THEOPHYLLINE-SR
Clinical safety rating: safe
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.
Inhibits phosphodiesterase, increasing intracellular cAMP; antagonizes adenosine receptors; reduces airway hyperresponsiveness and inflammation.
| Metabolism | Hepatic via CYP1A2, CYP2E1, and CYP3A4; also via N-demethylation and oxidation. |
| Excretion | Renal (10% unchanged); hepatic metabolism (90%): 1,3-dimethyluric acid (40-50%), 3-methylxanthine (20-30%), 1-methyluric acid (10-20%). Fecal <5%. |
| Half-life | Terminal elimination half-life: 6-12 hours in healthy adults; 3-5 hours in children; 1-9 hours in smokers (tobacco/marijuana); 20-30 hours in premature neonates; 12-60 hours in hepatic cirrhosis; 20-30 hours in congestive heart failure. Clinical context: steady-state achieved in 2-3 days in adults; dose adjustments needed based on clearance. |
| Protein binding | Approximately 40% bound to albumin; binding decreases in neonates, cirrhosis, and uremia. |
| Volume of Distribution | 0.3-0.5 L/kg (actual body weight); clinical meaning: distributes into extracellular water; decreased Vd in obesity; increased Vd in neonates; reflects low tissue binding. |
| Bioavailability | Oral immediate-release: 96-100%; oral sustained-release: 100% relative to oral solution (but may vary by formulation, with some brands showing 80-90%); rectal: approximately 80-90% (variable). |
| Onset of Action | Oral immediate-release: 30-60 minutes; oral sustained-release: 1-3 hours; intravenous: immediate (end of infusion); rectal: variable, typically 30-60 minutes. |
| Duration of Action | Oral immediate-release: 4-6 hours; oral sustained-release: 8-12 hours (therapeutic serum levels maintained); intravenous: depends on infusion rate; clinical note: sustained-release formulations provide more stable levels for once or twice daily dosing. |
300-600 mg orally every 12 hours, adjusted to maintain serum theophylline concentrations of 5-15 mcg/mL. Starting dose for adults not currently on theophylline: 300 mg orally once daily for 3 days, then increase to 300 mg every 12 hours.
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for GFR > 10 mL/min. For GFR < 10 mL/min: reduce dose by 50% and monitor serum levels closely due to accumulation of active metabolites. |
| Liver impairment | Child-Pugh A: reduce dose by 50%. Child-Pugh B: reduce dose by 75%. Child-Pugh C: avoid use or use with extreme caution (reduce dose by 75% and monitor levels). Dosing adjustments are based on increased half-life and decreased clearance. |
| Pediatric use | For children 1-9 years: starting dose 4-5 mg/kg orally every 12 hours (target serum concentration 5-15 mcg/mL). For children 10-16 years: 3-4 mg/kg orally every 12 hours. Not recommended for infants < 6 months without therapeutic drug monitoring. |
| Geriatric use | In elderly patients (>60 years), lower starting dose (300 mg orally once daily) and titrate slowly. Monitor serum concentrations closely as clearance is reduced. Target serum concentration 5-10 mcg/mL to reduce risk of toxicity. |
| 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.
| FDA category | Animal |
| Breastfeeding | Theophylline excreted into breast milk; M/P ratio approximately 0.6-0.7. Infant serum levels may reach therapeutic range; monitor infant for irritability and insomnia. Consider alternative if infant has apnea or cardiovascular instability. |
| Teratogenic Risk |
■ FDA Black Box Warning
None formally; however, narrow therapeutic index requires monitoring.
| Common Effects | COPD |
| Serious Effects |
["Hypersensitivity to theophylline or xanthines","Active seizure disorder (relative)"]
| Precautions | ["Risk of toxicity due to narrow therapeutic range","Seizures and arrhythmias at high serum levels","Drug interactions with CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine)","Use caution in heart failure, hepatic impairment, elderly"] |
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| Theophylline is not associated with major congenital malformations. First trimester: no increased risk of birth defects. Second and third trimesters: risk of fetal tachycardia and jitteriness at high maternal serum concentrations; intrauterine growth restriction possible with uncontrolled asthma. |
| Fetal Monitoring | Maternal: serum theophylline levels, heart rate, CNS effects (nausea, insomnia, tremor). Fetal: heart rate monitoring for tachycardia; ultrasound for growth if prolonged use. |
| Fertility Effects | No adverse effects on fertility reported in humans or animals. |