Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Immediate Release Oral Products

General Considerations

The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/ml range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/ml in about 30% of patients, 10-20 mcg/ml in about 50% and 20-30 mcg/ml in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose,if judged to be clinically indicated, in small increments. Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Final dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and TABLE 5.) Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS).

If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours.

Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

The following list contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. TABLE 5 contains recommendations for final theophylline dosage adjustment based on serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration.

A. Infants <1 year old.

1. Initial Dosage.

a. Premature Neonates:

<24 days postnatal age; 1.0 mg/kg every 12 hr
³24 days postnatal age; 1.5 mg/kg every 12 hr



b. Full term infants and infants up to 52 weeks of age:

2. Total daily dose (mg) = [(0.2 × age in weeks)+5.0] × (Kg body Wt).

up to age 26 weeks; divide dose into 3 equal amounts administered at 8 hour intervals.
>26 Weeks of age; divide dose into 4 equal amounts administered at 6 hour intervals.

Final Dosage: Adjusted to maintain a peak steady-state serum theophylline concentration of 5-10 mcg/ml in neonates and 10-15 mcg/ml in older infants (see TABLE 5) Since the time required to reach steady-state is a function of theophylline half-life, up to 5 days may be required to achieve steady-state in a premature neonate while only 2-3 days may be required in a 6 month old infant without other risk factors for impaired clearance in the absence of a loading dose. If a serum theophylline concentration is obtained before steady-state is achieved, the maintenance dose should not be increased, even if the serum theophylline concentration is < 10 mcg/ml.

Children (1-15 years) and adults (16-60 years) without risk factors for impaired clearance.

TABLE 4 - Dosing titration (as anhydrous theophylline).*^,†

Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations

In children 1-15 years of age, the initial theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ³16 years and adults, including the elderly, the initial theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.

Loading Dose for Acute Bronchodilatation

An inhaled beta-2 selective agonist, alone or in combination with a systemically administered corticosteroid, is the most effective treatment for acute exacerbations of reversible airways obstruction. Theophylline is a relatively weak bronchodilator, is less effective than an inhaled beta-2 selective agonist and provides no added benefit in the treatment of acute bronchospasm. If an inhaled or parenteral beta agonist is not available, a loading dose of an oral immediate release theophylline can be used as a temporary measure. A single 5 mg/kg dose of theophylline, in a patient who has not received any theophylline in the previous 24 hours, will produce an average peak serum theophylline concentration of 10 mcg/ml (range 5-15 mcg/ml). If dosing with theophylline is to be continued beyond the loading dose, the guidelines in Sections A.1.b., B.3, or C., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.

TABLE 5 - Final dosage adjustment guided by serum theophylline concentration.

Sustained Action Capsules

Sprinkling Contents on Food

Theo-Dur Sprinkle may be administered by carefully opening the capsule and sprinkling the beaded contents on a spoonful of soft food such as applesauce or pudding. The soft food should be swallowed immediately without chewing and followed with a glass of cool water or juice to ensure complete swallowing of the beads. It is recommended that the food used should not be hot and should be soft enough to be swallowed without chewing. Any bead/food mixture should be used immediately and not stored for future use. The small amount of food (one spoonful) used to administer the dose will not alter the bioavailability of Theo-Dur Sprinkle; however, the dosing should be at least 1 hour before or 2 hours after a meal. SUBDIVIDING THE CONTENTS OF A CAPSULE IS NOT RECOMMENDED.

Dosage Guidelines

Because administration of Theo-Dur Sprinkle at the time of food ingestion has been shown to result in significantly lower peak-serum concentrations and reduced extent of absorption (bioavailability). patients should be instructed to take this medication at least 1 hour before or 2 hours after a meal (see DRUG INTERACTIONS).

Taking Theo-Dur Sprinkle at 12-hour intervals under the above restrictive recommendations in regard to food ingestion may be difficult for the patient to follow. Under such circumstances, consideration should be given to prescribing this drug every 8 hours (giving one-third of the 24-hour dosage requirement with each dose), if this regimen would more easily permit dosing under fasting conditions.

