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Intravenous Dilution Guidelines

Aminophylline

The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

D5W, NS

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Loading dose:
[0 - 250mg] [50ml] [30 minutes] or
[251-500 mg] [ 100 ml ] [30 minutes]

Continuous infusion:
[500 mg] [500 ml] [Titrate]

Fluid Restricted:
[500 mg] [250 ml] [Titrate]

Stability / Miscellaneous

EXP: 1 day (RT). Maximum rate: 0.36 mg/kg/minute, and no greater than 25 mg/minute. I.M. administration is not recommended.

DOSAGE AND ADMINISTRATION
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 (5.7 mg/kg as aminophylline), calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a 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 (0.5 mg/kg/hr as aminophylline) 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 (5.7 mg/kg as aminophylline) followed by a constant intravenous infusion of 0.8 mg/kg/hr (1.0 mg/kg/hr as aminophylline). 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 the concentration is accumulating or declining from the post loading dose level. If the level is declining 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 taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr (21 mg/hr as aminophylline) 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

Postnatal age beyond 24 days

1 mg/kg q12h/‡

1.5 mg/kg q12h/‡

Infants 6-52 weeks old mg/kg/hr= (0.008)(age in weeks) + 0.21
Young children 1-9 years 0.8
Older children 9-12 years 0.7
Adolescents

(cigarette or marijuana

smokers)

12-16 years 0.7
Adolescents (nonsmokers) 12-16 years 0.5 §
Adults

(otherwise healthy

nonsmokers)

16-60 years 0.4 §
Elderly > 60 years 0.3 i
Cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock   0.2 i
     
* 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.
i 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 children 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 hour intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen.
15-19.9 mcg/mL Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶
20-24.9 mcg/mL Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment.
25-30 mcg/mL Stop infusion for 12 hours in children and 24 hours in adults and decrease subsequent infusion rate at least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in children and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated (see package insert for recommendations for chronic overdosage).

 

> 30 mcg/mL Stop the infusion and treat overdose as indicated (see package insert for recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in children 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 package insert for WARNINGS).


Pharmacokinetics
:

Overview The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients.

It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients receiving intravenous theophylline (e.g., at 24-hr. intervals). More frequent measurements should be made during the initiation of therapy and in the presence of any condition that may significantly alter theophylline clearance.

Table I. Mean And Range Of Total Body Clearance And Half-Life Of Theophylline Related To Age And Altered Physiological States¶
Population Characteristics

Age

Total Body Clearance*

mean (range)††

(mL/kg/min)

Half-Life

mean (range)††

(hr)

Premature neonates

postnatal age 3 - 15 days

postnatal age 25 - 57 days

0.29 (0.09 - 0.49)

0.64 (0.04 - 1.2)

30 (17 - 43)

20 (9.4 - 30.6)

Term infants

postnatal age 1 - 2 days

postnatal age 3 - 30 weeks

NR† 

NR†

25.7 (25 - 26.5)

11 (6 - 29)

Children

1 - 4 years

4 - 12 years

13 - 15 years

6 - 17 years

1.7 (0.5 - 2.9)

1.6 (0.8 - 2.4)

0.9 (0.48 - 1.3)

1.4 (0.2 - 2.6)

3.4 (1.2 - 5.6)

NR†

NR†

3.7 (1.5 - 5.9)

Adults (16 - 60 years)

otherwise healthy

nonsmoking asthmatics

0.65 (0.27 - 1.03) 8.7 (6.1 - 12.8)
Elderly (> 60 years)

nonsmokers with normal cardiac,

liver, and renal function

0.41 (0.21 - 0.61) 9.8 (1.6 - 18)
Concurrent Illness Or Altered Physiological State  
Acute pulmonary edema 0.33** (0.07 - 2.45) 19** (3.1 - 8.2)
COPD- > 60 years, stable

nonsmoker> 1 year

0.54 (0.44 - 0.64) 11 (9.4 - 12.6)
COPD with cor pulmonale 0.48 (0.08 - 0.88) NR†
Cystic fibrosis (14 - 28 years) 1.25 (0.31 - 2.2) 6 (1.8 - 10.2)
Fever associated with acute viral respiratory  
illness (children 9 - 15 years) NR† 7 (1.0 - 13)
Liver disease - cirrhosis

acute hepatitis

cholestasis

0.31** (0.1 - 0.7)

0.35 (0.25 - 0.45)

0.65 (0.25 - 1.45)

32** (10 - 56)

19.2 (16.6 - 21.8)

14.4 (5.7 - 31.8)

Pregnancy - 1st trimester

2nd trimester

3rd trimester

NR†

NR†

NR†

8.5 (3.1 - 13.9)

8.8 (3.8 - 13.8)

13 (8.4 - 17.6)

Sepsis with multi-organ failure 0.47 (0.19 - 1.9) 18.8 (6.3 - 24.1)
Thyroid disease - hypothyroid

hyperthyroid

0.38 (0.13 - 0.57)

0.8 (0.68 - 0.97)

11.6 (8.2 - 25)

4.5 (3.7 - 5.6)

¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.
* Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations, < 20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to nonlinear pharmacokinetics.
†† Reported range or estimated range (mean ± 2 SD) where actual range not reported.
† NR = not reported or not reported in a comparable format.
** Median

Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.

Store at controlled room temperature 15° to 30°C (59° to 86°F). [See USP.] PROTECT FROM LIGHT. Store in carton until time of use. SINGLE-DOSE CONTAINER. Discard unused portion.

Source: ©Hospira 2004 EN-0207 Printed in USA HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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