Derkaст®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DERKAST® (DERKAST)

Composition:

Active substances: 1 ml of solution contains theophylline monohydrate (calculated as theophylline) 2 mg, potassium chloride 0.3 mg, magnesium chloride hexahydrate (calculated as magnesium chloride) 0.2 mg;

Excipients: disodium succinate, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Systemic agent for obstructive respiratory diseases. Xanthines. Theophylline, combination without psychotropic agents.

ATC code R03DA54.

Pharmacological properties.

Pharmacodynamics.

Theophylline is a broncholytic and spasmolytic agent.

The mechanism of broncholytic 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 contraction, and improves the function of respiratory and intercostal muscles.

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

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 (inhibits platelet-activating factor and prostaglandin F2-α), increases erythrocyte resistance to deformation (improves blood rheological properties), reduces thrombosis, and normalizes microcirculation.

It stimulates the central nervous system and cardiac activity, increases the force and rate of cardiac contractions, enhances coronary blood flow and myocardial oxygen demand. Reduces vascular tone (mainly in cerebral, skin, and renal vessels). Decreases perifocal and general cerebral edema, lowers cerebrospinal and, consequently, intracranial pressure. Reduces pulmonary vascular resistance and decreases pressure in the pulmonary circulation. Increases renal blood flow, exerts a moderate diuretic effect. Dilates extrahepatic bile ducts.

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

Potassium, the major intracellular fluid cation, participates in carbohydrate utilization and protein synthesis, and is required for regulation of nerve conduction and cardiac muscle contraction.

Magnesium stabilizes myocardial membranes and inhibits myosin phosphorylase activity, resulting in accumulation of adenosine triphosphate (ATP) reserves within cells. The protective effects of magnesium and potassium are additive.

Pharmacokinetics.

The bioavailability of the drug is 80–100%. Plasma protein binding is about 60%. It crosses the placental barrier and is excreted into breast milk. Metabolism occurs in the liver (90%) via 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 – 50%). In infants, a significant portion is excreted as caffeine (due to immaturity of further metabolic pathways). The elimination half-life (T1/2) 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. T1/2 is prolonged in patients with liver cirrhosis, renal insufficiency, and alcoholism. Total drug clearance is reduced in patients with cachexia, severe respiratory, hepatic, or cardiac insufficiency, viral infections, and in patients aged 55 years and older.

Potassium ions (K+) are freely filtered in the glomeruli but almost completely reabsorbed in the proximal tubules, with only 10% of filtered K+ ions being excreted. Secretion in the distal tubules and collecting ducts can significantly increase K+ elimination. The kidneys have a limited capacity to maintain K+ concentration.

After parenteral administration, magnesium rapidly distributes into organs and tissues, penetrates the blood-brain barrier and placenta, and enters breast milk at high concentrations. The drug is excreted predominantly in the urine.

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, decompensated chronic heart failure, paroxysmal tachycardia, extrasystoles, atrioventricular conduction disorders, severe arterial hypertension or hypotension, generalized atherosclerosis of blood vessels, pulmonary edema, hemorrhagic stroke, retinal hemorrhage, glaucoma, history of bleeding, peptic ulcer of the stomach and duodenum (in the exacerbation phase), gastroesophageal reflux, epilepsy, increased seizure susceptibility, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, severe hepatic and/or renal insufficiency, porphyria, sepsis, acidosis, hyperkalemia of various origins, hyperchloremia, acute dehydration, severe burns, intestinal obstruction, Addison's disease, patient age > 70 years. Pediatric age (under 18 years). Pregnancy and breastfeeding period.

Interaction with other medicinal products and other types of interactions.

During treatment, alcoholic beverages should not be consumed, nor large amounts of food and drinks containing methylxanthines (coffee, tea, cocoa, chocolate, Coca-Cola), or drugs related to theophylline (caffeine, theobromine, pentoxifylline), as these substances may enhance the stimulant effect of theophylline on the central nervous system.

