Neophylline

Neophylline is a bronchodilator of the methylxanthines group.

Indications Neophyllin

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

Release form

Prolonged-acting tablets.

Basic physicochemical properties:

• tablets 100 mg - white color, flat-cylindrical shape, beveled;
• 300 mg tablets - white color, flat-cylindrical shape, beveled and grooved.

1 tablet contains theophylline monohydrate in terms of theophylline - 100 mg or 300 mg;

excipients: lactose monohydrate, ammonium methacrylate copolymer dispersion, methacrylate copolymer dispersion, magnesium stearate, talc.

Pharmacodynamics

The mechanism of action is mainly due to blocking of adenosine receptors, inhibition of phosphodiesterases, increase of intracellular cAMP content, decrease of intracellular concentration of calcium ions, as a result of which the smooth muscle of bronchi, gastrointestinal tract, biliary tract, uterus, coronary, cerebral and pulmonary vessels relaxes, peripheral vascular resistance decreases; increases the tone of respiratory muscles (intercostal muscles and diaphragm), reduces pulmonary vascular resistance and improves blood oxygenation, activates the respiratory center of the medulla oblongata, increases its sensitivity to carbon dioxide, improves alveolar ventilation, which leads to a decrease in the severity and frequency of apnea episodes; eliminates angiospasm, increases collateral blood flow and blood oxygenation, reduces perifocal and general cerebral edema, reduces liquor and, consequently, intracranial pressure; improves blood rheological properties, reduces thrombosis, inhibits platelet aggregation (by inhibiting platelet activation factor and prostaglandin F2α), normalizes microcirculation; has an anti-allergic effect, inhibiting degranulation of mast cells and reducing the level of allergy mediators (serotonin, histamine, leukotrienes); increases renal blood flow, has a diuretic effect due to a decrease in tubule reabsorption, increases excretion of water, chlorine ions, sodium.

Pharmacokinetics

When taken orally, theophylline is completely absorbed in the gastrointestinal tract, bioavailability is about 90%, when taking theophylline in the form of prolonged-acting tablets, the maximum concentration is reached in 6 hours. Binding to blood plasma proteins is: in healthy adults - about 60%, in patients with liver cirrhosis - 35%. It penetrates through histohematic barriers, distributing in tissues. About 90% of theophylline is metabolized in the liver with the participation of several cytochrome P450 isoenzymes to inactive metabolites - 1,3-dimethyl uric acid, 1-methyl uric acid and 3-methylxanthine. Excreted mainly by the kidneys in the form of metabolites; unchanged excreted in adults up to 13%, in children - up to 50% of the drug. Partially penetrates 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 - 3-4 hours; in smokers - 4-5 hours; in elderly people and in case of heart failure, liver dysfunction, pulmonary edema, chronic obstructive pulmonary disease and bronchitis - more than 24 hours, which requires appropriate correction of the interval between drug intake.

Therapeutic concentrations of theophylline in blood are: for bronchodilator effect - 10-20 µg/ml, for excitatory effect on respiratory center - 5-10 µg/ml. Toxic concentrations are above 20 µg/mL.

Dosing and administration

The drug should be taken orally 30-60 minutes before a meal or 2 hours after a meal, drinking enough liquid. A 300 mg tablet can be divided in half (100 mg tablets - do not divide), but should not be crushed, chewed or dissolved in water. In some cases, to reduce the irritant effect on the gastric mucosa, the drug should be taken during or immediately after a meal.

Dosing regimen is established individually, depending on the age, body weight of the patient and metabolic peculiarities.

The initial daily dose for adults and children from 12 years of age with body weight more than 45 kg is 300 mg (1 tablet of 300 mg once a day or 3 tablets of 100 mg once a day). After 3 days of drug administration the daily dose can be increased to 450 mg (1½ tablets of 300 mg), after another 3 days of treatment, if necessary, the daily dose can be increased to 600 mg (1 tablet of 300 mg 2 times a day or 3 tablets of 100 mg 2 times a day).

Dose escalation is possible only if well tolerated.

