Theo-Dur (Theophylline)

THEO-DUR® AstraZeneca Theophylline Bronchodilator

Action and Clinical

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels to relieve bronchospasm and increase flow rates and vital capacity. It also produces other actions typical of the xanthine derivatives: coronary vasodilation, diuresis, increase in gastric secretion, and cardiac, cerebral, and skeletal muscle stimulation. The actions of theophylline may be mediated through inhibition of phosphodiesterase and a resultant increase in intracellular cyclic adenosine monophosphate, but the exact mechanism(s) has not been determined. Theophylline is usually readily absorbed and distributed into all body compartments. Protein binding accounts for some 55 to 65%. The liver is the primary site of metabolism.

The therapeutic serum concentration of theophylline is accepted as 55 to 110 mol/L (10 to 20 mg/L); levels above 20 mg/L are associated with toxic reactions. The pharmacokinetics of theophylline are influenced by a number of variables such as: age, disease state, smoking, concomitant medication. Therefore the optimum therapeutic maintenance dose should be determined by individual titration.

The sustained-release tablets produce peak blood levels between 5 to 8 hours after dosing in adults, and between 4 to 6 hours after dosing in children 6 years of age and older. Once the steady state level has been reached (3 days) the therapeutic blood levels persist for 12 hours in most adult patients. The mean elimination half-life of theophylline in children is about 4 hours and in nonsmoking adults, about 8 hours.

Indications And Clinical Uses:

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

Contra-Indications:

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:

In clinical situations where immediate bronchodilatation is required, such as status asthmaticus, Theo-Dur is not suitable. Theophylline has a narrow therapeutic range; the margin of safety above therapeutic doses is small. In patients showing intolerance to theophylline, the therapy should be reassessed. Theophylline clearance can be changed by various disease states, as well as by the age of the patient, concomitant use of other medications and lifestyle habits (see Precautions).

The use of Theo-Dur in children under the age of 6 years is not recommended as a dose schedule in this age group has not been established.

Precautions:

Theo-Dur tablets should not be chewed or crushed, but may be halved.

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. Smokers and children are usually high metabolizers. Dosage regimens should therefore be individualized.

Theophylline half-life is shorter in smokers than in nonsmokers. Smokers may require larger or more frequent doses of theophylline.

Ideally, serum theophylline 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 82.5 mol/L (15 mg/L) and levels above 110 mol/L (20 mg/L) may produce toxic effects in most adult patients. 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.

Reduced theophylline clearance has been documented in the following readily identifiable groups: patients with impaired renal or hepatic function; patients over 55 years of age, particularly males and those with chronic lung disease; those with cardiac failure from any cause; patients taking certain drugs (i.e., macrolide antibiotics, cimetidine or fluvoxamine). Decreased clearance may be associated with either influenza immunization or active infection with influenza; those with acute viral infections or other conditions with fever.

Laboratory monitoring of serum theophylline is especially appropriate in the above individuals to maintain an appropriate theophylline dosage and to avoid accumulation of theophylline to potentially toxic serum concentrations (greater than 110 mol/L=20 mg/L).

Serious side effects such as tachycardia, arrhythmia, seizures, vascular collapse and even death may occur without warning and may not be preceded by less severe symptoms such as nausea and restlessness. These serious side effects usually appear in patients at high plasma concentrations of theophylline (above 25 mg/L).

Use with caution in patients with severe cardiac disease, severe hypoxemia, hypertension, hyperthyroidism, acute myocardial injury, cor pulmonale, congestive heart failure, liver disease, in the elderly (especially males).

Patients with congestive heart failure frequently have markedly prolonged serum levels with theophylline persisting in serum for long periods following discontinuation of the drug.

Theophylline may occasionally act as a local irritant to the gastrointestinal tract although gastrointestinal symptoms are more commonly centrally mediated and associated with serum drug concentrations over 110 mol/L (20 mg/L).

Theophylline increases gastric secretion, and caution should be exercised in patients with a history of peptic ulcer.

Theophylline may potentiate hypokalemia if administered concomitantly with b 2-agonists, steroids, diuretics or in hypoxic and severe asthmatic patients. Serum potassium levels should be monitored in these situations.

