal tachycardia, extrasystoles, severe arterial hypertension or hypotension, generalized atherosclerosis, pulmonary edema, hemorrhagic stroke, retinal hemorrhage, glaucoma, history of bleeding, peptic ulcer of the stomach and duodenum (in the acute phase), gastroesophageal reflux, epilepsy, increased seizure susceptibility, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, severe hepatic and/or renal insufficiency, porphyria, sepsis, concomitant use in children with ephedrine.

Interaction with other medicinal products and other forms of interaction.

During treatment, alcoholic beverages and large amounts of food and beverages containing methylxanthines (coffee, tea, cocoa, chocolate, Coca-Cola and similar tonic drinks), medicinal products related to theophylline (caffeine, theobromine, pentoxifylline), α- and β-adrenergic agonists (selective and non-selective), glucagon should not be consumed, as these substances may enhance the central nervous system (CNS) stimulant effect of theophylline.

Medicinal products that reduce theophylline clearance.

The effect of theophylline may be enhanced when used concomitantly with allopurinol, acyclovir, carbimazole, zafirlukast, cimetidine, ranitidine, nizatidine, disulfiram, phenylbutazone, fluvoxamine, fluconazole, fluoroquinolones (ofloxacin, norfloxacin; when co-administered with ciprofloxacin, theophylline dose should be reduced by at least 60%, and with enoxacin – by 30%), furosemide, imipenem, isoprenaline, alpha-interferon, oxpentifylline, isoniazid, calcium channel blockers (verapamil, diltiazem), lincomycin, macrolides (clarithromycin, erythromycin), amiodarone, mexiletine, methotrexate, paracetamol, pentoxifylline, oral contraceptives, probenecid, propafenone, propranolol, ranitidine, tacrine, thiabendazole, ticlopidine, viloxazine, or influenza vaccine. In patients receiving one or more of these medicinal products concomitantly with theophylline, serum theophylline concentration should be monitored and the dose reduced if necessary.

Combination of theophylline with fluvoxamine should be avoided. If avoidance is not possible, patients should receive half the dose of theophylline and plasma concentrations of theophylline should be closely monitored.

Medicinal products that increase theophylline clearance.

The effect of theophylline may be reduced when taken concomitantly with antiepileptic agents (e.g., phenytoin, carbamazepine, primidone), barbiturates (especially phenobarbital and pentobarbital), aminoglutethimide, magnesium hydroxide, isoproterenol, lithium, moracizine, rifampicin, ritonavir, or sulfinpyrazone. The effect of theophylline may also be reduced in smokers. In patients receiving one or more of these medicinal products concomitantly with theophylline, serum theophylline concentration should be monitored and the dose adjusted if necessary.

Plasma concentration of theophylline may be reduced when used concomitantly with herbal products containing St. John's wort (Hypericum perforatum).

Concomitant use of theophylline and phenytoin may lead to decreased levels of the latter.

Ephedrine enhances the effect of theophylline.

Theophylline may enhance the effect of β-adrenergic agonists, diuretics, and reserpine. Theophylline may reduce the effectiveness of adenosine, lithium carbonate, and β-adrenergic receptor antagonists.

Concomitant use of theophylline and β-adrenergic receptor antagonists should be avoided, as theophylline may lose its efficacy.

Combinations of theophylline with adenosine, 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 and quinolones may reduce the seizure threshold; with β-blockers it may antagonize its bronchodilator effect; with doxapram it may cause CNS stimulation.

Hypokalemia may occur during treatment with theophylline or other xanthines, especially during combined therapy with β-adrenergic receptor agonists, thiazide diuretics, furosemide, corticosteroids, and in the presence of hypoxemia. This particularly applies to hospitalized patients with severe asthma; therefore, periodic monitoring of serum potassium levels is recommended.

Conflicting evidence exists regarding potentiation of theophylline effects during influenza-like conditions.

Special precautions for use.

The solution must be warmed to body temperature before administration.

Use with caution in patients with cardiovascular diseases, liver disorders, viral infections, prolonged hyperthermia, history of benign prostatic hyperplasia (due to the risk of urinary retention), severe hypoxia, diabetes mellitus, glaucoma, and in elderly individuals (aged 60 years and older).