In children from 6 to 12 years of age with body weight 20-45 kg the daily dose is 150 mg (½ tablet 300 mg once a day). After 3 days of drug administration the daily dose can be increased to 300 mg (½ tablet 300 mg 2 times a day), after another 3 days of treatment the daily dose can be increased to 450-600 mg (1½ tablets 300 mg 1 time a day or 1 tablet 300 mg 2 times a day, or 3 tablets 100 mg 2 times a day).

For elderly patients with cardiovascular diseases the recommended daily dose is 8 mg/kg body weight. The maximum therapeutic effect begins to appear on day 3-4 after the start of treatment.

For patients who smoke, the daily dose can be gradually increased to 900-1050 mg (3-3½ 300 mg tablets).

Patients with central nocturnal apnea syndrome can take a single dose of the drug at bedtime.

Further dose increases are recommended based on the determination of serum theophylline concentrations.

The dosage should be selected individually, but usually the tablets are taken 2 times a day. In patients with the most severe clinical manifestation of symptoms, higher morning or evening doses are appropriate.

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

When prescribing high doses, plasma concentrations of theophylline are monitored during treatment (therapeutic concentration is within 10-15 µg/mL).

The total dose should not exceed 24 mg/kg body weight for children and 13 mg/kg for adults. Nevertheless, determination of plasma theophylline levels 4-8 hours after administration and at least 3 days after each dose change allows a more accurate assessment of the need for a specific dose due to the presence of significant individual differences in the degree of excretion in individual patients.

Kids.

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

Contraindications

Hypersensitivity to the drug components and other xanthine derivatives (caffeine, pentoxifylline, theobromine), acute heart failure, angina pectoris, acute myocardial infarction, acute cardiac rhythm disturbances, paroxysmal tachycardia, extrasystole, severe arterial hyper- and hypotension, widespread atherosclerosis, pulmonary edema, hemorrhagic stroke, glaucoma, retinal hemorrhage, bleeding in the anamnesis, gastric and duodenal ulcer (in exacerbation), gastroesophageal reflux, epilepsy, increased seizure readiness, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, liver and/or renal dysfunction, porphyria, sepsis, use in children simultaneously with ephedrine.

Side effects Neophyllin

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

Respiratory system, chest and mediastinal organs: increased respiratory rate.

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

Liver and biliary tract: liver dysfunction, jaundice.

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

Metabolism: hypokalemia, hypercalcemia, hyperuricemia, hyperglycemia, rhabdomyolysis, metabolic acidosis.

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

Cardiovascular system: palpitations, tachycardia, decreased blood pressure, arrhythmias, cardialgia, increased frequency of angina attacks, extrasystole (ventricular, supraventricular), heart failure.

Blood and lymphatic system: aplasia of erythrocytes.

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

Skin and subcutaneous tissue: skin rash, exfoliative dermatitis, skin itching, urticaria.

General disorders: increased body temperature, weakness, feeling of fever and facial hyperemia, increased sweating, dyspnea.

Laboratory parameters: electrolyte imbalance, acid-base imbalance and increased blood creatinine levels.

In most cases, side effects decrease when the dose of the medication is reduced.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of a medicinal product is an important procedure. This allows continued monitoring of the benefit/risk ratio for the medicinal product in question. Health professionals should report any suspected adverse reactions through the national reporting system.

Overdose

Overdose is observed if the serum theophylline concentration exceeds 20 mg/mL (110 µmol/L).

Symptoms. Severe symptoms may develop 12 hours after overdose with the prolonged-release dosage form.

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

Central nervous system: delirium, agitation, anxiety, dementia, toxic psychosis, tremor, increased limb reflexes and convulsions, muscular hypertension. In very severe cases, coma may develop.

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

Metabolic disorders: metabolic acidosis, hypokalemia (through the transfer of potassium from plasma to cells can develop rapidly and severely), hypophosphatemia, hypercalcemia, hypomagnesemia, hyperglycemia, rhabdomyolysis.

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

Treatment. Discontinuation of the drug, gastric lavage, intravenous activated charcoal, osmotic laxatives (within 1-2 hours after overdose); hemodialysis. Control of theophylline level in blood serum until normalization of indices, monitoring of ECG and renal function.

