THEOPHYL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for THEOPHYL (THEOPHYL).
Theophylline is a methylxanthine that causes bronchodilation primarily through inhibition of phosphodiesterase (PDE) and antagonism of adenosine receptors. It also has mild anti-inflammatory effects and enhances mucociliary clearance.
| Metabolism | Primarily metabolized by hepatic CYP1A2, with minor contributions from CYP2E1 and CYP3A4. Metabolism is saturable, leading to non-linear pharmacokinetics. |
| Excretion | Renal: 10% unchanged in adults (higher in neonates). Hepatic metabolism to inactive metabolites (1,3-dimethyluric acid, 3-methylxanthine, 1-methyluric acid) excreted renally; fecal excretion <5%. |
| Half-life | Terminal elimination half-life: Adults nonsmokers: 6–12 h (mean 8.7 h); adult smokers: 4–5 h; children: 3–5 h; neonates: 20–30 h; hepatic cirrhosis: up to 30 h. Half-life increases with congestive heart failure, fever, and concurrent CYP1A2 inhibitors (e.g., cimetidine, fluvoxamine). |
| Protein binding | 40% bound, primarily to albumin. |
| Volume of Distribution | 0.3–0.7 L/kg (mean 0.45 L/kg). Higher Vd in neonates (0.6–0.9 L/kg) and patients with cirrhosis. Vd approximates total body water; distribution is rapid into well-perfused tissues, less into adipose tissue. |
| Bioavailability | Oral immediate-release: 96%–100% (almost complete). Oral sustained-release: 80%–100% (variable due to formulation-dependent release; food may increase rate but not extent for some products). Rectal: variable, approximately 80–90% (solution/suppository dependent). |
| Onset of Action | IV: immediate (within minutes); oral immediate-release: 30–60 min; oral sustained-release: 1–3 h (variable, depends on formulation). |
| Duration of Action | IV: 6–8 h (depending on dose); oral immediate-release: 6–8 h; oral sustained-release: 8–12 h (some formulations up to 24 h with once-daily dosing). Clinical effect duration correlates with serum concentration; sustained-release formulations designed for twice-daily dosing to maintain therapeutic levels (5–15 mg/L). |
300 mg orally every 6 hours or 400-600 mg extended-release orally every 12-24 hours; intravenous loading dose 5-6 mg/kg over 20-30 minutes, then continuous infusion 0.4-0.6 mg/kg/h
| Dosage form | TABLET, CHEWABLE |
| Renal impairment | No dose adjustment required for GFR > 10 mL/min; for GFR < 10 mL/min, reduce dose by 50% and monitor serum levels |
| 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 and monitor levels |
| Pediatric use | Initial 5 mg/kg/day in divided doses every 6-8 hours, titrate based on serum levels; typical maintenance: 1-12 years: 20 mg/kg/day (max 800 mg/day), >12 years: 16 mg/kg/day (max 900 mg/day) |
| Geriatric use | Start at lower end of dosing range (e.g., 300 mg/day extended-release) with frequent monitoring due to decreased clearance; avoid doses exceeding 400 mg/day without serum level guidance |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for THEOPHYL (THEOPHYL).
| Breastfeeding | Theophylline is excreted into breast milk with a milk-to-plasma ratio of approximately 0.7. Infant exposure is estimated at 1-10% of maternal weight-adjusted dose. Caution is advised; monitor infant for irritability or jitteriness. The American Academy of Pediatrics considers it compatible with breastfeeding, but risk-benefit assessment should be individualized. |
| Teratogenic Risk | Theophylline is not considered a major human teratogen. First trimester: Limited data show no increased risk of major malformations above baseline. Second and third trimesters: No known teratogenic effects; however, neonatal withdrawal (irritability, jitteriness, apnea) may occur with third-trimester exposure. High maternal levels may be associated with fetal tachycardia and intrauterine growth restriction. |
■ FDA Black Box Warning
No FDA black box warning for theophylline.
| Serious Effects |
Hypersensitivity to theophylline or any component of the formulation. Concurrent use of other methylxanthines.
| Precautions | Narrow therapeutic index; monitor serum levels. Risk of cardiac arrhythmias and seizures, especially at high levels. Use with caution in patients with cardiac disease, hepatic impairment, or those receiving other methylxanthines. |
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| Fetal Monitoring | Monitor maternal serum theophylline levels (therapeutic range 5-15 mcg/mL), heart rate, and respiratory status. Fetal monitoring: assess fetal heart rate for tachycardia; perform nonstress test or biophysical profile if signs of fetal distress. Adjust dose to maintain lower end of therapeutic range due to decreased clearance in late pregnancy. |
| Fertility Effects | No known adverse effects on fertility in humans. Theophylline has not been associated with impairment of reproductive function in standard animal studies. No specific human fertility data reported. |