ELIXOPHYLLIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ELIXOPHYLLIN (ELIXOPHYLLIN).
Inhibits phosphodiesterase, increasing intracellular cAMP, leading to bronchodilation and anti-inflammatory effects.
| Metabolism | Primarily hepatic via cytochrome P450 enzymes, mainly CYP1A2 and CYP3A4. |
| Excretion | Theophylline is primarily eliminated by hepatic metabolism (approximately 90%), with less than 10% excreted unchanged in urine. Renal excretion of unchanged drug accounts for about 10% in adults, but in neonates and infants, it may be higher (up to 50%). Fecal excretion is negligible (<1%). |
| Half-life | Terminal elimination half-life in adults is approximately 7-9 hours (range 3-12 hours) for non-smokers, and 4-5 hours for smokers. In children (1-9 years), half-life averages 3-4 hours; in neonates, it is prolonged (20-30 hours). Clinical context: Half-life may be increased in hepatic impairment, congestive heart failure, and with concurrent administration of drugs that inhibit CYP1A2 and CYP3A4 (e.g., cimetidine, erythromycin, ciprofloxacin). Decreased half-life occurs with enzyme inducers (e.g., phenytoin, carbamazepine, rifampin, smoking). |
| Protein binding | Approximately 40-60% bound to plasma proteins, primarily albumin. Binding is saturable and may decrease in uremia or with elevated bilirubin. In neonates, protein binding is lower (about 20-30%) due to decreased albumin concentrations. |
| Volume of Distribution | Volume of distribution: approximately 0.45 L/kg (range 0.3-0.7 L/kg). Clinical meaning: Theophylline distributes into total body water, with some accumulation in tissues. Vd is increased in neonates (0.6-0.9 L/kg) and decreased in obesity (0.3-0.4 L/kg adjusted for ideal body weight). |
| Bioavailability | Oral immediate-release: 90-100% (well absorbed). Oral extended-release: 80-100% (inter- and intra-subject variability exists). Rectal solution: 80-90%. Rectal suppository: 60-70% (erratic absorption). Intravenous: 100%. |
| Onset of Action | Oral immediate-release: 15-30 minutes (peak effect 1-2 hours). Intravenous: immediate (within minutes). Oral extended-release: 30-60 minutes (peak effect 4-8 hours). Rectal: 15-30 minutes. |
| Duration of Action | Immediate-release oral: 4-6 hours. Extended-release oral: 8-12 hours (or 12-24 hours for 24-hour formulations). Intravenous: duration of effect depends on infusion rate and half-life. Clinical note: Theophylline has a narrow therapeutic index (10-20 mcg/mL), and duration of action is influenced by individual metabolism and formulation. |
Theophylline (Elixophyllin) immediate-release: Initial dose 300 mg/day PO divided every 6-8 hours; titrate based on serum theophylline concentration (target 5-15 mcg/mL). Typical adult dose 400-600 mg/day PO divided every 6-8 hours. Sustained-release: 400-600 mg/day PO every 12 hours.
| Dosage form | CAPSULE |
| Renal impairment | Theophylline pharmacokinetics are not significantly altered in renal impairment. No dose adjustment recommended for GFR >15 mL/min. For end-stage renal disease (GFR <15 mL/min), monitor serum theophylline concentrations closely as clearance may be reduced; consider 25% dose reduction and follow levels. |
| Liver impairment | Child-Pugh Class A: Reduce dose by 50% of usual. Child-Pugh Class B: Reduce dose by 50-75% of usual. Child-Pugh Class C: Contraindicated or reduce dose by 80% with close monitoring. Serum theophylline concentration monitoring is mandatory. |
| Pediatric use | Immediate-release: Initial dose 16 mg/kg/day or 400 mg/day (whichever is less) PO divided every 6-8 hours; titrate based on serum theophylline concentration. Typical maintenance: <1 year: 0.2 x age in weeks + 5 mg/kg/day; 1-9 years: 24 mg/kg/day; >9 years: 16 mg/kg/day. Maximum dose 800 mg/day. |
| Geriatric use |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ELIXOPHYLLIN (ELIXOPHYLLIN).
| Breastfeeding | Theophylline is excreted into breast milk with an M/P ratio of approximately 0.7. Peak milk levels occur 2-4 hours after dose. Infant serum levels are typically low (10-30% of maternal levels). Risk of irritability and jitteriness in infants. Use with caution; monitor infant for adverse effects. |
| Teratogenic Risk | Pregnancy Category C. First trimester: Studies in animals have shown an increased risk of fetal malformations (e.g., cardiac defects, cleft palate) at high doses. Human data limited; may be associated with intrauterine growth restriction and neonatal withdrawal if used near term. Second trimester: Risk of tachyarrhythmias and fetal hypoxia due to maternal toxicity. Third trimester: Increased risk of neonatal apnea, jitteriness, and irritability due to transplacental passage. Avoid use unless clearly needed. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
Hypersensitivity to theophylline or any component of the formulation; peptic ulcer disease; seizure disorder (unless adequately controlled).
| Precautions | Monitor serum theophylline levels due to narrow therapeutic index; risk of toxicity with levels >20 mcg/mL. Use caution in patients with cardiac disorders, hepatic impairment, elderly, and those on medications that alter theophylline metabolism. |
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| Elderly patients (>60 years) have reduced theophylline clearance. Initial dose 300 mg/day PO divided every 8-12 hours; maximum recommended dose 400 mg/day. Monitor serum theophylline concentrations closely and adjust to avoid levels >15 mcg/mL due to increased risk of toxicity. |
| Fetal Monitoring | Monitor maternal theophylline serum concentrations (therapeutic range 5-15 mcg/mL). Assess maternal heart rate, respiratory rate, and signs of toxicity (nausea, vomiting, tachycardia, seizures). Fetal monitoring: Nonstress test or biophysical profile if fetal distress suspected. Perform ultrasound for fetal growth if used chronically. |
| Fertility Effects | No known direct effects on fertility in humans. Animal studies show no impairment of fertility at therapeutic doses. However, use during pregnancy may affect fetal development indirectly through maternal toxicity. |