Diazepam is indicated for seizure syndrome.

In patients without bronchial asthma, in case of severe tachycardia, non-selective β-adrenoblockers may be used. In severe cases it is possible to accelerate theophylline elimination by hemosorption or hemodialysis.

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

If large amounts of potassium are used, hyperkalemia may develop during recovery. If plasma potassium level is low, plasma magnesium concentration should be measured as soon as possible.

Antiarrhythmic drugs that have anticonvulsant action, such as lidocaine, should be avoided in ventricular arrhythmias because of the risk of worsening seizures. Antiemetics such as metoclopramide or ondansetron should be used for vomiting.

In tachycardia with adequate cardiac debit, it is better not to use treatment.

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

Further treatment depends on the degree of overdose and the course of intoxication, as well as the symptoms present.

Interactions with other drugs

Drugs that increase the clearance of theophylline: aminoglutethimide, antiepileptics (e.g. Phenytoin, carbamazepine, primidone), magnesium hydroxide, isoproterenol, lithium, moracizine, rifampicin, ritonavir, sulfinpyrazone, barbiturates (especially phenobarbital and pentobarbital). The effect of theophylline may also be less in smokers. In patients taking one or more of the above-mentioned medicinal products concomitantly with theophylline, it is necessary to monitor the concentration of theophylline in serum and adjust the dose, if necessary.

Drugs that reduce the clearance of theophylline: allopurinol, acyclovir, carbimazole, phenylbutazone, fluvoxamine, imipenem, isoprenaline, cimetidine, fluconazole, furosemide, pentoxifylline, disulfiram, interferon, nizatidine, calcium antagonists (verapamil, diltiazem), amiodarone, paracetamol, probenecid, ranitidine, tacrine, propafenone, propanolol, oxpentifylline, isoniazid, lincomycin, methotrexate, zafirlukast, mexiletine, fluoroquinolones (ofloxacin, norfloxacin, when using ciprofloxacin it is necessary to reduce the dose by at least 60%, enoxacin - by 30%), macrolides (clarithromycin, erythromycin), ticlopidine, thiabendazole, viloxazine hydrochloride, oral contraceptives, influenza vaccine. In patients who concomitantly take one or more of the above-mentioned drugs with theophylline, the concentration of theophylline in serum should be monitored and the dose should be reduced, if necessary.

Plasma concentration of theophylline may be decreased by concomitant use of theophylline with herbal medicines containing St. John's wort (Hypericum perforatum).

Co-administration of theophylline and phenytoin may result in decreased levels of the latter.

Ephedrine enhances the effects of theophylline.

The combination of theophylline and fluvoxamine should be avoided. If it is impossible to avoid this combination, patients should take half dose of theophylline and carefully monitor plasma concentrations of the latter.

The combinations of theophylline and adenosine, benzodiazepine, halothane and lomustine should be used with special caution. Halothane anesthesia may cause serious cardiac rhythm disturbances in patients taking theophylline.

Simultaneous use of theophylline and large amounts of food and drinks containing methylxanthines (coffee, tea, cocoa, chocolate, coca-cola and similar tonic drinks), drugs containing xanthine derivatives (caffeine, theobromine, pentoxifylline), α and β-adrenergic agonists (selective and non-selective), glucagon should be avoided considering potentiation of theophylline effects.

Co-administration of theophylline with β-adrenoblockers may antagonize its bronchodilating effect; with ketamine, quinolones - reduces the seizure threshold; with adenosine, lithium carbonate and β-receptor antagonists - reduces the effectiveness of the latter; with doxapram - may cause stimulation of the central nervous system.

Theophylline may potentiate the effects of diuretics and reserpine.

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

There is conflicting evidence for potentiation of theophylline effects in influenza states.

Xanthines may exacerbate hypokalemia due to therapy with β-adrenoreceptor agonists, steroids, diuretics and hypoxia. This applies to hospitalized patients with severe asthma and there is a need to monitor serum potassium levels.

Storage conditions

Store in the original package at a temperature not exceeding 25 °С.

Keep out of reach of children.

