Aminophylline (Page 7 of 8)

Specific Recommendations:

  • Acute Overdose
    1. Serum Concentration >20<30 mcg/mL
      1. Administer a single dose of oral activated charcoal.
      2. Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
    2. Serum Concentration >30<100 mcg/mL
      1. Administer multiple dose oral activated charcoal and measures to control emesis.
      2. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
      3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal).
    3. Serum Concentration ≥100 mcg/mL
      1. Consider prophylactic anticonvulsant therapy.
      2. Administer multiple-dose oral activated charcoal and measures to control emesis.
      3. Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal).
      4. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Chronic Overdosage
    1. Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity)
      1. Administer a single dose of oral activated charcoal.
      2. Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
    2. Serum Concentration >30 mcg/mL in patients <60 years of age
      1. Administer multiple-dose oral activated charcoal and measures to control emesis.
      2. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
      3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal).
    3. Serum Concentration >30 mcg/mL in patients ≥60 years of age.
      1. Consider prophylactic anticonvulsant therapy.
      2. Administer multiple-dose oral activated charcoal and measures to control emesis.
      3. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal).
      4. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal:

Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

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 V). 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 (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI). 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.

Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI 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 V. Dosing initiation and titration ╖ [*Aminophylline equivalent in (*)]

╖ Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.

A. Children (1-15 years) and adults (16-60 years) without risk factors for impaired clearance.
Titration Step Children < 45 kg Children > 45 kg and adults
1. Starting Dosage 12-14 (*15.2-17.7) mg/kg/day up to a maximum of 300 (*380)mg/day divided Q4-6 hrs ╖ 300 (*380) divided Q6-8 hrs ╖
2. After 3 days, if tolerated,, increase dose to: 16 (*20.3) mg/kg/day up to a maximum of 400 (*507) mg/day divided Q4-6 hrs ╖ 400 (*507) mg/day divided Q6-8 hrs ╖
3. After 3 more days, if tolerated.increase dose to: 20 (*25.3) mg/kg/day up to a maximum of 600 mg (*760) mg/day divided Q4-6 hrs ╖ 600 (*760) mg/day divided Q6-8 hrs ╖

B. 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 final theophylline dose should not exceed 16 (*20.3) mg/kg/day up to a maximum of 400 (*507) 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 ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 (*507) 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.

C. 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.3, or B., above, should be utilized and serum theophylline concentration monitored at 24 hour intervals to adjust final dosage.

Table VI. Dosage adjustment guided by serum theophylline concentration.

¶ 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).

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% eyen 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.

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