Neoephillin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOPHYLLINE (NEOPHYLLINE)

Composition:

Active substance: theophylline;

One tablet contains theophylline monohydrate equivalent to 100 mg or 300 mg of theophylline;

Excipients: lactose monohydrate, ammonio-methacrylate copolymer dispersion, methacrylic copolymer dispersion, magnesium stearate, talc.

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical properties:

100 mg tablets – white, flat cylindrical shaped, bevelled edge;

300 mg tablets – white, flat cylindrical shaped, bevelled edge with a score line.

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

Pharmacological Properties

Pharmacodynamics

Theophylline is a bronchodilator belonging to the methylxanthine group. Its mechanism of action is primarily due to blockade of adenosine receptors, inhibition of phosphodiesterase, increased intracellular cAMP levels, and reduction of intracellular calcium ion concentration. As a result, smooth muscles of the bronchi, gastrointestinal tract, bile ducts, uterus, coronary, cerebral, and pulmonary vessels are relaxed; peripheral vascular resistance decreases; respiratory muscle tone (intercostal muscles and diaphragm) increases; pulmonary vascular resistance decreases and blood oxygenation improves; the respiratory center in the medulla oblongata is stimulated, its sensitivity to carbon dioxide increases, alveolar ventilation improves, leading to reduced severity and frequency of apnea episodes; angiospasm is eliminated, collateral blood flow increases, blood oxygen saturation improves, perifocal and general brain edema decreases, cerebrospinal fluid production and, consequently, intracranial pressure are reduced; blood rheological properties improve, thrombosis decreases, platelet aggregation is inhibited (by suppressing platelet-activating factor and prostaglandin F2α), microcirculation is normalized; anti-allergic effect is observed due to inhibition of mast cell degranulation and reduction of allergy mediators (serotonin, histamine, leukotrienes); renal blood flow is enhanced, diuretic effect occurs due to reduced tubular reabsorption, increasing excretion of water, chloride and sodium ions.

Pharmacokinetics

After oral administration, theophylline is completely absorbed in the gastrointestinal tract; bioavailability is approximately 90%. When administered as prolonged-release tablets, maximum plasma concentration is reached within 6 hours. Plasma protein binding is approximately 60% in healthy adults and 35% in patients with liver cirrhosis. Theophylline penetrates histohematogenous barriers and distributes into tissues. Approximately 90% of theophylline is metabolized in the liver via several cytochrome P450 isoenzymes into inactive metabolites—1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine. Excretion is primarily renal in the form of metabolites; up to 13% of the unchanged drug is excreted in adults and up to 50% in children. Theophylline partially passes into breast milk. The elimination half-life of theophylline depends on age and presence of concomitant diseases and is as follows: in adult patients with bronchial asthma—6–12 hours; in children from 6 months of age—3–4 hours; in smokers—4–5 hours; in elderly patients and in cases of heart failure, impaired liver function, pulmonary edema, chronic obstructive pulmonary diseases, and bronchitis—over 24 hours, which requires appropriate adjustment of the dosing interval.

Therapeutic blood concentrations of theophylline are: for bronchodilation—10–20 mcg/mL; for respiratory center stimulation—5–10 mcg/mL. Toxic concentrations are over 20 mcg/mL.

Clinical Characteristics.

Indications.

• Bronchial asthma.
• Chronic obstructive pulmonary diseases (chronic obstructive bronchitis, pulmonary emphysema).
• Pulmonary hypertension.
• Central sleep apnea syndrome.

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, paroxysmal tachycardia, extrasystoles, severe arterial hypertension or hypotension, generalized atherosclerosis of vessels, pulmonary edema, hemorrhagic stroke, glaucoma, retinal hemorrhage, history of bleeding, peptic ulcer of the stomach and duodenum (in the stage of exacerbation), gastroesophageal reflux, epilepsy, increased seizure susceptibility, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, hepatic and/or renal dysfunction, porphyria, sepsis, concomitant use with ephedrine in children.

Interaction with other medicinal products and other types of interactions.

