What are the side effects of Theophylline?

Theophylline Side Effects

Theophylline has significant side effects including nausea, vomiting, headache, insomnia, gastroesophageal reflux, diarrhea, irritability, restlessness, fine skeletal muscle tremors, and at higher concentrations can cause cardiac arrhythmias and seizures which can be lethal. 1

Common Side Effects (at therapeutic concentrations <20 mcg/mL)

• Caffeine-like adverse effects occur in approximately 50% of patients when therapy is initiated at higher than recommended doses 1
• Gastrointestinal side effects are threefold higher with theophylline compared to other bronchodilators, including:
  • Nausea and vomiting 1
  • Gastroesophageal reflux 2
  • Abdominal pain 1
  • Diarrhea 1
• Neurological effects:
  • Headache 1
  • Insomnia 1
  • Irritability and restlessness 1
  • Fine skeletal muscle tremors 1
• Cardiovascular effects:
  • Tachycardia 2
• Other effects:
  • Transient diuresis 1
  • Altered sleep and behavior patterns, especially in school-age children 1

Severe Side Effects (at concentrations >20 mcg/mL)

• Persistent vomiting 1
• Cardiac arrhythmias, including:
  • Multifocal atrial tachycardia and flutter (can occur even at concentrations ≥15 mcg/mL in patients with hypoxia secondary to COPD) 1
  • Ventricular arrhythmias with hemodynamic instability 1
• Neurological complications:
  • Intractable seizures which can be lethal 1
  • Seizures have been reported even at concentrations <20 mcg/mL in elderly patients or those with underlying neurological disease 1
• Metabolic disturbances:
  • Hypokalemia 1
  • Hyperglycemia 1
  • Acid/base disturbances 1
• Rhabdomyolysis 1
• Death (in cases of severe toxicity) 1

Risk Factors and Monitoring

• Elderly patients are at higher risk of toxicity due to decreased protein binding, resulting in higher unbound (active) drug concentrations 1
• Patients with hypoxia secondary to COPD are at increased risk of cardiac arrhythmias 1
• Regular monitoring of serum theophylline levels is mandatory for patients on maintenance therapy 3
• The therapeutic window is narrow (10-20 mcg/mL), requiring careful dose adjustment 1, 4
• In approximately 10% of adults and 3% of children, caffeine-like adverse effects persist even at therapeutic concentrations 1

Clinical Considerations

• Theophylline should be initiated at low doses with slow titration to reduce the frequency of adverse effects 1
• Dosage reduction may alleviate caffeine-like adverse effects, but persistent adverse effects should prompt reevaluation of continued therapy 1
• Patients on long-term theophylline without regular monitoring are at risk for chronic toxicity, which may present with nonspecific symptoms that can be misdiagnosed 5
• Drug interactions through the hepatic cytochrome P450 system can significantly affect theophylline levels 2, 6
• Abrupt discontinuation should be avoided in patients on long-term therapy; gradual weaning is recommended 7

Monitoring Recommendations

• Serum levels should be monitored regularly (5-15 mg/L for theophylline) 2
• When patients on theophylline present with vomiting, headache, or seizures, serum concentrations should be checked immediately, even if recent levels were within therapeutic range 3
• The American College of Chest Physicians recommends using the lowest effective dose to avoid adverse effects 4

Theophylline's unfavorable side effect profile compared to inhaled agents makes it less preferable as a first-line treatment for respiratory conditions 2, 6. It is now usually used as an add-on therapy in patients not well controlled on other medications 6.