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Pulmonary - Aminophylline and Theophylline

Aminophylline Theophylline

aminophylline  top of page icon

Aminophylline is a 2:1 complex of theophylline and ethylenediamine. Theophylline is structurally classified as a methylxanthine. Aminophylline occurs as a white or slightly yellowish granule or powder, with a slight ammoniacal odor.

INDICATIONS AND USAGE
Intravenous theophylline is 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
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 four-fold 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 I). 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 I contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table II 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 I. Initial aminophylline infusion rates following an appropriate loading dose.
Patient population Age Aminophylline infusion rate (mg/kg/hr)*†
Neonates Postnatal age up to 24 days 1.27 mg/kg q 12h (1.0 mg/kg q 12h)*‡
Postnatal age beyond 24 days 1.90 mg/kg q 12h (1.5 mg/kg q 12h)*‡
Infants 6-52 weeks old mg/kg/hr=([0.008][age in weeks] + 0.21)/0.79 ([0.008][age in weeks]+0.21)*
Young children 1-9 years 1.01 mg/kg/hr (0.8 mg/kg/hr)*
Older children 9-12 years 0.89 mg/kg/hr (0.7 mg/kg/hr)*
Adolescents (cigarette or marijuana smokers) 12-16 years 0.89 mg/kg/hr (0.7 mg/kg/hr)*
Adolescents (nonsmokers) 12-16 years 0.63 mg/kg/hr (0.5 mg/kg/hr)*§
Adults (otherwise healthy nonsmokers) 16-60 years 0.51 mg/kg/hr (0.4 mg/kg/hr)*§
Elderly > 60 years 0.38 mg/kg/hr (0.3 mg/kg/hr)*||
Cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multi- organ failure, or shock 0.25 mg/kg/hr (0.2 mg/kg/hr)*||

* Equivalent Theophylline Dosage Indicated in Parenthesis

† 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 II. 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.
>30 mcg/mL Stop the infusion and treat overdose as indicated. 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.

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

HOW SUPPLIED
Aminophylline Injection, USP (25 mg/mL) is available as follows:

NDC 0517-3810-25 10 mL Single Dose Vial
250 mg/10 mL (25 mg/mL) Packed in boxes of 25

NDC 0517-3820-25 20 mL Single Dose Vial
500 mg/20 mL (25 mg/mL) Packed in boxes of 25

Theophylline  top of page icon

Mechanism of Action:
Theophylline has two distinct actions in the airways of patients with reversible obstruction: smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.


DOSAGE AND ADMINISTRATION - (Extended-release tablets)

Taking theophylline extended-release tablets immediately after a high-fat content meal may result in a somewhat higher Cmax and delayed Tmax, and somewhat greater extent of absorption. However, the differences are usually not great and this product may normally be administered without regard to meals.

Theophylline extended-release tablets are recommended for chronic or long-term management and prevention of symptoms, and not for use in treating acute symptoms of asthma and reversible bronchospasm.


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 (see Table I). 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. Dosage adjustment should be guided by serum theophylline concentration measurement. 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.

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements, 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.

Table I contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table II contains recommendations for 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 I. Dosing initiation and titration (as anhydrous theophylline).*
Children (6-15 years) and adults (16-60 years) without risk factors for impaired clearance.
Titration Step
1. Starting Dosage
Children <45 kg 12-14 mg/kg/day up to a maximum of 300 mg/day divided Q12 hrs* Children >45 kg and adults 300 mg/day divided Q12 hrs*
2. After 3 days, if tolerated. increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q12 hrs* 400 mg/day divided Q12 hrs*
3. After 3 more days, if tolerated. increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided Q12 hrs* 600 mg/day divided Q12 hrs*

* Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 8 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.


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 6-15 years of age, the final 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 or if it is not feasible to monitor serum theophylline concentrations.

In adolescents greater than or equal16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance or if it is not feasible to monitor serum theophylline concentrations.

Table II. 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 dose about 25%. Recheck serum concentration after three days for further dosage adjustment.
10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month 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 dose to provide greater margin of safety even if current dosage is tolerated.*
20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment.
25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage).
>30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days 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

 Once-Daily Dosing: The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers with appropriate total body clearance and other patients with low dosage requirements. Once-daily dosing should be considered only after the patient has been gradually and satisfactorily titrated to therapeutic levels with q12h dosing. Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval. The trough concentration (Cmin) obtained following conversion to once-daily dosing may be lower (especially in high clearance patients) and the peak concentration (Cmax) may be higher (especially in low clearance patients) than that obtained with q12h dosing. If symptoms recur, or signs of toxicity appear during the once-daily dosing interval, dosing on the q12h basis should be reinstituted.

It is essential that serum theophylline concentrations be monitored before and after transfer to once-daily dosing.

Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates of theophylline from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended that theophylline extended-release once-daily dosing be administered at night.

HOW SUPPLIED
Theophylline Extended-release Tablets:

100 mg - White, round, bisected tablets in bottles of 100 and 500.
Debossed: PLIVA 483

200 mg - White, oval-shaped, bisected tablets in bottles of 100, 500 and 1000.
Debossed: PLIVA 482

300 mg - White, capsule-shaped, bisected tablets in bottles of 100, 500 and 1000.
Debossed: PLIVA 459

450 mg - White, capsule-shaped, bisected tablets in bottles of 100, 250 and 500.
Debossed: PLIVA 518

Dispense in a well-closed container as defined in the USP.
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].
Manufactured by: PLIVA® Inc., Pomona, NY 10970
Distributed by: Barr Laboratories, Inc., Pomona, NY 10970
Revised FEBRUARY 2007


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