Medicinal products that increase theophylline clearance: aminoglutethimide, antiepileptic agents (e.g., phenytoin, carbamazepine, primidone), magnesium hydroxide, isoproterenol, lithium, moricizine, rifampicin, ritonavir, sulfinpyrazone, barbiturates (especially phenobarbital and pentobarbital). The effect of theophylline may also be reduced in smokers. In patients who are concurrently receiving one or more of the above-mentioned medicinal products with theophylline, serum theophylline concentrations should be monitored and the dose adjusted if necessary.

Medicinal products that decrease theophylline clearance: allopurinol, acyclovir, carbimazole, phenylbutazone, fluvoxamine, imipenem, isoprenaline, cimetidine, fluconazole, furosemide, pentoxifylline, disulfiram, interferon, ranitidine, nizatidine, calcium channel antagonists (verapamil, diltiazem), amiodarone, paracetamol, probenecid, ranitidine, tacrine, propafenone, propranolol, oxpentifylline, isoniazid, lincomycin, methotrexate, zafirlukast, mexiletine, fluoroquinolones (ofloxacin, norfloxacin; when ciprofloxacin is used, the dose should be reduced by at least 60%, enoxacin – by 30%), macrolides (clarithromycin, erythromycin), ticlopidine, thiabendazole, viloxazine hydrochloride, oral contraceptives, influenza vaccine. In patients who are concurrently receiving one or more of the above-mentioned medicinal products with theophylline, serum theophylline concentrations should be monitored and the dose reduced if necessary.

Plasma concentrations of theophylline may be reduced when used concomitantly with herbal medicinal 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.

Combination of theophylline and 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.

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

Concomitant use of theophylline with large amounts of food and beverages containing methylxanthines (coffee, tea, cocoa, chocolate, Coca-Cola, and similar tonic drinks), medicinal products containing xanthine derivatives (caffeine, theobromine, pentoxifylline), α- and β-adrenergic agonists (selective and non-selective), and glucagon should be avoided due to potential potentiation of theophylline effects.

Concomitant use of theophylline with β-blockers may antagonize its bronchodilating effect; with ketamine and quinolones – may lower the seizure threshold; with adenosine, lithium carbonate, and β-receptor antagonists – their effectiveness may be reduced; with doxapram – may cause stimulation of the central nervous system.

Theophylline may enhance the effects of diuretics and reserpine.

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

There are conflicting data regarding potentiation of theophylline effects during influenza-like illnesses.

Xanthines may potentiate hypokalemia induced by therapy with β-adrenoceptor agonists, steroids, diuretics, and hypoxia. This is particularly relevant in hospitalized patients with severe asthma, and monitoring of serum potassium levels is required.

Special precautions for use.

Theophylline should be administered only when urgently needed and with caution in patients with unstable angina, cardiac diseases in which tachyarrhythmia may occur; in hypertrophic obstructive cardiomyopathy, renal and hepatic dysfunction, hyperthyroidism, acute porphyria, chronic alcoholism, and pulmonary diseases, as well as in patients with a history of peptic ulcer and in patients aged 60 years and older.

The use of theophylline in patients with severe atherosclerosis or sepsis is possible with caution and under physician supervision if there are clear indications for theophylline use. Restrictions regarding theophylline use in gastroesophageal reflux disease are related to its effect on smooth muscles of the cardioesophageal sphincter, which may worsen the patient's condition by increasing reflux.

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

During theophylline therapy, careful monitoring is required and dose reduction should be considered in patients with heart failure, chronic alcoholism, impaired liver function (especially cirrhosis), hypoxemia, fever, pneumonia, or viral infections (particularly influenza), due to possible decreased theophylline clearance. Plasma theophylline levels should be monitored regularly, especially when levels exceed normal values.

Close monitoring is necessary when treating patients with peptic ulcer disease, cardiac arrhythmias, arterial hypertension, other cardiovascular disorders, hyperthyroidism, or acute febrile conditions.

Theophylline should be avoided in patients with a history of seizures; alternative treatments should be used.

