Theocron (Theophylline)

THEOCHRON® SR Riva Theophylline Bronchodilator

Action and Clinical

Theophylline is a bronchodilator which directly relaxes the smooth muscle of the bronchial airways and pulmonary and coronary blood vessels. These actions may be mediated through inhibition of phosphodiesterase and a resultant increase in intracellular cyclic AMP.

Theophylline sustained release tablets produce peak blood levels of theophylline between 5 and 8 hours following dosing in adults. Once a steady state level has been reached, the therapeutic blood levels of theophylline persist for 12 hours in most adult patients.

Theophylline is usually well absorbed following oral administration. In the therapeutic blood range of between 5 and 20 g/mL (28 to 111 mol/L), about 55 to 65% of theophylline is found bound to plasma protein. The half-life of theophylline is influenced by a number of known variables. In adult nonsmokers with uncomplicated asthma the half-life ranges from 3 to 9 hours. In older adults (over 55 years of age), patients with chronic obstructive lung disease, impaired hepatic or renal function, or chronic alcoholism, the half-life is usually longer, sometimes exceeding 24 hours. The half-life of theophylline in smokers and young children is, on the other hand, shorter. Between 3 months and 2 years may be necessary to reverse the effect of smoking on theophylline pharmacokinetics. The time required to reach steady state varies between subjects but is related to the half-life for theophylline in that subject. Steady state is generally reached within 5 half-lives.

Theophylline is metabolized by the liver to 3-methyl-xanthine, 1-methyl-uric acid and 1,3-dimethyluric acid. About 10% of a dose is excreted unchanged in the urine.

Biliary excretion, with subsequent reabsorption, may occur but has not been demonstrated in man.

Indications And Clinical Uses:

For the symptomatic treatment of reversible bronchospasm associated with asthma, chronic bronchitis, emphysema and related bronchospastic disorders.

Contra-Indications:

In patients with hypersensitivity to theophylline or xanthine derivatives; peptic ulcer; coronary artery disease (when, in the physician’s judgment, myocardial stimulation might prove harmful).

Warnings in Clinical States:

Children: The margin of safety above the therapeutic dose is small. The use of theophylline sustained release tablets in children under the age of 12 years is not recommended as a dose schedule in this age group has not been established.

Precautions:

Marked differences in serum levels may be seen in patients receiving the same theophylline dose. This may be explained by differences between patients in the rate of metabolism. Dosage regimens should therefore be individualized.

Ideally, serum theophylline levels should be monitored in all patients and a theophylline half-life calculated which would enable doses and dosing regimens to be tailored to each patient to maintain a therapeutic level, to ensure optimal clinical response and to avoid toxicity.

The incidence of toxicity increases at serum theophylline levels greater than 15 g/mL (83 mol/L) and levels above 20 g/mL (111 mol/L) are usually quite toxic in most patients (adults). High serum levels may be seen in some patients receiving doses considered to be conventional. The possibility of overdose should therefore not be considered with large doses only. Overdosage of theophylline may cause peripheral vascular collapse.

Careful monitoring of serum levels is particularly advisable in patients with hepatic dysfunction since theophylline metabolism may be impaired, resulting in toxic levels.

Theophylline should also be used with caution in elderly patients, and patients with severe hypoxemia, uncompensated cardiac failure, cor pulmonale, or hyperthyroidism.

Theophylline may also worsen pre-existing arrhythmias.

Caution should be exercised when theophylline is used concurrently with sympathomimetic amines, since the incidence and severity of adverse reactions may be increased. The concurrent administration of other theophylline derivatives along with theophylline sustained release tablets is not recommended.

In the interpretation of biochemistry tests, it should be remembered that theophylline may cause an elevation of urine catecholamines and plasma free fatty acids.

Pregnancy: Theophylline crosses the placental barrier and also passes freely into breast milk, where concentrations are similar to plasma levels. Safe use in pregnancy has not been established relative to possible adverse effects on fetal development, but neither have adverse effects on fetal development been established. Therefore, use of theophylline in pregnant women should be balanced against the risk of uncontrolled asthma.

Lactation: It has been reported that theophylline distributes readily into breast milk and may cause adverse effects in the infant. Caution must be used if prescribing xanthines to a mother who is nursing, taking into account the risk-benefit of this therapy.

Drug Interactions:

Cimetidine, erythromycin, influenza vaccine and propranolol may increase the effect of theophylline by decreasing theophylline clearance.

Smoking may decrease theophylline effect by increasing clearance.

Acidifying agents, by increasing urinary excretion of weak bases such as xanthines, may inhibit theophylline action. Alkalinizing agents, by decreasing urinary excretion, may potentiate the action of theophylline.

The actions of thiazide diuretics and digitalis glycosides may be potentiated by xanthine derivatives such as theophylline.

The effects of coumarin anticoagulants may be antagonized by methylxanthine-induced increases of prothrombin and fibrinogen.

Theophylline has been shown to increase the ratio of clearance of lithium/creatinine and may thus decrease serum lithium to ineffective levels.