Although Theo-Dur has pharmacokinetic properties similar to other controlled-release theophylline products, it is not possible to ensure interchangeability between different products. Careful clinical monitoring is required when changing from one drug product to another.

The concurrent administration of other theophylline derivatives along with Theo-Dur is not recommended.

Laboratory Test Interactions : In the interpretation of biochemistry tests, it should be remembered that theophylline may cause an elevation of urine catecholamines and serum free fatty acids. When serum levels of theophylline are measured by spectrophotometric methods, coffee, tea, cola beverages, chocolate and acetaminophen contribute to falsely high values.

When high pressure liquid chromatography (HPLC) method is used, serum theophylline concentration may be falsely increased by caffeine, some cephalosporin and sulfa medications.

Food Interactions: Theophylline clearance is increased when diet includes a low carbohydrate, high protein intake, or a high carbohydrate, low protein intake and there is a chronic ingestion of charcoal broiled meats. However, the administration of Theo-Dur with meals appears not to significantly affect the release of theophylline from Theo-Dur tablets.

Pregnancy and Lactation: Theophylline crosses the placental barrier and also passes freely into breast milk, where concentrations are similar to serum 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 for uncontrolled asthma in pregnant women and nursing mothers, should be balanced against the risk of potential effects on the fetus or on the nursing newborn.

Drug Interactions:

Theophylline pharmacokinetics are altered by the concurrent use of various drugs:

Effect of Various Drugs on Theophylline Pharmacokinetics

Drugs Theophylline

Cimetidine, propranolol, t 1/2, clearance

allopurinol, macrolide antibiotics (i.e., troleandomycin, erythromycin), oral contraceptives

Alkalinizing agents Ât 1/2, clearance

Influenza vaccine t 1/2, clearance reported to be decreased or no change

Phenytoin, barbiturates, t 1/2, clearance

carbamazepine, isoproterenol, rifampin

Smoking (tobacco) t 1/2, clearance

Acidifying agents t 1/2, clearance

Quinolones (ciprofloxacin, norfloxacin) t 1/2, clearance

Disulfiram t 1/2, clearance

Aminoglutethimide t 1/2, clearance

Mexiletine­ t 1/2, clearance

Serotonin reuptake inhibitors (e.g., fluvoxamine t 1/2, clearance

Ranitidine, thiabendazole clearance

Nifedipine, verapamil plasma levels

Effect of Theophylline on Certain Drugs

Drug Effects

Digitalis glycosides – cardiac effect

Thiazides – diuresis

Nephrotoxic drugs – nephrotoxicity

Lithium – ratio of lithium/creatinine clearance, thus decrease serum lithium

Sympathomimetic amines – toxicity, ­CNS stimulation

Coumarin anticoagulants – anticoagulant activity, increase prothrombin and fibrinogen blood concentrations, shorten prothrombin time

Allopurinol – antihyperuricemic action

Probenecid and pyrazolon – uricosuric action

Ketamine – threshold value for inducing convulsions

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, cardiac 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. In rare cases, theophylline has been reported to adversely affect the behavior and school performance of children.

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

Respiratory: tachypnea.

Renal: albuminuria, diuresis, hematuria.

Others: exanthema, urticaria, hyperglycemia, inappropriate ADH syndrome.

Symptoms And Treatment Of Overdose:

Symptoms: Insomnia, restlessness, mild excitement or irritability, and rapid pulse are the 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: A.Monitoring Serum Theophylline Levels: Following intake of Theo-Dur, the blood theophylline peak levels may not show until 5 to 8 hours post-ingestion in adults and 4 to 6 hours in children. Patients ingesting overdoses of sustained-release theophylline formulations may have, after the initial rise in blood theophylline, also a secondary increase in theophylline levels. One report on fatal self-poisoning has attributed this to compacted tablet masses in the gastrointestinal tract. Careful clinical and laboratory monitoring of stabilized patients is advisable.

B. 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.

C. If patient is having a seizure: Establish an airway. Administer oxygen. Treat the seizure with i.v. diazepam, 0.1 to 0.3 mg/kg up to a total dose of 10 mg. Monitor vital signs, maintain blood pressure and provide adequate hydration.