Increased caution is required when administering the drug to patients suffering from insomnia and in elderly men with a history of benign prostatic hyperplasia due to the risk of urinary retention.

If aminophylline (theophylline-ethylenediamine) must be administered to patients already receiving theophylline, plasma theophylline levels should be monitored again.

Due to the inability to guarantee bioequivalence between different sustained-release theophylline formulations, switching from Neophyllin sustained-release tablets to another sustained-release xanthine derivative must be done with dose re-titration and after clinical evaluation.

Particular caution is required when using theophylline in severe asthma. In such cases, serum potassium levels should be monitored.

Worsening asthma symptoms require immediate medical attention. In case of acute asthmatic attack in a patient receiving prolonged-action theophylline, intravenous aminophylline should be administered very cautiously.

Only half of the recommended loading dose of aminophylline (usually 6 mg/kg) should be administered cautiously, i.e., 3 mg/kg.

When theophylline is used in children with fever or in children with epilepsy and a history of seizures, careful clinical monitoring and plasma theophylline level monitoring are required. Theophylline is not a drug of choice for children with bronchial asthma.

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

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

Important information about excipients.

This medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

Theophylline crosses the placenta.

The use of this medicinal product during pregnancy is possible only in the absence of safer alternatives and when the expected benefit to the mother outweighs the potential risk to the fetus. Pregnant women require more frequent monitoring of serum theophylline concentrations, and dosage adjustments should be made accordingly. Theophylline use should be avoided toward the end of pregnancy because it may inhibit uterine contractions and cause fetal tachycardia.

Breastfeeding.

Theophylline passes into breast milk, and therapeutic concentrations in serum may be achieved in infants. Its use in breastfeeding mothers is acceptable only if the expected benefit to the mother outweighs the potential risk to the newborn.

Theophylline may cause increased irritability in the newborn; therefore, the therapeutic dose of theophylline should be kept as low as possible.

Breastfeeding should be performed immediately before taking the drug. Any effects of theophylline on the infant should be closely monitored. If higher therapeutic doses are required, breastfeeding should be discontinued.

Fertility.

There are no clinical data on fertility in humans. Preclinical data indicate an adverse effect of theophylline 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, patients should refrain from driving vehicles or performing tasks requiring concentration during theophylline therapy.

Dosage and Administration

The medicinal product should be taken orally, 30–60 minutes before a meal or 2 hours after a meal, with an adequate amount of liquid. The 300 mg tablet may be divided in half (tablets of 100 mg must not be divided), but must not be crushed, chewed, or dissolved in water. In some cases, to reduce the irritating effect on the gastric mucosa, the medicinal product should be taken during or immediately after a meal.

The dosage regimen should be individually determined depending on the patient's age, body weight, and metabolic characteristics.

The initial daily dose for adults and children aged 12 years and older with body weight over 45 kg is 300 mg (one 300 mg tablet once daily or three 100 mg tablets once daily). After 3 days of treatment, the daily dose should be increased to 450 mg (1½ tablets of 300 mg once daily). After another 3 days of treatment, if necessary, the daily dose may be further increased to 600 mg (one 300 mg tablet twice daily or three 100 mg tablets twice daily).

Dose escalation is possible only if the drug is well tolerated.

For children aged 6 to 12 years with body weight 20–45 kg, the daily dose is 150 mg (½ of a 300 mg tablet once daily). After 3 days of treatment, the daily dose should be increased to 300 mg (½ of a 300 mg tablet twice daily). After another 3 days of treatment, the daily dose may be increased to 450–600 mg (1½ tablets of 300 mg once daily, or one 300 mg tablet twice daily, or three 100 mg tablets twice daily).

For elderly patients with cardiovascular diseases, the recommended daily dose is 8 mg/kg body weight. The maximum therapeutic effect usually becomes apparent on day 3–4 of treatment.

For patients who smoke, the daily dose may be gradually increased up to 900–1050 mg (3–3½ tablets of 300 mg).

Patients with central sleep apnea syndrome may take a single dose of the medicinal product at night.

