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Theophylline dosing
I. Introduction
Theophylline was once the cornerstone in the management of both the acute
and chronic phases of reversible airway obstruction. However, it has
fallen out of favor and is seldom used these days. One reason may be that it
has a narrow therapeutic index. Fortunately, theophylline serum
levels correlate well with both therapeutic and toxic effects.
Concentrations of 10-20 mg/l are needed to produce bronchodilation
with a minimum of side effects. Serum levels exceeding 20 mg/l
are associated with an unacceptable incidence of adverse reactions.
Theophylline levels above 35 mg/l increase the incidence of seizures
and cardiac arrythmias.
The clearance of theophylline is affected by many variables which
necessitate carefully individualized dosage. Age, smoking,
congestive heart failure, other diseases and drug interactions all
contribute to a change in the metabolism of theophylline. These
factors all necessitate dosage adjustments in order to achieve
and maintain therapeutic serum levels and avoid toxicity.
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So wide is the variation in clearance rates that no dose which will
produce effective levels of theophylline in most patients will fail
to produce toxic levels in a few. Serum theophylline measurements
are essential for accurate dosage adjustment.
There have been clinical reports suggesting dose-dependent
elimination of theophylline in some patients, especially at the
higher end of the therapeutic range and most obviously at concentrations
greater than 20 mg/l. For these patients, small increases in
doses may result in dramatic increases in serum concentrations.
Such patients have not been well characterized. Therefore, to
minimize the risk of toxicity, doses of theophylline should be
increased cautiously, especially at the upper levels of the therapeutic
range.
II. Monitoring Parameters
- An accurate and thorough patient history is essential for proper
dosing of theophylline.
Take special note the following conditions:
- Smoking history
- Previous theophylline therapy
- CHF or other serious cardiac disease
- Hepatic disease
- Drug interactions: macrolide antibiotics, quinolones, cimetidine.
- Serum theophylline level monitoring
- If the patient has taken a theophylline product
within the previous 24 hours, obtain a level before administering
any IV theophylline.
- Monitoring IV theophylline
Obtain theophylline levels at 1, 7 and 24 hours after
initiating IV therapy and every 24 hours while receiving IV theophylline.
- Monitoring oral theophylline
When initiating oral therapy obtain theophylline levels daily until stable.
- Other monitoring parameters
- pulse and blood pressure four times a day
- Signs of toxicity daily (nausea, insomnia, etc.)
- The traditional therapeutic range of theophylline has been
10 to 20 mcg/ml, however there is recent trend to lower the
target range to 5 to 15 mcg/ml. This lower target range may be
especially suited to outpatients in order to avoid potential
toxicity.
III. Precautions
- Adjust dosage carefully
Theophylline has a relatively long half-life in certain
patient populations (the elderly and CHF patients), consequently
it may take several days to reach steady state. Dosage increases
should be made with caution. The patient must be followed closely
for signs of toxicity.
- Proper serum sampling is important when monitoring
oral theophylline. Suggested serum sampling times:
- Rapid release: at least 2 hours post dose.
- Slow release : at least 4 hours post dose.
- Factors affecting theophylline elimination
- Hepatic disease
Patients with decompensated cirrhosis, acute hepatitis,
and, possible, cholestasis have reduced theophylline clearance.
A correlation between slow hepatic metabolism and serum albumin
and bilirubin concentration has been made in patients with cirrhosis.
- Cardiac disease
Patients with CHF have decreased theophylline clearance
due to diminished blood flow to the liver. With treatment of CHF,
theophylline clearance increases.
- Fever
Acute illnesses associated with fever have been reported
to prolong theophylline half-life. If fever is high and sustained,
e.g., >102 for >24 hours, dosage should be reduced.
- Diet
Ingestion of a high protein, low carbohydrate diet
accelerates theophylline metabolism presumably by increasing liver
enzyme activity. Dietary intake of methylxanthines, caffeine in
particular, decreases theophylline metabolism by acting as a substrate
for metabolizing enzymes.
- Cigarette smoking
Smoking of cigarettes has a profound effect on theophylline
metabolism. There is a dose-related increase in theophylline
clearance, with heavy smokers metabolizing theophylline twice
as fast as nonsmokers.
- Drug interactions are of major clinical importance
Cimetidine, macrolide antibiotics, and quinolones
significantly decrease theophylline metabolism.
Phenytoin, phenobarbital, and rifampin significantly
increase theophylline metabolism.
- Age
Most studies report slower clearance in the elderly.
IV. Program procedure
Before calculating an initial dose or adjusting the maintenance
dose the program must know the dosage form, whether the patient
is in acute congestive failure and whether any interacting drugs
are being concurrently administered.
- Initial dosing
The program calculates an ideal loading dose and maintenance dose
based on lean body weight and the presence or absence of various
factors which affect theophylline metabolism. The user then chooses a
practical dose and the program calculates an estimated steady-state
serum level.
- Dosage adjustment based on serum levels
For IV dosage adjustment, the program utilizes either
the linear method or the Chiou method. For oral dosage adjustment,
only the linear method may be used. The program checks against
population averages to see if the most recent serum level is drawn
at steady-state. If the patient is not close to steady-state, the
program will utilize the alternate method of dosing which gives more
conservative dosage recommendations.
V. Theophylline dosing flow chart

VI. Pharmacokinetic formulas
The theophylline model is not hard-coded into the program. The parameters are
found in the drug model database and are fully user-editable. You can
tailor each drug model to fit your patient population, or you can create
your own models. See the Edit drug models
section of the help file for further information.
