Spophyllin Retard (Tablets) Instructions for Use

ATC Code

R03DA04 (Theophylline)

Active Substance

Theophylline

Clinical-Pharmacological Group

Bronchodilator drug – phosphodiesterase inhibitor

Pharmacotherapeutic Group

Bronchodilator agent – phosphodiesterase inhibitor

Pharmacological Action

Phosphodiesterase inhibitor, methylxanthine. It increases the accumulation of cAMP in tissues, blocks adenosine (purine) receptors; reduces the entry of calcium ions through cell membrane channels, and reduces the contractile activity of smooth muscles. It relaxes the muscles of the bronchi and blood vessels (mainly vessels of the brain, skin, and kidneys); has a peripheral vasodilating effect, increases renal blood flow, and has a moderately pronounced diuretic effect. It stabilizes mast cell membranes and inhibits the release of allergic reaction mediators.

It increases mucociliary clearance, stimulates diaphragm contraction, improves the function of respiratory and intercostal muscles, and stimulates the respiratory center. By normalizing respiratory function, it promotes blood oxygen saturation and reduces the concentration of carbon dioxide; it stimulates the respiratory centers. It enhances lung ventilation under conditions of hypokalemia.

It has a stimulating effect on heart activity, increases the strength of heart contractions and heart rate, increases coronary blood flow and myocardial oxygen demand. It reduces the tone of blood vessels (mainly vessels of the brain, skin, and kidneys). It reduces pulmonary vascular resistance and lowers pressure in the pulmonary circulation.

It increases renal blood flow and has a moderate diuretic effect. It dilates extrahepatic bile ducts. It inhibits platelet aggregation (suppresses platelet-activating factor and PgE_2α), increases the resistance of erythrocytes to deformation (improves the rheological properties of blood), reduces thrombus formation, and normalizes microcirculation.

Pharmacokinetics

When taken orally, Theophylline is rapidly and completely absorbed from the gastrointestinal tract. The presence of food in the stomach can affect the rate (but not the extent) of theophylline absorption, as well as its clearance. When using the conventional duration of action dosage form, C_max in plasma is reached in 1-2 hours.

After intramuscular injection, absorption is slow and incomplete.

Plasma protein binding is approximately 40%; in newborns and also in adults with diseases, binding is reduced.

Theophylline is metabolized in the liver with the participation of several cytochrome P450 isoenzymes, the most important of which is CYP1A2. During metabolism, 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine are formed. These metabolites are excreted in the urine. In unchanged form, 10% is excreted in adults. In newborns, a significant portion is excreted as caffeine (due to the immaturity of its further metabolic pathways), and 50% is excreted unchanged.

Significant individual differences in the rate of hepatic metabolism of theophylline are the cause of pronounced variability in clearance values, plasma concentration, and T_1/2. Hepatic metabolism is influenced by factors such as age, tobacco smoking habit, diet, diseases, and concurrent drug therapy.

The T_1/2 of theophylline in non-smoking patients with bronchial asthma with practically no pathological changes in other organs and systems is 6-12 hours, in children – 1-5 hours, in smokers – 4-5 hours, in newborns and premature infants – 10-45 hours.

The T_1/2 of theophylline increases in elderly individuals and in patients with heart failure or liver diseases.

Clearance decreases in heart failure, impaired liver function, chronic alcoholism, pulmonary edema, and in COPD.

Indications

Broncho-obstructive syndrome of various origins: bronchial asthma (the drug of choice for exercise-induced asthma and as an additional agent for other forms of bronchial asthma), COPD (chronic obstructive bronchitis, pulmonary emphysema). Pulmonary hypertension, cor pulmonale, edematous syndrome of renal origin (as part of combination therapy), nocturnal apnea.

ICD codes

Dosage Regimen

Tablets

The dose is set individually. The initial dose is on average 400 mg/day. Provided good tolerance, the dose can be increased by approximately 25% of the initial dose every 2-3 days until the optimal therapeutic effect is achieved.

Maximum doses that can be used without monitoring the plasma concentration of theophylline: children aged 3-9 years – 24 mg/kg/day, 9-12 years – 20 mg/kg/day, 12-16 years – 18 mg/kg/day; patients aged 16 years and older – 13 mg/kg/day or 900 mg/day.