Further dose increases should be based on serum theophylline concentration measurements.

Dosage should be individually adjusted, but tablets are usually taken twice daily. Patients with the most severe clinical symptoms may benefit from higher morning or evening doses.

For patients whose symptoms persist during the night or day, regardless of other ongoing therapies or if they have not previously received theophylline, treatment may be supplemented with the recommended single morning or evening daily dose of theophylline.

When high doses are prescribed, plasma theophylline concentrations should be monitored (therapeutic concentration range: 10–15 mcg/mL).

The total daily dose should not exceed 24 mg/kg body weight in children and 13 mg/kg in adults. Nevertheless, measuring plasma theophylline levels 4–8 hours after administration and no sooner than 3 days after any dosage adjustment allows for a more accurate assessment of the required dose due to significant individual differences in elimination rates among patients.

The table below may be used as a guideline for appropriate dosing.

Children.

The medicinal product should not be used in children under 6 years of age with body weight less than 20 kg.

Overdose.

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

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

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

Central nervous system: delirium, excitement, anxiety, dementia, toxic psychosis, tremor, hyperreflexia and 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, may develop rapidly and in severe form), hypophosphatemia, hypercalcemia, hypomagnesemia, hyperglycemia, rhabdomyolysis.

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

Treatment. Discontinue the medicinal product, gastric lavage, oral activated charcoal, osmotic laxatives (within 1–2 hours after overdose); hemodialysis. Monitor serum theophylline levels until normalization, ECG monitoring and renal function.

For seizure management, diazepam is indicated.

In patients without bronchial asthma, nonselective β-adrenoblockers may be used in case of pronounced tachycardia. In severe cases, theophylline elimination may be accelerated by hemoperfusion or hemodialysis.

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

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

Avoid using antiarrhythmic agents with convulsant properties such as lidocaine in ventricular arrhythmias due to the risk of seizure aggravation. For control of vomiting, antiemetics such as metoclopramide or ondansetron should be used.

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

In life-threatening overdose with cardiac rhythm disturbances, propranolol may be administered to non-asthmatic patients (1 mg for adults and 0.02 mg/kg body weight for children). This dose may be repeated every 5–10 minutes until heart rhythm normalizes, but the maximum dose should not exceed 0.1 mg/kg body weight. Propranolol may cause severe bronchospasm in asthmatic patients; therefore, verapamil should be used in such cases.

Further treatment depends on the degree of overdose, course of intoxication, and presence of symptoms.

Adverse Reactions

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

Respiratory, thoracic and mediastinal disorders: increased respiratory rate.

Gastrointestinal disorders: heartburn, decreased appetite/anorexia with prolonged use, nausea, vomiting, abdominal pain, diarrhea, gastroesophageal reflux, exacerbation of peptic ulcer, stimulation of gastric acid secretion, intestinal atony, gastrointestinal bleeding.

Hepatobiliary disorders: liver function abnormalities, jaundice.

Renal and urinary disorders: increased diuresis, especially in children; urinary retention in elderly men.

Metabolism and nutritional disorders: hypokalemia, hypercalcemia, hyperuricemia, hyperglycemia, rhabdomyolysis, metabolic acidosis.

Nervous system disorders: dizziness, headache, irritability, anxiety, restlessness, excitement, sleep disturbances, insomnia, tremor, confusion/loss of consciousness, delirium, seizures, hallucinations, presyncopal state, acute encephalopathy.

Cardiac disorders: palpitations, tachycardia, decreased blood pressure, arrhythmias, cardialgia, increased frequency of angina attacks, extrasystoles (ventricular, supraventricular), heart failure.

Blood and lymphatic system disorders: erythrocyte aplasia.

Immune system disorders: hypersensitivity reactions, including angioneurotic edema, anaphylactic and anaphylactoid reactions, bronchospasm.

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

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

Laboratory findings: electrolyte imbalance, acid-base disturbances, increased blood creatinine levels.

In most cases, adverse effects diminish upon dose reduction.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activity.

13, Boryspilska Street, Kyiv, 02093, Ukraine.