Special instructions

Theophylline should be administered only when absolutely necessary and with caution in unstable angina pectoris, heart diseases in which tachyarrhythmia may be observed; in hypertrophic obstructive cardiomyopathy, renal and hepatic dysfunction, in hyperthyroidism, in acute porphyria, in chronic alcoholism and lung diseases, patients with a history of peptic ulcer disease and patients over 60 years of age.

Use of theophylline in severe atherosclerosis, sepsis is possible with caution, under medical supervision, if there are indications for the use of theophylline. Restriction on the use of theophylline in gastroesophageal reflux is associated with the effect on smooth muscles of the cardioesophageal sphincter, which may worsen the patient's condition in gastroesophageal reflux, increasing reflux.

Smoking and alcohol consumption may lead to an increase in the clearance of theophylline and, consequently, to a decrease in its therapeutic effect and the need for higher doses.

During treatment with theophylline it is necessary to carry out close monitoring and reduce the dose in patients with heart failure, chronic alcoholism, liver dysfunction (especially in cirrhosis), with reduced oxygen concentration in the blood (hypoxemia), with fever, patients with pneumonia or viral infections (especially influenza) due to possible decrease in clearance of theophylline. At the same time it is necessary to monitor plasma levels of theophylline that exceed the normal range.

Observation is required when treating patients with peptic ulcer, cardiac arrhythmias, arterial hypertension, other cardiovascular diseases, hyperthyroidism, or acute febrile states with theophylline.

Patients with a history of seizures should avoid theophylline and use alternative treatment.

Increased attention is required when using the drug in patients suffering from insomnia, as well as in elderly men with a previous history of prostate enlargement due to the risk of urinary retention.

If aminophylline (theophylline-ethylenediamine) is required, patients who have already been using theophylline should have their plasma theophylline levels monitored again.

Taking into account the impossibility to guarantee bioequivalence of individual medicinal products containing theophylline with prolonged release, switching from the therapy with the medicinal product Neophylline, in the form of prolonged-release tablets, to another medicinal product of the xanthine group with prolonged release should be performed by repeated dose titration and after clinical evaluation.

During treatment with theophylline, special care should be taken in severe asthma. In such situations, it is recommended to monitor the serum potassium level.

Worsening asthma symptoms require urgent medical attention. In the case of an acute asthmatic attack in a patient receiving long-acting theophylline, intravenous aminophylline should be administered very cautiously.

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

If it is necessary to use theophylline in children with pyrexia or children with epilepsy and seizures in the anamnesis, it is necessary to carefully observe their clinical condition and monitor plasma theophylline levels. Theophylline is not the drug of choice for children with bronchial asthma.

Theophylline can alter some laboratory values: increase fatty acids and catecholamine levels in the urine.

In case of development of adverse reactions it is necessary to control the level of theophylline in the blood.

Important information on excipients.

This medicine contains lactose, therefore it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy or lactation.

Pregnancy.

Theophylline penetrates the placenta.

Use of the medicinal product during pregnancy is possible in the absence of a safe alternative, if the expected benefit to the mother exceeds the potential risk to the fetus. In pregnant women, the serum theophylline concentration should be determined more frequently and the dose should be adjusted accordingly. Theophylline should be avoided at the end of the gestational period, because it may inhibit uterine contraction and cause tachycardia in the fetus.

Breastfeeding.

Theophylline penetrates into breast milk, therefore therapeutic concentrations in serum can be achieved in children. Its use in breastfeeding mothers is allowed only if the anticipated benefit to the mother exceeds the risk to the newborn.

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

Breastfeeding should be carried out immediately before taking the medicine. Any effects of theophylline in infants should be carefully monitored. If higher therapeutic doses are needed, breastfeeding should be discontinued.

Fertility.

There are no clinical data on fertility in humans. Adverse effects of theophylline on male and female fertility are known from preclinical data.

Ability to affect reaction speed when driving motor transport or other mechanisms.

Taking into account that sensitive patients may experience adverse reactions (dizziness) when using the medicinal product, they should refrain from driving vehicles and other activities requiring concentration of attention while taking the medicinal product.

Shelf life

2 years.