Theophylline use in asthma

INTRODUCTION — Theophylline was first identified as having potential for asthma as a bronchodilator in 1921 and 1922 [1], but general use as a bronchodilator was not seen until the 1930s. The combination of theophylline and ephedrine was described in a 1940 publication [2]. Such preparations, often with a mild sedative added, dominated the market for oral theophylline products until 1975 when the addition of ephedrine was demonstrated to add adverse effects without additive clinical benefit [3]. Theophylline was demonstrated to be the active ingredient in those combinations and a dose-response effect from theophylline was apparent.

The indications for theophylline in the treatment of asthma and recommendations for its safe use will be discussed here. Overviews of the treatment of acute and chronic asthma are provided elsewhere. (See "Acute exacerbations of asthma in adults: Home and office management" and "An overview of asthma management".)

BACKGROUND INFORMATION

Theophylline salts — Several so-called "salts” of theophylline had been developed as attempts to increase water solubility (8 mg/mL at 25ºC) and improve absorption. While salts of theophylline may be formed with a base at high pH, theophylline is only slightly ionized at physiological pH (pK_a = 8.8). Therefore, these so-called salts are merely mixtures of theophylline and base, and they have no effect on the pharmacologic activity of theophylline.

Since absorption of methylxanthines relates more to their lipophilic characteristics than to their water solubility, there is no rationale for older formulations containing ethylenediamine, calcium salicylate, sodium glycinate, choline, or other bases. Even with aminophylline injection still commonly used, the ethylenediamine only serves to increase pH sufficiently to dissolve theophylline at the packaged concentration.

All dosage and labeling of theophylline formulations should therefore be in terms of the anhydrous theophylline content. For example, aminophylline injection USP, 25 mg/mL, is more appropriately labeled "theophylline injection, 20 mg/mL." Intravenous theophylline solution in aqueous solution with 5 percent dextrose without ethylenediamine is available in various concentrations up to 4 mg/mL.

Therapeutic actions — Though traditionally classified as a bronchodilator, the ability of theophylline to control chronic asthma appears disproportionately greater than is explainable by its modest degree of bronchodilator activity alone [4-10]. Theophylline has anti-inflammatory, immunomodulatory, and bronchoprotective effects that potentially contribute to its efficacy as a prophylactic anti-asthma drug [11-16] and for chronic obstructive pulmonary disease (COPD). (See "Management of refractory chronic obstructive pulmonary disease", section on 'Theophylline, monitored by drug levels'.)

The molecular mechanism of bronchodilatation by theophylline is inhibition of phosphodiesterase (PDE)3, but the anti-inflammatory effect may be due to inhibition of PDE4 and activation of histone deacetylases, which are reduced in severe asthma and COPD [17]. Activation of histone deacetylase-2 leads to switching off of activated inflammatory genes, which in turn may contribute to reversal of glucocorticoid resistance by theophylline.

Theophylline down-regulates inflammatory and immune cell function in vitro and in vivo in animals with airway inflammation [18-20]. In patients with allergic asthma, it attenuates the late phase increase in airway obstruction and airway responsiveness to histamine, decreases allergen-induced migration of activated eosinophils into the bronchial mucosa, and decreases the sputum eosinophil count [11,12,18]. Moreover, withdrawal of theophylline from patients with severe chronic asthma receiving high-doses of inhaled glucocorticoid therapy results in increased symptoms of asthma accompanied by an increase in the number of activated cytotoxic T-lymphocytes in the bronchial mucosa and an increase in helper T-lymphocytes in the airway epithelium [10]. The reduction in nocturnal worsening of lung function when theophylline is used is associated with both a decrease in the percentage of neutrophils and a decrease in stimulated leukotriene B4 from macrophages in early morning bronchoalveolar lavage fluid [19]. An in depth review of in vitro and in vivo studies demonstrating the immunomodulatory, anti-inflammatory, and glucocorticoid-sparing effects of theophylline has been published [20].

