Clinical Use Of Theophylline In Asthma

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Although intravenous aminophylline has been standard treatment for status asthmaticus since the early 1940s, the value of aminophylline in the emergency room setting for acute asthma has been questioned recently. Various authors have suggested that theophylline adds little in terms of bronchodilator activity while increasing adverse effects when optimal therapy with aerosolized p-agonists have been given. In an early study of the use of intranenous theophylline in the treatment of acute asthma, theophylline was compared with subcutaneous epinephrine in an emergency department. The bronchodilator effect of theophylline was inferior to that achieved by the epinephrine. Subsequent studies have generally confirmed the observation that in acute asthma, the bronchodilator effect of aminophylline is less than that of optimal administration of aerosolized p2-agonists. However, published data support the addition of intravenous aminophylline in the treatment of patients who fail optimal aerosolized agonist and steroid therapy and who require hospital admission. For example, Pierson and associates showed clinical benefit and pulmonary function improvement in status asthmaticus in a double-blind study of intravenous aminophylline in children with status asthmaticus. An emergency department study of adults with acute airway obstructive disease showed a threefold decrease in hospital admission rates for subjects treated with aminophylline in comparison with placebo recipients. Sakamoto and colleagues reported on results of a study of intravenous aminophylline administration in 12 asthmatic patients with acute episodes varying from mild to moderate to severe. They found progressive improvement in FEV1 over the range of 5-15 |g/mL; the greatest bron-chodilator effect was observed in patients whose initial airway obstruction was of a lesser degree. The possible extrapulmonary effects of theophylline both in improving diaphragmatic function and delaying the onset of muscle fatigue are a useful additional benefit of theophylline administration. For intravenous therapy with aminophylline, some simple calculations can be used to determine the correct loading and maintenance therapy doses. In the case of drugs, like theophylline, that are distributed rapidly from the plasma to the tissues, there is a relationship among plasma concentration (Cp), dose (D) and volume of distribution (Vd) so that

If an average Vd of 0.5 L/kg is assumed, it is easy to determine that for each miligram per kilogram (ideal body weight) infused, there will be an increase of approx 2 |g/mL in peak plasma concentration. The loading dose (aminophylline) needed to achieve a given theophylline plasma concentration is determined as follows (in the following equations 0.8 is used in the denominator to correct for the fact that aminophylline is 80% theophylline):

Loading dose (D) = (Vd) [desired plasma concentration (Cp)]/0.8 (2)

In this equation, it is assumed that the patient has not previously been receiving theophylline. If theophylline has been taken on an outpatient basis, the loading dose should be reduced unless an immediate serum theophylline determination is available. Once the observed level of theophylline is known, it can be subtracted from the desired level and multiplied by the volume of distribution:

The dose of aminophylline required to maintain a desired steady state of serum theo-phylline concentration (Cpss) may be calculated as follows:

where Cl is the clearance in L/h/kg and Cpss is the average plasma concentration at steady state. A theophylline level determined from a serum sample obtained 1 h after the loading dose is useful in determining the need for an additional bolus loading dose. Therefore, Eq. 1 can be used to calculate the subsequent loading dose if needed. A subsequent determination 4 h after the initiation of a constant infusion shows the trend of the serum concentration; the rate can be either increased or decreased as needed. Additional samples after 12 and 24 h guide further intravenous dosing.

To convert the intravenous dose to an equivalent oral dose, the hourly dose is multiplied by the dosing interval to be used for oral therapy. It is important to correct the aminophylline dose to obtain the theophylline equivalent by multiplying the aminophylline dose by 0.8. In this calculation, it is assumed that the oral product is completely absorbed.

The use of theophylline in chronic asthma is being redefined. Over the 4-yr period from 1989 to 1993, prescriptions for theophylline written by pediatricians decreased from 27 to 7% of all asthma medicines. According to the most recent Expert Panel Report of the National Heart, Lung and Blood Institution's (NHLBI) National Asthma Education of Prevention Program, theophylline has been relegated to a second-line position for patients who fail to respond to optimal p2-agonist and inhaled steroid treatment. However, abundant data accumulated over the past 20 yr indicate that theophylline is as effective as cromolyn in young children and provides additional control of symptoms even in patients taking inhaled steroids. In several well-designed studies of patients with severe asthma, withdrawal of theophylline resulted in significant deterioration in their clinical condition. In addition, many physicians have noted deterioration of asthma in patients previously well controlled with theophylline therapy in whom the drug was withdrawn as a requirement for a drug study, especially those subjects with moderate to severe asthma. Extended-release theophylline is more effective than extended-release oral p2-agonists in nocturnal asthma, although p2-agonists cause less disturbance of sleep architecture. A recent study of twice-daily salmeterol and extended-release theophylline in nocturnal asthma demonstrated no major clinical advantage of one drug over the other. However, there was a small benefit in sleep quality, quality of life, and daytime cognitive functioning with salmeterol.