D. Post-seizure Coma: Maintain airway and oxygenation. If a result of oral medication, follow above recommendations to prevent drug absorption, but intubation and lavage will have to be performed instead of inducing vomiting, 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, if serum levels exceed 257 mol/L (50 mg/L), charcoal hemoperfusion may be indicated.

Dosage And Administration:

Therapeutic serum levels are generally considered to be between 55 and 110 mol/L (10 and 20 mg/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 4 to 8 hours after Theo-Dur dosing. It should be ascertained that all doses have been taken for 60 hours prior to blood sampling (steady state is usually achieved within 3 days). 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.

Theo-Dur tablets should not be chewed or crushed but may be halved.

Adults: The usual initial dose is 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 450 mg every 12 hours or higher (900 mg/day) should not be given unless serum theophylline concentration can be monitored. It should not be necessary to exceed a daily dose of 16 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.

Children: The usual initial dose (age 6 to 12 years) is 6 mg/kg given every 12 hours (12 mg/kg/day).

If the desired response is not obtained after 3 days, and there are no adverse effects, dosage may be increased to 8 mg/kg every 12 hours (16 mg/kg/day). This dose should be considered the maximum unless serum theophylline concentrations can be monitored to guide further dose increases.

If serum concentrations are monitored, and there are no adverse effects, the dosage may be increased by 2 to 3 mg/kg/day at intervals of not less than 3 days, until the desired response is obtained, or until side effects appear. It should not be necessary to exceed a daily dose of 21 mg/kg to obtain an adequate response in children. Even with serum theophylline concentration monitoring, this dose (21 mg/kg/day) may lead to side effects because of day-to-day variations of blood levels within individual patients.

Dividing the daily dosage into 3 doses administered at 8-hour intervals may be indicated if symptoms repeatedly occur at the end of 12 hour dosing intervals.

Availability And Storage:

100 mg: Each white, round, biconvex, sustained-release tablet, engraved on one side and scored in the transverse direction on the opposite side, contains: anhydrous theophylline 100 mg. Nonmedicinal ingredients: acacia, cellulose acetate phthalate, cetyl alcohol, cornstarch, diethyl phthalate, glycerol monostearate, lactose powder, magnesium stearate, myristyl alcohol, nonpareil seeds, sodium lauryl sulfate, sucrose, talc and white wax. Energy: 0.42 kJ (0.1 kcal). Gluten- and tartrazine-free. Bottles of 100.

200 mg: Each white, slightly convex, sustained-release, elliptical tablet with bevelled edges, engraved on one side and scored in the transverse direction on the opposite side, contains: anhydrous theophylline 200 mg. Nonmedicinal ingredients: cellulose acetate phthalate, cetyl alcohol, diethyl phthalate, glycerol monostearate, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, myristyl alcohol, nonpareil seeds and white wax. Energy: 0.84 kJ (0.2 kcal). Gluten-, sodium- and tartrazine-free. Bottles of 100 and 500.

300 mg: Each white, biconvex, staff-shaped, sustained-release tablet, with parallel sides and rounded ends, engraved on one side and scored in the transverse direction on the opposite side, contains: anhydrous theophylline 300 mg. Nonmedicinal ingredients: cellulose acetate phthalate, cetyl alcohol, diethyl phthalate, glycerol monostearate, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, myristyl alcohol, nonpareil seeds and white wax. Energy: 1.26 kJ (0.3 kcal). Gluten-, sodium- and tartrazine-free. Bottles of 100 and 500.

450 mg: Each white, biconvex, staff-shaped, sustained-release tablet, with parallel sides and rounded ends, engraved on one side and scored in the transverse direction on the opposite side, contains: anhydrous theophylline 450 mg. Nonmedicinal ingredients: cellulose acetate phthalate, cetyl alcohol, diethyl phthalate, glycerol monostearate, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, myristyl alcohol, nonpareil seeds and white wax. Energy: 1.89 kJ (0.45 kcal). Gluten-, sodium- and tartrazine-free. Bottles of 100.

THEO-DUR® AstraZeneca Theophylline Bronchodilator

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