When is Theophylline (methylxanthine) recommended for patients with asthma or Chronic Obstructive Pulmonary Disease (COPD) and what is the typical starting dose?

From the Guidelines

Theophylline is recommended as a third-line therapy for patients with asthma or COPD when symptoms remain uncontrolled despite optimal inhaled therapy, with a typical starting dose of 200-300 mg daily in extended-release form, usually divided into two doses, as suggested by the American College of Chest Physicians and Canadian Thoracic Society guideline 1. The decision to use theophylline should be based on the patient's individual needs and medical history, taking into account its potential benefits and risks.

• Theophylline has been shown to be effective in preventing acute exacerbations of COPD, particularly in stable patients, with a Grade 2B recommendation 1.
• The medication requires careful monitoring due to its narrow therapeutic window, with target serum concentrations between 10-20 μg/mL, and dose adjustments should be made gradually based on serum levels and clinical response.
• Patients should be monitored for side effects, including nausea, headache, insomnia, and cardiac arrhythmias, and a thorough medication review is essential before initiating therapy due to numerous potential drug interactions, particularly with certain antibiotics, seizure medications, and cardiac drugs.
• Theophylline works as a bronchodilator by inhibiting phosphodiesterase enzymes and antagonizing adenosine receptors, which helps relax airway smooth muscle, and it also has mild anti-inflammatory properties that can benefit patients with chronic airway diseases.
• According to the expert panel report 3 (EPR-3) guidelines for the diagnosis and management of asthma, theophylline may be used as alternative, not preferred, therapy for step 2 care (for mild persistent asthma) or as adjunctive therapy with ICS in patients 5 years of age, with monitoring of serum theophylline concentration being essential 1.

From the FDA Drug Label

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). Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances.

• Titration StepChildren < 45 kgChildren > 45 kg and adults

1. Starting Dosage12-14 mg/kg/day up to a maximum of 300 mg/day divided Q4-6 hrs300 mg/day divided Q6-8 hrs

Theophylline is recommended for patients with asthma or Chronic Obstructive Pulmonary Disease (COPD) when other treatments are not effective or as an add-on therapy.

• The typical starting dose for children < 45 kg is 12-14 mg/kg/day up to a maximum of 300 mg/day divided Q4-6 hrs.
• The typical starting dose for children > 45 kg and adults is 300 mg/day divided Q6-8 hrs. Key points to consider when using theophylline:
• The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements.
• Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days.
• Serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. 2

From the Research

Theophylline Recommendations for Asthma and COPD

• Theophylline is recommended as an add-on therapy for patients with asthma not well controlled on inhaled corticosteroids with or without long-acting β2-agonists 3.
• It is also recommended for patients with COPD with severe disease not controlled by bronchodilator therapy 3.
• Theophylline is considered an alternate therapy for the treatment of asthma and COPD, with inhaled corticosteroids and inhaled bronchodilators being the preferred treatments 4.

Typical Starting Dose

• The typical starting dose of theophylline is not explicitly stated in the provided studies, but it is mentioned that low-dose theophylline (400 to 750 mg daily) can be effective in reducing eosinophil accumulation and improving pulmonary function in patients with asthma 5.
• In patients with COPD, a dose of 200 mg once or twice a day has been used in clinical trials, with the dose determined by ideal body weight and smoking status 6.

Mechanism of Action and Side Effects

• Theophylline has anti-inflammatory effects, which may be due to inhibition of phosphodiesterase (PDE)4 and histone deacetylase-2 activation 3.
• Side effects of theophylline are related to plasma concentrations and include nausea, vomiting, and headaches due to PDE inhibition, as well as cardiac arrhythmias and seizures at higher concentrations due to adenosine A1-receptor antagonism 3.