Although several molecular mechanisms have been proposed to explain the actions of theophylline, the non-specific inhibition of phosphodiesterase that occurs at clinically relevant drug concentrations appears to be the most important. Theophylline increases the intracellular concentration of cyclic nucleotides in airway smooth muscle and inflammatory cells by inhibiting phosphodiesterase-mediated hydrolysis. However, inhibition of specific isozymes may also be important; inhibition of phosphodiesterase type III and type IV relaxes smooth muscles in pulmonary arteries and in airways [21], while anti-inflammatory and/or immunomodulatory actions probably result from inhibition of the type IV isozymes [22]. This information has stimulated interest in investigating more specific inhibitors of phosphodiesterase type IV for asthma therapy [23,24]. Theophylline also increases histone deacetylase-2 activity, which may increase glucocorticoid responsiveness in patients with glucocorticoid-resistant severe asthma and in patients with asthma who are cigarette smokers [25].

INDICATIONS — Clinical circumstances for which theophylline may be considered in the treatment of asthma include the following (see "An overview of asthma management"):

●Additive maintenance therapy in a patient whose asthma is not adequately controlled with conventional doses of inhaled therapies such as inhaled glucocorticoids, long-acting beta-agonists, and long-acting muscarinic antagonists [26]. Biologic therapies are generally preferred for this group of patients. However, not all patients qualify for biologic therapies and these therapies are also not universally available.

●Primary maintenance therapy when the administration of an inhaled glucocorticoid is difficult or cumbersome (eg, toddlers and preschool-age children) and montelukast is not effective, although theophylline is not a preferred agent.

●Primary maintenance therapy in a patient who is more likely to adhere to an oral than an inhaled regimen and montelukast is not sufficiently effective.

●Possibly, additive acute therapy in the intensive care unit for patients failing to respond to vigorous use of inhaled beta2-selective agonists in combination with ipratropium and/or intravenous magnesium and systemically administered glucocorticoids, although evidence for benefit in this situation is lacking. (See 'Additive or maintenance acute therapy for hospitalized patients' below.)

EVIDENCE OF EFFICACY, BY INDICATION

Add-on to maintenance inhaled glucocorticoids — Moderate and even high doses of inhaled glucocorticoids (GC) may provide inadequate control of asthma in some patients despite optimal compliance and technique [5,8,10,27-30] and may be accompanied by systemic side effects. (See "Major side effects of inhaled glucocorticoids".)

Randomized trials confirm that the addition of theophylline results in better pulmonary function and symptom control than an increased dose of inhaled GC (figure 1 and figure 2) [5,8,10,29]. (See "Treatment of moderate persistent asthma in adolescents and adults".)

●For example, one study randomly assigned 62 patients to treatment with 800 mcg/day of inhaled budesonide or the combination of theophylline and 400 mcg/day of inhaled budesonide [29]. The doses of theophylline administered were 250 mg or 375 mg, twice daily, for patients weighing <80 kg or ≥80 kg, respectively. The median serum concentration was 8.7 mcg/mL, below the commonly-employed therapeutic range (10 to 20 mcg/mL). Combination therapy resulted in significantly greater forced expiratory flow in the first second (FEV₁) and forced vital capacity (FVC), while there were no differences between the groups in terms of beta-agonist use or peak expiratory flow variability. Adverse events were similar in both treatment groups. (See 'Target peak serum concentration' below.)

●In another trial, withdrawal of theophylline in a double blind fashion from 27 patients with severe chronic asthma resulted in a significant increase in asthma symptoms, particularly at night, and a fall in spirometry and morning peak flow performance [10].

The ability of theophylline to help control chronic asthma in these and other studies has been disproportionate to its relatively mild bronchodilator activity. For this reason, additional mechanisms of theophylline activity have been postulated [31], including anti-inflammatory and immunomodulatory effects [10-12,20]. (See 'Therapeutic actions' above.)

Comparison with other add-on therapies — There are few studies directly comparing the addition of theophylline to the addition of other controller therapies (antileukotriene agents, long-acting beta-agonists [LABAs], biologic agents) in patients receiving inhaled GC therapy. Anti-leukotriene agents and theophylline have the "real-world" advantage of being orally administered rather than inhaled. Many patients find an oral agent simpler to administer than an additional metered dose inhaler, and adherence is greater, on average, with an oral medication [32].