When theophylline is used for the management of chronic asthma, it is most effectively administered as one of the sustained-release formulations. Use of sustained-release products minimizes the peak-and-trough fluctuation of serum concentration. Depending on an individual's serum theophylline clearance, an 8- or 12-h or even 24-h dosing interval is appropriate. In general, the younger the child (under 9 yr of age), the more likely it is that an 8-h dosing interval will be required to minimize peak-and-trough fluctuations in theophylline concentration. Determination of theophylline serum concentration during the initial weeks of treatment is useful in adjusting the dose and dosing interval. Sustained-release theophylline products that are completely absorbed and whose bioavailability is insignificantly affected by concomitant food administration are preferred. Once-a-day dosing is inappropriate in most children, who, because of their relatively rapid theophylline clearance, show unacceptable peak-and-trough differences in theophylline concen-

Table 3

Dosing Titration (as Anhydrous Theophylline)"'^

Infants < 1 yr old Initial dosage Premature neonates

<24 do postnatal age; 1.0 mg/kg every 12 h >24 d postnatal age; 1.5 mg/kg every 12 h Full-term infants and infants up to 52 wk of age

Total daily dose (mg) = [(0.2 x age in wk) + 5.0] x (kg body wt)

Up to age 26 wk; divide dose into three equal amounts administered at 8-h intervals >26 wk of age; divide dose into four equal amounts administered at 6-h intervals

Final dosage

Adjusted to maintain a peak steady-state serum theophylline concentration of 5-10 pg/mL in neonates and 10-15 pg/mL in older infants. Since the time required to reach steady state is a function of theophylline half-life, up to 5 d may be required to achieve steady state in a premature neonate, whereas only 2-3 d may be required in a 6-mo-old infant without other risk factors for impaired clearance in the absence of a loading dose. If a serum theophylline concentration is obtained before steady state is achieved, the maintenance dose should not be increased, even if the serum theophylline concentration is < 10 pg/mL

Children (1-15 yr) and adults (16-60 yr) without risk factors for impaired clearance

Titration step Children < 45 kg Children > 45 kg and adults

Starting dosage: 10 mg/kg/d up to a maximum 300 mg/d divided every of 300 mg/d divided every 8 h 8 h

After 3 d, if 13 mg/kg/d up to a maximum 400 mg/d divided every tolerated, increase of 400 mg/d divided every 8 h dose to: 8 h

After 3 more days, 16 mg/kg/d up to a maximum 600 mg/d divided every if tolerated, of 600 mg/d divided every 8 h increase dose to: 8 h

Patients with risk factors for impaired clearance, the elderly (>60 yr), and those in whom it is not feasible to monitor serum theophylline concentrations:

In children 1-15 yr of age, the initial theophylline dose should not exceed 16 mg/kg/d up to a maximum of 400 mg/d in the presence of risk factors for reduced theophylline clearance or if it is not feasible to monitor serum theophylline concentrations. In adolescents >16 yr and adults, including the elderly, the initial theophylline dose should not exceed 400 mg/d in the presence of risk factors for reduced theophylline clearance or if it is not feasible to monitor serum theophylline concentrations. Loading dose for acute bronchodilatation:

An inhaled p2-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 p2-selective agonist and provides no added benefit in the treatment of acute bronchospasm. If an inhaled or parenteral p-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 theophylline in the previous 24 h will produce an average peak serum

Table 3 (continued) Dosing Titration (as Anhydrous Theophylline)3'^

theophylline concentration of 10 |g/mL (range 5-15 |g/mL). If dosing with theophylline is to be continued beyond the loading dose, the above guidelines should be utilized and serum theophylline concentration monitored at 24-h intervals to adjust final dosage.

Final dosage adjustment guided by serum theophylline concentration

Peak serum concentration Dosage adjustment

<9.9 |g/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after 3 d for further dosage adjustment 10-14.9 |g/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 mo intervals/ If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to treatment regimen

15-19.9 |g/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.d 20-24.9 |g/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 d to guide further dosage adjustment 25-30 |g/mL Skip next dose and decrease subsequent doses at least

25% even if no adverse effects are present. Recheck serum concentration after 3 d to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage) >30 |g/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 d to guide further dosage adjustment aPatients with more rapid metabolism, clinically identifi ed 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.

bFor products containing theophylline salts, the appropriate dose of the theophylline salt should be substituted for the anhydrous theophylline dose. To calculate the equivalent dose for theophylline salts, divide the anhydrous theophylline dose by 0.8 for aminophylline, by 0.65 for oxtriphylline, and by 0.5 for the calcium salicylate and sodium glycinate salts.

cDosing recommendation taken from Hendeles L, Weinberger M, Szefler S, et al. Safety and efficacy of theophylline in children with asthma. J Pediatr 1992;120:177-183.

dDose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiological abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued.

tration and may become symptomatic toward the end of the 24-h dosing interval. With pellet formulations, the beads should be added to moist food (e.g., applesauce) to ensure their dissolution. Sustained-release tablets should not be crushed because this destroys their slow-release properties. An algorithm for initial dosing and final dosage adjustment based on serum concentration measurement may be found in a recent review of safety and efficacy of theophylline in children with asthma (Hendeles et al.). Because adverse effects of theophylline become manifest as the serum concentration of 20 |g/mL is approached, it is best to aim for the 8-15 |g/mL range in the majority of patients. Also in in vitro animal models and human studies, theophylline has anti-inflammatory/ immunomodulatory effects at serum concentrations in the 5-10 |g/mL range. (See dosing recommendations in Table 3.) A recent head-to-head study of oral theophylline vs inhaled beclomethasone showed similar rates of asthma exacerbation in pregnant women with moderate asthma. There were more minor adverse reactions in the theophylline group. The results of this study are consistent with earlier studies in children with mild to moderate asthma, which showed no difference in outcome measures between the two regimens. As noted above, the most compelling evidence for the efficacy of theophylline comes from studies of patients with severe asthma controlled on inhaled steroids and theophylline whose asthma deteriorates when theophylline is withdrawn. In a similar vein, patients with severe asthma poorly controlled on high-dose inhaled steroids improve when theophylline is added. As noted above, theophylline is also effective in nocturnal asthma, but its use in this context has been largely subplanted by the new generation of long-acting p2-agonists.

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