The effect of theophylline may be enhanced when used concomitantly with allopurinol, acyclovir, carbimazole, zafirlukast, cimetidine, ranitidine, nizatidine, disulfiram, phenylbutazone, fluvoxamine, fluconazole, fluoroquinolones, furosemide, imipenem, isoprenaline, interferon alpha, isoniazid, calcium channel blockers (verapamil, diltiazem), lincomycin, macrolides, amiodarone, mexiletine, methotrexate, paracetamol, pentoxifylline, oral contraceptives, probenecid, propafenone, propranolol, ranitidine, tacrine, thiabendazole, ticlopidine, viloxazine, or influenza vaccine. In patients receiving theophylline concurrently 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 ciprofloxacin is taken concurrently, the theophylline dose should be reduced by at least 60%, and when enoxacin is taken concurrently, 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, magnesium hydroxide, moricizine, rifampicin, ritonavir, or sulfinpyrazone. The effect of theophylline may also be reduced in smokers.
In patients who are taking one or more of the above-mentioned drugs concurrently with theophylline, 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 lower 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 β-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 administration.

Use with caution in patients with cardiovascular diseases, liver disorders, viral infections, prolonged hyperthermia, benign prostatic hyperplasia, severe hypoxia, diabetes mellitus, glaucoma, and in elderly individuals (aged 60 to 70 years).

The drug should be prescribed with caution and only in case of acute necessity in patients with impaired renal function 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, 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 and thus reduce its therapeutic effect, 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.

During treatment, it is recommended to regularly monitor serum potassium levels and perform electrocardiography (ECG), as well as monitor blood acid-base balance, especially in patients with cardiovascular and renal disorders.

Animal studies have shown that repeated administration of Derkaft**®** may reduce hemoglobin, erythrocyte, and leukocyte levels to the lower limits of normal. Therefore, the drug is not recommended for patients with already reduced levels of these parameters. Available data indicate a weak toxic effect of Derkaft**®** on reproductive function in male rats and moderate mutagenic activity in mammalian somatic cells (mice).

Patients of different racial and/or ethnic backgrounds may exhibit CYP gene polymorphisms, leading to variable activity of liver enzymes responsible for theophylline metabolism. This may result in theophylline accumulation in the blood and increase the risk of adverse reactions. Therefore, monitoring of serum theophylline levels during treatment with Derkaft**®** is recommended in patients of different racial backgrounds.

Due to the narrow therapeutic index of theophylline and the potential for adverse effects, monitoring of plasma theophylline concentrations is advisable during long-term therapy.

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 (e.g., dizziness) may occur in sensitive patients during treatment, patients should refrain from driving vehicles and performing other tasks requiring high concentration during therapy.

Dosage and Administration

The drug should be administered intravenously, following standard procedures for intravenous administration. The dosage should be individualized, taking into account possible variations in elimination rate.

If the patient is taking oral theophylline preparations, the dose of parenteral theophylline 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.

Administer intravenously by slow infusion at a rate of 30–50 drops per minute.

Derkaст is administered at a daily dose of 5 ml/kg body weight (theophylline 10 mg/kg body weight), on average 300–400 ml (600–800 mg theophylline), divided into 3 infusions. In patients with cachexia or low initial body weight, the daily dose should be reduced to 200–250 ml (400–500 mg theophylline); in such cases, no more than 100–125 ml (200–250 mg theophylline) should be administered during the first infusion.

Therapeutic effects develop within 5–15 minutes after intravenous administration and last for 4–6 hours.

If palpitations, dizziness, or nausea occur, the infusion rate should be reduced.

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 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 is contraindicated in children (under 18 years of age).

Overdose

Rapid intravenous administration may lead to seizures, arrhythmias, severe arterial hypotension, angina pectoris, apathy, weight loss, psychiatric disorders, and ECG changes.

At plasma theophylline concentrations above 20 mg/ml (110 µmol/l), symptoms may include nausea, vomiting (repeated vomiting, sometimes with blood, potentially leading to dehydration), diarrhea, restlessness, tremor, arterial hypertension, hyperventilation, supraventricular and ventricular arrhythmias, arterial hypotension, seizures, and metabolic disturbances (hypokalemia, hypercalcemia, hypophosphatemia, hyperuricemia, hyperglycemia, metabolic acidosis, respiratory alkalosis). Other toxic effects 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 if needed. For seizure control, intravenous diazepam is recommended. The use of barbiturates is not advisable. In cases of ventricular arrhythmias, antiarrhythmic drugs with proconvulsant effects, such as lidocaine, should be avoided due to the risk of seizure exacerbation.

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

Adverse reactions.

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

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

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

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

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

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

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

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibility.

Do not mix with other medicinal products.

Packaging.

100 ml in bottles, 1 bottle per pack.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of its business activity.

108, Kobzarska Street, Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.