Only inhaled LABAs, such as salmeterol and formoterol, have been demonstrated to be superior to theophylline in head-to-head studies for additive effect [33,34], although not all patients benefit from LABAs. Mixed results have been noted in comparisons with leukotriene receptor antagonists, such as montelukast [35-39]. Inhaled cromolyn will generally have much less effect [4,40,41] and is only available as a nebulizer solution in the United States. (See 'Add-on to maintenance inhaled glucocorticoids' above and "Antileukotriene agents in the management of asthma".)

Primary maintenance therapy when oral agents are preferred — Inhaled GC are the most effective long-term maintenance medications for chronic asthma, but their inherent efficacy matters little if patients do not take them consistently enough to receive benefit. A twice daily slow-release theophylline regimen may produce better health outcomes in certain patients who can swallow a tablet whole, through improved adherence.

Several reports indicate poor adherence to regimens of inhaled maintenance medications, while theophylline appears to cause less difficulty with adherence [32,42].

Additive or maintenance acute therapy for hospitalized patients — In general, limited benefit is derived by adding intravenous theophylline, in the form of theophylline or aminophylline (theophylline with ethylenediamine in an 80-85/15-20 percent ratio), to intensely administered inhaled beta agonists and systemic glucocorticoids for patients hospitalized with an acute asthma exacerbation [43,44]. More detailed discussions of the use of theophylline in the management of acute exacerbations of asthma in adults and children are provided separately. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Ineffective therapies'.)

SAFE USE OF THEOPHYLLINE — Theophylline has a narrow therapeutic index and wide interpatient variability in clearance. Consequently, dosing must be individually titrated to appropriate steady-state serum concentrations in order to achieve maximal benefit and safety. This requires skill and knowledge on the part of the clinician and an ability of patients or caregivers to follow instructions properly [45,46]. Failure to adequately monitor theophylline use can lead to potentially fatal drug intoxication. (See "Theophylline poisoning".)

Theophylline is well tolerated and there is little risk of serious toxicity when the drug is administered properly [45]. As an example, one epidemiologic investigation of 36,000 ambulatory patients who received 225,000 prescriptions for theophylline over a nine year period found that the risk of hospital admission due to complications of chronic theophylline use was less than 1 per 1000 patient-years of exposure [47].

Factors that must be considered to maximize the safety of theophylline include proper target serum concentration, appropriate dosage titration, the presence of conditions or factors that affect theophylline metabolism, and proper product and dosing interval selection.

Target peak serum concentration — The efficacy and toxicity of theophylline are closely related to the peak serum concentration (table 1). In patients receiving theophylline monotherapy, doses providing a peak serum concentration of 10 to 20 mg/L (mcg/mL) are best documented to improve symptoms and reduce the need for rescue therapy [48-50]. Targeting a peak of 15 mg/L allows for some dose-to-dose fluctuation and avoids exceeding 20 mg/L and the associated adverse effects [45,51].

There has been interest in using lower concentrations [10,12,29,52]. However, the results of these studies have been divergent, likely in part due to nonstandardized or absent individual patient-level monitoring. The best studies of low-dose theophylline have not been favorable. For example, in one placebo-controlled trial of 489 adults and adolescents >15 years, addition of low-dose theophylline (300 mg/d) to inhaled corticosteroids did not improve asthma control [36].

Initiating and titrating oral therapy — When beginning theophylline for maintenance therapy, the initial dose should be sufficiently low to avoid transient caffeine-like side effects such as insomnia and irritability. In non-smoking adults without risk factors for reduced theophylline clearance, a starting daily dose of 300 mg is appropriate in most cases. A sustained release product should be used from the beginning. For children, an appropriate starting dose is 10 mg per kg of body weight per day to a maximum of 300 mg/day. In patients with obesity, ideal body weight is used in this calculation (calculator 1).

The dose is then increased at intervals of three days or more until the average dose requirements for age are approached (table 2). If a particular dose increase produces unacceptable side effects (eg, tremor, tachycardia, vomiting, abdominal pain), the dose should be reduced to that which had been previously tolerated. A single peak serum concentration measurement is then obtained at the highest tolerated dose, and the final dose is adjusted accordingly (table 2). Fewer than 3 percent of children and 10 percent of adults experience intolerance to theophylline at peak serum concentrations less than 20 mg/L if a slow titration schedule is used, such as the one listed in the table (table 2) [45]. (See "Theophylline poisoning".)

