THEOPHYLLINE
Clinical safety rating: safe
Animal studies have demonstrated safety
Nonselective phosphodiesterase inhibitor; adenosine receptor antagonist; increases intracellular cAMP and cGMP, leading to bronchodilation and anti-inflammatory effects.
| Metabolism | Hepatic via CYP1A2, CYP2E1, CYP3A4; major metabolite is 3-methylxanthine. |
| Excretion | Primarily hepatic metabolism (90%) by CYP1A2 and CYP3A4, with only ~10% excreted unchanged in urine. Minor biliary/fecal elimination (<1%). |
| Half-life | Terminal elimination half-life: 6-12 hours in healthy adults (nonsmokers); prolonged to 20-30 hours in congestive heart failure, liver cirrhosis, or COPD; shortened to 4-6 hours in smokers or children. |
| Protein binding | Approximately 40% (primarily to albumin, less to alpha-1-acid glycoprotein). |
| Volume of Distribution | 0.3-0.7 L/kg (adults); 0.5-0.9 L/kg in children; higher in neonates (0.8-1.2 L/kg). Clinical meaning: distributes widely into body water. |
| Bioavailability | Oral immediate-release: 96-100%; Oral sustained-release: 80-100% (due to incomplete absorption); Rectal: 80-100%; Intravenous: 100%. |
| Onset of Action | Intravenous: 15-30 min; Oral immediate-release: 30-60 min; Oral sustained-release: 1-2 hours. |
| Duration of Action | Intravenous: 6-8 hours; Oral immediate-release: 6-8 hours; Oral sustained-release: 12-24 hours (dose-dependent). |
300-600 mg orally once daily or divided every 12 hours, adjusted based on serum theophylline concentrations to maintain 5-15 mcg/mL.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for renal impairment; however, monitor serum levels and consider reduced dosing in patients with end-stage renal disease due to altered clearance. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: reduce dose by 50-75% and monitor levels closely. |
| Pediatric use | Loading dose: 5 mg/kg IV (if not on theophylline) or 2.5 mg/kg IV (if on theophylline); maintenance: 1-6 months: 0.2 mg/kg/hr; 6-12 months: 0.4 mg/kg/hr; 1-9 years: 0.8 mg/kg/hr; 10-16 years: 0.6 mg/kg/hr (all IV, adjust to target serum concentration 5-15 mcg/mL). |
| Geriatric use | Start at lower end of dosing (300 mg/day) with slower titration; monitor serum levels frequently due to decreased clearance and increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Many drugs can increase (eg ciprofloxacin) or decrease (eg phenytoin) levels due to CYP1A2 metabolism Has a narrow therapeutic index and can cause seizures and arrhythmias in overdose.
| Breastfeeding | Theophylline is excreted into breast milk with a milk-to-plasma ratio (M/P) of approximately 0.7. Infant exposure is estimated to be 1-10% of maternal weight-adjusted dose. Monitor infant for irritability, insomnia, and poor feeding. Alternative agents with lower transfer are preferred if possible. |
| Teratogenic Risk | Theophylline crosses the placenta. First trimester: No increased risk of major malformations based on human data, but animal studies are insufficient. Second and third trimesters: Chronic use may cause neonatal irritability, tachycardia, emesis, and transient tachypnea; higher risk of fetal tachycardia if maternal serum levels >20 mcg/mL. Withdrawal symptoms (e.g., jitteriness, vomiting) may occur in neonates after chronic exposure. |
■ FDA Black Box Warning
No FDA boxed warning.
| Common Effects | COPD |
| Serious Effects |
Hypersensitivity to theophylline or other xanthines; active peptic ulcer disease; untreated seizure disorders (relative).
| Precautions | Narrow therapeutic index; monitor serum concentrations; risk of toxicity (seizures, arrhythmias) with levels >20 mcg/mL; use caution in hepatic impairment, heart failure, elderly, and concurrent medications affecting CYP1A2. |
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| Fetal Monitoring | Monitor maternal serum theophylline levels (target 5-15 mcg/mL; lower end preferred in third trimester); maternal heart rate, symptoms of toxicity (nausea, vomiting, palpitations, seizures). Fetal monitoring: ultrasound for growth restriction if chronic use, nonstress test or biophysical profile if signs of fetal tachycardia. Neonatal monitoring: observe for withdrawal symptoms (jitteriness, vomiting, tachycardia) for 24-48 hours post-delivery. |
| Fertility Effects | Theophylline has no known significant effects on human fertility. In vitro studies suggest possible inhibition of sperm motility at high concentrations, but clinical relevance is uncertain. |