- Initial dosing
- Determine loading dose of IV aminophylline.
- No theophylline within 24 hrs = 6 mg/kg LBW
- Any theophylline within 24 hrs = 3 mg/kg LBW
- If theophylline is selected, multiply by 0.8
- Determine initial maintenance dose of IV aminophylline, using LBW.
ko = 0.5 x LBW x Smoking x Age factor x CHF/Liver x Drug factor
Factors
- Smoker = 1.5
- Age > 70 = 0.8
- Acute CHF or Liver failure = 0.6
- Interacting drugs = 0.75
- If theophylline is selected, multiply by 0.8
- Dosage adjustment before Steady State
- Chiou Method
Two serum levels are required, the first level drawn
one hour after the constant infusion started, and the second drawn
at least one half-life later. The rate of infusion must be constant
during the time between the two levels and the patient should
not have received any oral theophylline 6 to 12 hours prior to
the IV dose.
- Calculate Clearance (CL)
CL = [(2 x ko) / (Cp1 + Cp2)] + [(2 x Vd x (Cp1 - Cp2)) / (Cp1 + Cp2) x (t2 -t1)]
where ko = administration rate (mg/hr)
Cp1 = level (mg/l) drawn 1 hour after start of infusion
Cp2 = level (mg/l) 6 hours later
Vd = 0.5 l/kg LBW
t1 = time Cp1 drawn
t2 = time Cp2 drawn
- Calculate Incremental Loading Dose (ILD) OR Temporary Interruption (TI)
- If Cpdes > 1.5 x Cpmeas then calculate Incremental Loading Dose
ILD = [Cpdes - Cpmeas] x Vd
- If Cpdes < 0.8 x Cpmeas then calculate Temporary Interruption
TI = -[ln Cpdes / Cpmeas ] / Ke
- Determine new infusion rate (ko')
ko' = Cpdes x CL
where ko' = new rate (mg/hr)
Cpdes= desired level (mg/l)
CL = clearance (l/hr)
- Alternate method
If serum level data does not meet the strict conditions
required for the Chiou method, the following general dosage recommendations
are made:
- >20 mg/l: Temporary Interruption and decrease infusion rate by 20%.
- 10-20 mg/l: Continue same.
- <10 mg/l: Calculate incremental loading dose then increase infusion rate by 20%.
- Dosage adjustment at Steady State
- Calculate Clearance (CL)
CL = ko / Cpss
where: ko = administration rate (mg/hr)
Cpss= steady state level (mg/l)
- Calculate Incremental Loading Dose (ILD) OR Temporary Interruption (TI)
-Same as above
- Determine new infusion rate (ko')
-Same as above
- Converting IV therapy to oral Theo-Dur
Daily dose = Cpdes x (CL x 24 hr)
where CL = Clearance (l/hr)
Cpdes = desired level (mg/l)
- Converting from oral Theo-Dur to IV therapy
- Calculate Clearance (CL)
CL = (Daily Dose/24) / Cpss
where: Daily dose = mg/day of theophylline
Cpss = steady state level (mg/l)
- Calculate Incremental Loading Dose (ILD) OR Temporary Interruption (TI)
-Same as above
- Determine new infusion rate (ko')
-Same as above
VII. Bibliography
- Mitenko P, Ogivie R. Rational intravenous doses
of theophylline. N Engl J Med 1973;289:600-603.
- Lesko LJ. Dose-dependent elimination kinetics
of theophylline. Clin Pharmacokinetics 1979;4:449-459.
- Hendeles L, Weinberger M. Theophylline: a state
of the art review. Pharmacotherapy 1983: 3:2-44.
- Mungall DE, et al. Individualizing theophylline
therapy: the impact of a clinical pharmacotherapeutics on patient
outcome: Ther Drug Monit 1983; 5:95-101.
- Iafrate RP, et al. Computer simulated conversion
from intravenous to sustained release oral theophylline. DICP
1982;16:19-25.
- Stein GE, et al. Conversion from intravenous
to oral dosing using sustained-release theophylline tablets. DICP
1982;16:772-774.
- Coleman RW, Hedberg RL. Comparison of three methods
for estimating theophylline pharmacokinetics. Clin Pharm 1983;2:148-52.
- Hatton RC, et al. Conversion from intravenous
aminophylline to sustained-release theophylline: computer simulation
versus in vivo results. Clin Pharm 1983; 2:347-352.
- Dunn G, Rybak MJ. Nonlinear theophylline kinetics
(letter). DICP 1984;18:155.
- Johnson MH, Burkle WS. Evaluation of Chiou
method for determining theophylline dosages. Clin Pharm 1984;
3:174-8.
- Hendeles L, et al. Update on pharmacodynamics
and pharmacokinetics of theophylline. Chest 1985; 88:10S-111S.
- Ellis E, Hendeles L. "Theophylline",
in Taylor WJ, Caviness MH (eds): A Textbook for the Clinical Application
of Therapeutic Drug Monitoring. Irving, Texas. Abbott Laboratories,
1986; pp. 185-201.
- Hendeles L, et al. "Theophylline" In: Applied
Pharmacokinetics, Second Edition. Spokane, WA: Applied
Therapeutics, Inc., 1986. pp 1105-1188.
- Leoni J, Carasiti ME. Practical guidelines for
intravenous theophylline dosing. Res Staff Physician 1987;Oct
153-155.
- Donahue T, et al. Pharmacist-based IV theophylline
therapy. Hosp Pharm 1989;24:440-448,460.
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