In patients with risk factors for reduced theophylline clearance or in whom the serum concentration cannot be measured in a timely fashion, the maximum daily dose should not exceed 10 mg per kg/day or 400 mg/day, whichever is lower [53].

Generally only one, and uncommonly two, serum concentration measurements are required to achieve a therapeutic peak concentration [45]. The initial measurement is made at the end of the dose titration schedule (table 2). To properly measure the peak concentration, a blood sample should be obtained at the time of an estimated peak concentration for the formulation used (table 1). In the absence of intercurrent illness associated with sustained fever or drug interactions, serum concentrations can be expected to remain relatively stable, and repeat measurement in 6 to 12 months is generally sufficient [45].

Factors affecting metabolism — Theophylline is metabolized predominately in the liver by the enzyme cytochrome P450 1A2, and to a lesser extent by P450 3A3 and P450 2E1 [54]. Genetic factors, concurrent diseases, environmental agents, and other drugs that alter the activity of these isozymes affect the metabolism of theophylline. When the rate of theophylline metabolism is reduced, the total daily dose must be appropriately decreased to prevent excessive accumulation and toxicity [55].

The following are risk factors for reduced theophylline clearance:

●Age less than 1 year or greater than 60 years.

●Concurrent diseases such as acute pulmonary edema, heart failure, cor pulmonale, fever above 38.9ºC (102ºF) for more than 24 hours, hypothyroidism, liver disease, reduced renal function in infants less than three months of age, and sepsis with multiorgan failure.

●Recent smoking cessation.

●Pregnancy, particularly during the third trimester, is associated with an increase in the volume of distribution and elimination half-life for theophylline [54]. Clearance of theophylline is therefore decreased in the third trimester but returns to normal postpartum [56]. Decreased binding to albumin during pregnancy results in an increased proportion of free drug in the circulation [62]. Decrease in binding means that more free-drug is available for metabolism. Because of these variables, theophylline serum concentration should be monitored during the last half of pregnancy and postpartum [57]. (See "Management of asthma during pregnancy".)

●Addition of a drug that inhibits theophylline metabolism (eg, azole antifungal agents such as ketoconazole, cimetidine, ciprofloxacin, erythromycin, tacrine) or discontinuation of a concurrently administered drug that enhances theophylline metabolism (eg, carbamazepine, rifampin) (table 3A-B). Common drugs that do NOT interact with theophylline are also shown (table 4).

Clinicians can obtain mean values for half-life and total body clearance for the above factors from the tables, which contain the revised FDA labeling guideline for oral theophylline dosage forms (table 3A-B) [54]. In practice, maintaining a safe and stable dose is most challenging for older patients with multiple comorbidities and complex medication regimens, and theophylline is rarely used in this setting. (See "Diagnosis and management of asthma in older adults".)

Selection of product and dosing interval — Slow-release formulations allow a longer dosing interval than rapid release formulations but vary in their rates and completeness of absorption (table 1).

●Food caused a precipitous increase in the rate of absorption and peak concentration with the formulation marketed as Theo-24 [58], whereas taking the formulation identified as Uniphyl on an empty stomach resulted in a marked decrease in absorption [55]. Only products that are completely and consistently absorbed should be selected. US Food and Drug Administration (FDA) AB-rated generic slow-release tablets or capsules for twice daily dosing are the preferred agents.

The difference between the peak and trough serum concentrations is a function of the rate of absorption of the product, the dosing interval selected by the clinician, and the rate of theophylline metabolism by the patient [59]. In patients with rapid metabolism, such as children, even a formulation as slowly absorbed as Uniphyl is likely to result in a large difference between the peak and trough, whereas administration of the Uniphyl formulation once-nightly in patients with slower metabolism, as in many adults, may provide acceptable fluctuations between the peak and trough concentrations [55].

Monitoring — After initial titration of the dose, we suggest checking the theophylline serum concentration at the estimated peak (table 1), every 12 months, unless a change in concomitant medications or health status (eg, pregnancy, symptoms of toxicity, or child with rapid growth) dictates a shorter interval.