Xanthines may antagonize the antihyperuricemic action of allopurinol; the uricosuric action of probenecid may also be antagonized.

Xanthines have been shown to be nephrotoxic with prolonged use at high dosage. Coincident toxicity should therefore be borne in mind when other potentially nephrotoxic drugs are administered concurrently. Combined use of several xanthines, or the concurrent use of sympathomimetics, may cause excessive CNS stimulation.

Adverse Reactions:

The most common adverse reactions are nausea, vomiting, epigastric pain, headache and tremor. These are usually early signs of toxicity; however, with high doses, ventricular arrhythmias or seizures may be the first signs to appear. Adverse reactions reported with theophylline preparations include: Gastrointestinal: nausea, vomiting, epigastric pain, hematemesis, diarrhea, anorexia, reactivation of peptic ulcer, intestinal bleeding.

CNS: headaches, irritability, restlessness, insomnia, hyperactivity, reflex hyperexcitability, muscle twitching, clonic and tonic generalized convulsions.

Cardiovascular: palpitation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, life-threatening ventricular arrhythmias.

Respiratory: tachypnea.

Renal: albuminuria, diuresis and hematuria.

Others: hyperglycemia and inappropriate ADH syndrome.

Symptoms And Treatment Of Overdose:

Symptoms: Insomnia, restlessness, mild excitement or irritability, and rapid pulse, are early symptoms which may progress to mild delirium.

Sensory disturbances such as tinnitus or flashes of light are common. Anorexia, nausea and vomiting are frequently early observations of theophylline overdosage.

Fever, diuresis, dehydration and extreme thirst may be seen. Severe poisoning results in bloody, syrup-like “coffee-ground” vomitus, tremors, tonic extensor spasm interrupted by clonic convulsions, extrasystoles, quickened respiration, stupor and finally coma. Cardiovascular disorders and respiratory collapse, leading to shock, cyanosis and death follow gross overdosages.

Treatment: If potential oral overdose is established and seizure has not occurred, induce vomiting. Administer a cathartic (this is particularly important when a sustained release preparation has been taken). Administer activated charcoal.

If patient is having a seizure, establish an airway. Administer oxygen. Treat the seizure with i.v. diazepam, 100 to 300 g/kg up to a total dose of 10 mg. Monitor vital signs, maintain blood pressure and provide adequate hydration.

Post-Seizure Coma: Maintain airway and oxygenation. If a result of oral medication, follow above recommendations to prevent absorption of drug, but intubation and lavage will have to be performed instead of inducing emesis, and the cathartic and charcoal will need to be introduced via a large bore gastric lavage tube. Continue to provide full supportive care and adequate hydration while waiting for the drug to be metabolized. In general, the drug is metabolized sufficiently rapidly so as not to warrant consideration of dialysis. However, charcoal or resin hemoperfusion should be considered if serum level monitoring indicates dose-dependent kinetics.

Dosage And Administration:

Therapeutic serum levels are generally considered to be between 10 and 20 g/mL (56 to 111 mol/L). Due to variable rates of elimination, there is patient-to-patient variation in dosage needed to achieve a therapeutic serum level. Because of the variation from patient-to-patient, the variation within the same patient, and the relatively narrow therapeutic range, dosage should be individualized. Monitoring of serum theophylline concentrations is also extremely important especially in the initial stages of therapy (see Precautions).

It is preferable to monitor peak concentrations rather than trough concentrations. Therefore, blood samples should be drawn 5 hours after dosing with theophylline sustained release tablets. It should be ascertained that all doses have been taken for 60 hours prior to blood sampling. Depending on the sensitivity of the assay method used, dietary xanthines may interfere with assay results.

If a dosage increase is not tolerated, dosage should be reduced to the previously tolerated level. Do not attempt to maintain a dosage which is not tolerated or which produces serum concentrations above the therapeutic range.

Theophylline sustained release tablets should not be chewed or crushed, but may be halved.

Adults: Usual Initial Dose: 200 to 300 mg every 12 hours. This dose may be increased by 50 to 100 mg every 12 hours at 3 day intervals until a satisfactory response is obtained or toxic effects appear. Dosage adjustments should be based upon serum theophylline concentration and/or upon the patient’s clinical response. However, doses of 400 mg every 12 hours or higher should not be given unless serum theophylline concentration can be monitored. It should not be necessary to exceed a daily dose of 18 mg/kg in adult patients. Even with serum level monitoring, this dose may lead to side effects because of day-to-day variations in blood levels within individual patients.

Availability And Storage:

200 mg: Each oval, concave-shaped, white, bisected tablet, imprinted IL/3583, contains: sustained release theophylline anhydrous 200 mg. Bottles of 100 and 500.

300 mg: Each capsule-shaped, white, scored tablet, imprinted IL/3581, contains: sustained release theophylline anhydrous 300 mg. Bottles of 100 and 500.

Store at controlled room temperature 15 to 30°C. Dispense in tight containers.

THEOCHRON® SR Riva Theophylline Bronchodilator

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