The medicinal product should be prescribed with caution only if urgently needed in cases of unstable angina, cardiac conditions associated with risk of tachyarrhythmia, hypertrophic obstructive cardiomyopathy, impaired renal or hepatic function, hyperthyroidism, acute porphyria, chronic alcoholism, pulmonary diseases, and in patients with a history of peptic ulcer disease of the stomach and duodenum. Patients with a history of seizure disorders should avoid theophylline use and alternative treatments should be considered. Theophylline should be administered cautiously and under medical supervision in patients with severe atherosclerosis or sepsis. Particular attention is required when administering the medicinal product to patients suffering from insomnia.

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

During theophylline treatment, careful monitoring is required and dosage reduction should be considered in patients with heart failure, cardiac arrhythmias, arterial hypertension, other cardiovascular disorders, chronic alcoholism, impaired liver function (especially cirrhosis), hypoxemia (low blood oxygen levels), hyperthyroidism, or acute febrile conditions in patients with pneumonia or viral infections (particularly influenza), due to the potential for reduced theophylline clearance. Plasma theophylline levels should be monitored simultaneously.

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

Particular caution is required during theophylline treatment in severe asthma. In such cases, monitoring of serum potassium levels is recommended.

If aminophylline needs to be administered to patients already receiving theophylline, plasma theophylline concentration should be monitored.

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

In the event of adverse reactions, theophylline blood levels should be monitored.

Important information about excipients.

This medicinal product contains sodium. Therefore, caution should be exercised when administering it to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy. If use of the medicinal product is necessary, breastfeeding should be discontinued.

Fertility.

There are no clinical data on fertility in humans. Preclinical data on theophylline indicate adverse effects on fertility in both males and females.

Ability to affect reaction speed when driving or operating machinery.

Given that adverse reactions (e.g., dizziness) may occur in sensitive patients during treatment with this medicinal product, patients should refrain from driving vehicles or engaging in other activities requiring high concentration during treatment.

Dosage and Administration

The medicinal product should be administered intravenously. The dose should be individually adjusted, taking into account possible variations in elimination rate.

If the patient is taking oral theophylline medicinal products, 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 medicinal product in 10–20 mL of 0.9% sodium chloride solution.
• For intravenous infusion, dilute a single dose of the medicinal product 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 per minute.

When administering the medicinal product, calculate the dose in milligrams of theophylline, considering that 1 mL of the medicinal product 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 of theophylline), 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.

Maximum doses for adults:

• Single dose: 250 mg
• Daily dose: 500 mg

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 doses for children:

• Single dose: 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
• Children aged 9–12 years: 20 mg/kg body weight
• Children aged 12–16 years: 18 mg/kg body weight
• Patients aged 16 years and older: 13 mg/kg body weight (or 900 mg)

Nevertheless, measuring theophylline plasma concentration 4–8 hours after administration and no less than 3 days after any dose adjustment helps to more accurately assess the necessity of a specific dose, due to significant individual differences in elimination rates among patients.

The table below may be used to determine the appropriate dosage.

For elderly patients with cardiovascular diseases, the recommended daily dose of the medicinal product is 8 mg/kg of body weight. The maximum therapeutic effect begins to manifest on day 3–4 after initiation of treatment.

For patients whose symptoms persist during nighttime or daytime, regardless of other ongoing therapies, or for those who have not received theophylline, therapy may be supplemented with administration of the recommended single morning or evening daily dose of theophylline.

When high doses are prescribed during treatment, plasma theophylline concentrations should be monitored (therapeutic concentration range is 10–15 µg/mL).

The duration of treatment depends on the severity and course of the disease, as well as sensitivity to the drug, and ranges from several days up to 2 weeks (but not longer than 14 days).

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

Children

The medicinal product must not be administered intravenously to children under 3 years of age.

Administration of the medicinal product to children aged 3 years and older is possible only under life-threatening indications and for no longer than 14 days.

Overdose

Rapid intravenous administration may lead to seizures, arrhythmias, severe hypotension, and angina.

Overdose occurs when plasma theophylline concentration exceeds 20 mg/mL (110 µmol/L).

Symptoms: Severe symptoms may develop within 12 hours after overdose with sustained-release formulations.

Gastrointestinal tract: nausea, vomiting (often severe), epigastric pain, diarrhea, hematemesis, pancreatitis.