If symptoms of toxic action appear when using the indicated doses or if it is necessary to further increase the dose (due to insufficient therapeutic effect), it is recommended to monitor the plasma concentration of theophylline. The optimal therapeutic concentrations of theophylline are 10-20 mcg/ml. At lower concentrations, the therapeutic effect is weak; at higher concentrations, no significant enhancement of the therapeutic effect is noted, while the risk of side effects increases significantly. The frequency of administration depends on the dosage form.

Adverse Reactions

From the central nervous system: dizziness, headache, insomnia, agitation, anxiety, irritability, tremor.

From the cardiovascular system: palpitations, tachycardia (including in the fetus when taken in the third trimester), arrhythmias, decreased blood pressure, cardialgia, increased frequency of angina attacks.

From the digestive system: gastralgia, nausea, vomiting, gastroesophageal reflux, heartburn, exacerbation of peptic ulcer, diarrhea, with long-term use – decreased appetite.

Allergic reactions: skin rash, itching, fever.

Other: chest pain, tachypnea, feeling of flushing to the face, albuminuria, hematuria, hypoglycemia, increased diuresis, increased sweating. Side effects decrease when the dose is reduced.

Contraindications

Epilepsy, gastric and duodenal ulcer in the acute phase, gastritis with high acidity, recent gastrointestinal bleeding, severe arterial hyper- or hypotension, severe tachyarrhythmias, hemorrhagic stroke, retinal hemorrhage, children’s age (under 3 years, for prolonged oral forms – under 12 years), hypersensitivity to theophylline and other xanthine derivatives (caffeine, pentoxifylline, theobromine).

Use in Pregnancy and Lactation

Theophylline crosses the placental barrier and is excreted in breast milk.

During pregnancy, Theophylline is used only if the intended benefit to the mother outweighs the potential risk to the fetus.

If use during lactation is necessary, it should be considered that Theophylline is excreted in breast milk.

Use in Hepatic Impairment

In severe liver diseases, the dose of theophylline should be reduced.

Pediatric Use

Contraindicated in children (under 3 years, for prolonged oral forms – under 12 years).

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Use with caution in severe coronary insufficiency (acute phase of myocardial infarction, angina pectoris), widespread vascular atherosclerosis, hypertrophic obstructive cardiomyopathy, ventricular extrasystole, chronic heart failure, increased convulsive readiness, in hepatic and/or renal failure, gastric and duodenal ulcer (in history), in uncontrolled hypothyroidism (possibility of accumulation) or thyrotoxicosis, prolonged hyperthermia, gastroesophageal reflux, prostatic hyperplasia, during pregnancy, during lactation, in elderly patients, in children (especially for oral forms).

Use rectally with caution in diarrhea and rectal diseases.

The intensity of theophylline’s action may decrease in smokers.

Theophylline should not be used simultaneously with other xanthine derivatives.

In severe diseases of the cardiovascular system, liver, viral infections, as well as in elderly patients, the dose of theophylline should be reduced.

Drug Interactions

With simultaneous use with macrolide antibiotics, allopurinol, cimetidine, oral contraceptives, isoprenaline, lincomycin, the clearance of theophylline decreases.

With simultaneous use, beta-blockers, especially non-selective ones, can cause bronchoconstriction, which reduces the bronchodilating effect of theophylline. A decrease in the effectiveness of beta-blockers is possible.

With simultaneous use of β₂-adrenergic receptor stimulants, caffeine, furosemide, the effect of theophylline is enhanced.

With simultaneous use with aminoglutethimide, a decrease in the effectiveness of theophylline is possible due to an increase in its excretion from the body.

With simultaneous use with acyclovir, an increase in the plasma concentration of theophylline and an increase in adverse reactions are possible.

With simultaneous use with verapamil, diltiazem, nifedipine, felodipine, the plasma concentration of theophylline usually changes slightly or moderately in the absence of changes in the bronchodilator effect. Cases of increased plasma concentration of theophylline and enhancement of its side effects have been described in patients simultaneously receiving verapamil or nifedipine.

With simultaneous use of disulfiram, the plasma concentration of theophylline increases and toxic reactions develop.

With simultaneous use of lithium salts, a decrease in their effectiveness is possible.

With simultaneous use with propranolol, the clearance of theophylline decreases.

With simultaneous use with phenytoin, the plasma concentrations of theophylline and phenytoin decrease and their therapeutic effectiveness decreases.

With simultaneous use with phenobarbital, rifampicin, isoniazid, carbamazepine, sulfinpyrazone, the intensity of theophylline’s action may decrease due to an increase in its clearance.

With simultaneous use with enoxacin or other fluoroquinolones, a significant increase in the plasma concentration of theophylline is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.