Dosing of IV theophylline — For patients who are on chronic theophylline and unable to take oral medication during an acute exacerbation, the serum level should be assessed and intravenous (IV) theophylline administered at a maintenance infusion rate, adjusted if needed to achieve a peak serum concentration of 10 to 20 mg/L.

For patients not previously receiving theophylline, a single intravenous loading dose of theophylline, 5 mg/kg, will provide a peak serum theophylline concentration of about 10 to 15 mcg/mL and may be justified for patients with severe acute symptoms that do not respond rapidly to routine measures. There is minimal risk for serious toxicity with such a dose, and a maintenance infusion may then be initiated if obvious clinical improvement results [60]. Choice of a maintenance infusion rate depends on factors such as age, smoking status, and concomitant medical problems that may alter theophylline clearance. Measurement of serum concentrations is performed approximately four hours after initiation of continuous infusion and then every 12 hours until a therapeutic and stable concentration is reached. After this point, there is no reason to repeat the measurement unless factors affecting theophylline pharmacokinetics change. (See 'Factors affecting metabolism' above.)

Additional information about intravenous administration of theophylline is provided separately. (See "Theophylline: Drug information".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Asthma in adolescents and adults".)

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Theophylline has bronchodilatory, anti-inflammatory, immunomodulating, and bronchoprotective effects. (See 'Therapeutic actions' above.)

●Indications – Theophylline remains a potentially useful and inexpensive medication as an add-on agent for patients with persistent asthma whose symptoms are not controlled with conventional doses of inhaled controller therapies and as bronchodilator therapy for those who cannot take or are poorly adherent to inhaled medications. (See 'Indications' above.)

●Efficacy

•The addition of theophylline to moderate- to high-dose inhaled glucocorticoids is more effective than increasing the dose of inhaled glucocorticoids. (See 'Add-on to maintenance inhaled glucocorticoids' above.)

•Theophylline is less effective than long-acting beta-agonists as add-on therapy and has not been compared with other add-on agents (including biologics). (See 'Comparison with other add-on therapies' above.)

•Theophylline has not been demonstrated to improve acute severe asthma in the intensive care unit.(See 'Additive or maintenance acute therapy for hospitalized patients' above.)

●Safe use of theophylline

•General principles – Theophylline has a narrow therapeutic index and wide interpatient variability in clearance. Safe use of oral theophylline as a maintenance therapy requires initiating treatment at a low dose, measuring a serum concentration to adjust the dose, and reducing the dose in the presence of physiologic states or medications that impair theophylline metabolism. (See 'Safe use of theophylline' above.)

•Targeting peak serum concentration – The efficacy and toxicity of theophylline are closely related to the peak serum concentration (table 1). In patients receiving theophylline monotherapy, doses providing a peak serum concentration of 10 to 20 mg/L (mcg/mL) are best documented to improve symptoms and reduce the need for rescue therapy. (See 'Target peak serum concentration' above.)

•Initiating and monitoring therapy – We use a starting daily dose of 300 mg (10 mg/kg ideal body weight to a maximum of 300 mg in children) in most cases. The dose should be increased at intervals of three days or more up to the average dose requirements for age (table 2). If a particular dose increase produces unacceptable side effects (eg, tremor, tachycardia, vomiting, abdominal pain), the dose should be reduced to that which had been previously tolerated. The dose is adjusted based on serum peak concentration obtained based on the formulation (table 1 and table 2). After initial titration of the dose, we check the theophylline peak serum concentration every 6 to 12 months unless there is a change in concomitant medications or health status.

•Factors affecting metabolism – Age less than 1 or greater than 60 years, pregnancy, recent smoking cessation, use of interacting pharmacologic agents (table 3A and table 3B), or concurrent comorbid disease affecting heart, liver, kidney, or thyroid function can alter theophylline metabolism and create the potential for toxicity. (See 'Factors affecting metabolism' above.)

•Selection of product and dosing interval – The absorption characteristics of specific formulations vary considerably, particularly with regards to the effects of food (table 1). Familiarity with these details is important. (See 'Selection of product and dosing interval' above.)

•Intravenous dosing – In patients already on theophylline, an infusion rate can be adjusted by serum level. (See 'Dosing of IV theophylline' above.)