Central nervous system: delirium, excitement, anxiety, dementia, toxic psychosis, tremor, hyperreflexia, seizures, muscle hypertonia. In very severe cases, coma may develop.

Cardiovascular system: sinus tachycardia, ectopic rhythm, supraventricular and ventricular tachycardia, arterial hypertension/hypotension, abrupt drop in blood pressure.

Metabolic disturbances: metabolic acidosis, hypokalemia (due to potassium shift from plasma into cells, it may develop rapidly and in severe form), hypophosphatemia, hypercalcemia, hyperuricemia, hypomagnesemia, hyperglycemia, rhabdomyolysis.

Others: respiratory alkalosis, hyperventilation, acute renal failure, dehydration, or exacerbation of other adverse reactions.

Treatment: Depends on 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. Serum theophylline levels should be monitored until normalization, along with continuous ECG and renal function monitoring.

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

Hypokalemia should be prevented. In case of hypokalemia, urgent intravenous infusion of potassium chloride solution is required, with continuous monitoring of plasma potassium and magnesium levels.

Hyperkalemia may develop during recovery if large amounts of potassium have been administered. If plasma potassium levels are low, plasma magnesium concentration should be measured as soon as possible.

Antiemetics such as metoclopramide or ondansetron should be used to control vomiting.

Seizures should be managed with intravenous diazepam. Barbiturates are not recommended. In case of ventricular arrhythmias, antiarrhythmic drugs with pro-convulsant effects (e.g., lidocaine) should be avoided due to the risk of seizure exacerbation.

In non-asthmatic patients, non-selective β-blockers may be used in case of pronounced tachycardia.

In cases of tachycardia with adequate cardiac output, treatment is better avoided.

In life-threatening overdose with cardiac rhythm disturbances in non-asthmatic patients, propranolol should be administered (1 mg for adults and 0.02 mg/kg body weight for children). This dose may be repeated every 5–10 minutes until normalization of heart rhythm or until the maximum dose of 0.1 mg/kg body weight is reached. Propranolol may cause severe bronchospasm in asthmatic patients; therefore, verapamil should be used in such cases.

Further management depends on the degree of overdose, course of intoxication, and the symptoms present.

Adverse Reactions

Adverse reactions usually occur at theophylline plasma concentrations > 20 mcg/mL.

Gastrointestinal disorders: stimulation of gastric acid secretion, stomach pain, decreased appetite, diarrhea, intestinal atony, gastroesophageal reflux, heartburn, exacerbation of peptic ulcer disease, nausea, vomiting.

Renal and urinary disorders: increased diuresis (due to increased glomerular filtration), in elderly patients – difficulty in urination (due to detrusor relaxation).

Metabolism and nutritional disorders: metabolic acidosis, hypokalemia, hypercalcemia, hyperuricemia, hyperglycemia, disturbances in blood acid-base balance, rhabdomyolysis.

Nervous system disorders: excitation, anxiety, restlessness, apprehension, sleep disturbances, insomnia (especially in children), headache, dizziness, tremor, irritability, seizures, hallucinations, delirium, epileptiform seizures, confusion/loss of consciousness, presyncopal state.

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

Immune system disorders: hypersensitivity reactions, including angioedema, anaphylactic and anaphylactoid reactions, anaphylactic shock, bronchospasm.

Skin and subcutaneous tissue disorders: skin rashes, exfoliative dermatitis, pruritus, erythema, swelling, urticaria.

General disorders and administration site conditions: increased body temperature, chills, facial hyperemia, sensation of heat, increased sweating, weakness, dyspnea, reactions at injection site (induration, hyperemia, pain).

Laboratory findings: during theophylline therapy, disturbances in acid-base balance, electrolyte imbalance, and increased blood creatinine levels may occur.

In most cases, adverse effects diminish upon dose reduction.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is an important procedure. It enables continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

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, fructose, or levulose solutions.

The pH of solutions used concomitantly with aminophylline should be considered: the medicinal product is pharmaceutically incompatible with acidic solutions.

Packaging.

5 mL in a vial; 5 vials in a blister pack; 2 blister packs in a carton.

Prescription status. By prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of its operations.

13, Borispilska Street, Kyiv, 02093, Ukraine.