Acute Symptoms

NOTE:Status asthmaticus should be considered a medical emergency and is defined as that degree of bronchospasm which is not rapidly responsive to usual doses of conventional bronchodilators. Optimal therapy for such patients frequently requires both additional medication,Parenterally administered, and close monitoring, preferably in an intensive care setting. Theo-Dur Sprinkle is not intended for patients experiencing an acute episode of bronchospasm (associated with asthma, chronic bronchitis, or emphysema). Such patients require rapid relief of symptoms and should be treated with an immediate release or intravenous theophylline preparation (or other bronchodilators) and not with controlled-release products.

Chronic Therapy

Initiating Therapy with an Immediate-Release Product: It is recommended that the appropriate dosage be established sing an immediate-release preparation. Children weighing less than 25 kg should have their daily dosage requirements established with a liquid preparation to permit small dosage increments. Slow clinical titration is generally preferred to help assure acceptance and safety of the medication, and to allow the patient to develop tolerance to transient caffeine-like side effects. Then, if the total 24-hour dose can be given by use of the sustained-release product, the patient can usually be switched to Theo-Dur Sprinkle, giving one-half of the daily dose at 12-hour intervals. Patients who metabolize theophylline rapidly such as the young, smokers, and some nonsmoking adults, are the most likely candidates for dosing at 8-hour intervals. Such patients can generally be identified as having trough-serum concentrations lower than desired for repeatedly exhibiting symptoms near the end of a dosing interval.

Initiating Therapy with Theo-Dur Sprinkle: Alternatively, therapy can be initiated with Theo-Dur Sprinkle since it is available in dosage strengths which permit titration and adjustments of dosage in adults and older children: Initial Dose: 16 mg/kg/24 hours or 400 mg/24 hours (whichever is less) of anhydrous theophylline in 2 divided doses, 12-hour intervals. Increasing Dose: The above dosage may be increased in approximately 25% increments at 3-day intervals so long as the drug is tolerated; until clinical response is satisfactory or the maximum dose as indicated in Section III (below) is reached. The serum concentration may be checked at these intervals, but at a minimum, should be checked at the end of this adjustment period.

Maintenance Dose of Theophylline where the Serum Concentration is not Measured: See TABLE 5

WARNING: DO NOT ATTEMPT TO MAINTAIN ANY DOSE T.A. IS NOT TOLERATED

TABLE 6 - Sustained-Release Capsules Not to exceed the following:

Measurement of Serum Theophylline Concentrations During Chronic Therapy

If the above maximum doses are to maintained or exceeded, serum theophylline measurement is recommended. The serum sample should be obtained at the time of peak absorption: 1 to 2 hours after administration for immediate-release products and 5 to 10 hours after dosing for Theo-Dur Sprinkle. It is important that the patient will have missed no doses during the previous 48 hours and the dosing intervals will have been reasonably typical with no added doses during that time. DOSAGE ADJUSTMENT BASED ON SERUM THEOPHYLLINE CONCENTRATION MEASUREMENTS WHEN THESE INSTRUCTIONS HAVE NOT BEEN FOLLOWED MAY RESULT IN RECOMMENDATIONS T.A. PRESENT RISK OF TOXICITY TO THE PATIENT.

Final Adjustment of Dosage

Caution should be exercised for younger children who cannot complain of minor side effects. Those with cor pulmonale, congestive heart failure, and/or other liver disease may have unusually low dosage requirements and thus may experience toxicity at the maximum dose recommended above. It is important that no patient be maintained on any dosage that is not tolerated. In instructing patients to increase dosage according to the schedule above, they should be instructed not to take a subsequent dose if apparent side effects occur and to resume therapy at a lower dose once adverse effects have disappeared.

TABLE 7 - Sustained-Release Capsules

Dosage Adjustment after serum theophylline measurement.

No information provided.

Storage

Keep tightly closed. Store at controlled room temperature 15-30°C (59-86°F).

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