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Theophylline in 5% Dextrose

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Theophylline 5% Dextrose Injection Excel

INDICATIONS

Theophylline in 5% Dextrose Injections USP are indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

DOSAGE AND ADMINISTRATION

These solutions are for intravenous use only.

General Considerations

The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a 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. 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. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:

C=LD/V

If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration.

Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:

D=(Desired C-Measured C) (V)

Where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours.

A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/kg/hr. Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient's clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; see Table I for the expected half-life in additional patient populations) to determine if theconcentration is accumulating or declining from the post loading dose level. If the level isdeclining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient's course.

In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those aking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.

Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon 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.

Table V. Initial theophylline infusion rates following an appropriate loading dose.

Patient population Age Theophylline infusion rate
(mg/kg/hr)*†
Neonates Postnatal age up to 24 days 1 mg/kg q12h/‡
Postnatal age beyond 24 days 1.5 mg/kg q12h/‡
Infants 6-52 we eks old mg/kg/hr=(0.008) (age in weeks) + 0.21
Young children 1-9 years 0.8
Older children 9-12 ye ars 0.7
Adolescents or marijuana 12-16 years 0.7
Adolescents 12-16 years 0.5
Adults (otherwise healthy nonsmokers) 16-60 years 0.4§
ElderlyCardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multi-organ failure, or shock > 60 years 0.3¶
0.2¶
* To achieve a target concentration of 10 mcg/mL. Aminophylline = theophylline/0.8. Use ideal body weight for obese patients.
† Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine).
‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea.
§ Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose.
¶ Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose.

Table VI. Final dosage adjustment guided by serum theophylline concentration.

Peak Serum Concentration Dosage Adjustment
< 9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase infusion rate about 25%. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults for further dosage adjustment.
10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24 hours intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.
15-19.9 mcg/m L Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶
20-24.9 mcg/m L Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment.
25-30 mcg/mL Stop infusion for 12 hours in pediatric patients and 24 hours in adults and decrease subsequent infusion rate a least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated (see recommendations for Chronic Overdosage).
> 30 mc g/mL Stop the infusion and treat overdose as indicated (see recommendations for Chronic Overdosage). If theophylline is subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment.
¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Theophylline in 5% Dextrose Injections USP are supplied sterile and nonpyrogenic in EXCEL® Containers. The 1000 mL containers are packaged 12 per case; the 500 mL and 250 Ml containers are packaged 24 per case.

NDC Cat. No. Solution Total Dose/Volume
0264-9554-00 P5540 0.08% Theophylline in 800 mg/1000 mL
0264-9554-10 P5541 5% Dextrose Injection USP 400 mg/500 mL
0264-9558-10 P5581 0.16% Theo phylline in 800 mg/500 mL
0264-9558-20 P5582 5% Dextrose Injection USP 400 mg/250 mL

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product.

Directions for Use of EXCEL® Container

Do not admix with other drugs.

Caution: Do not use plastic container in series connection.

To Open

Tear overwrap down at notch and remove solution container. Check for minute leaks by squeezing solution container firmly. If leaks are found, discard solution as sterility may be impaired.

NOTE: Before use, perform the following checks:

Inspect each container. Read the label. Ensure solution is the one ordered and is within the expiration date.

Invert container and carefully inspect the solution in good light for cloudiness, haze, or particulate matter. Any container which is suspect should not be used.

Use only if solution is clear and container and seals are intact.

Preparation for Administration

  1. Remove plastic protector from sterile set port at bottom of container.
  2. Attach administration set. Refer to complete directions accompanying set.

Revised: November 2007. EXCEL is a registered trademark of B. Braun Medical Inc. B. Braun Medical Inc., Irvine, CA USA 92614-5895. FDA rev date: 04/08/08

Last reviewed on RxList: 8/28/2008
This monograph has been modified to include the generic and brand name in many instances.

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