THEOPHYL
Clinical safety rating
cautionComprehensive 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). |
| Molecular Weight | 180.16 |
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 | Crosses placenta; associated with increased risk of congenital malformations and spontaneous abortion; avoid if possible. |
| 2nd trimester | Use with caution; monitor maternal serum levels and adjust dose; risk of fetal tachycardia and neonatal withdrawal. |
| 3rd trimester | Use with caution near term; may cause neonatal irritability, tachycardia, and respiratory distress; dose adjustment may be needed. |
Clinical note
Comprehensive clinical and safety monograph for THEOPHYL (THEOPHYL).
| Placental transfer | Theophylline readily crosses the placenta, achieving maternal and fetal serum concentrations approximately equal. |
| Breastfeeding | Theophylline is excreted into breast milk in small amounts (about 1% of maternal dose). Adverse effects in breastfed infants are rare but may include irritability and insomnia. Monitor infant for signs of toxicity, especially if maternal levels are high. Use with caution; consider alternative agents if infant is premature or has compromised hepatic function. |
| Lactation Rating | L3 (Moderately Safe) |
| 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. |
| 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. |
■ FDA Black Box Warning
No FDA black box warning for theophylline.
| Serious Effects |
Hypersensitivity to theophylline or any component of the formulationConcurrent use of ephedrine in pediatric patients
| 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. |
| Food/Dietary | High-carbohydrate, low-protein diets can increase theophylline toxicity by reducing clearance. Charcoal-broiled meats and cruciferous vegetables (broccoli, Brussels sprouts, kale) may increase metabolism, potentially reducing efficacy. Avoid large amounts of caffeine-containing products (coffee, tea, cola, energy drinks) as they can exacerbate CNS and cardiac adverse effects. |
| Clinical Pearls | Theophylline has a narrow therapeutic index (5-15 mcg/mL). Monitor serum levels closely, especially when interacting drugs (e.g., cimetidine, fluoroquinolones, macrolides) are added or removed. Use with caution in patients with hepatic impairment, heart failure, or COPD exacerbation as clearance decreases. Cigarette smoking induces metabolism, requiring dose adjustments. Slow IV infusion over 20-30 minutes to avoid hypotension and arrhythmias. |
| Patient Advice | Take exactly as prescribed; do not change dose or stop without consulting your doctor. · Avoid smoking or use of nicotine products as they alter theophylline levels. · Report nausea, vomiting, insomnia, palpitations, or seizures immediately. · Limit caffeine intake (coffee, tea, chocolate, cola) as it may increase side effects. · Store medication at room temperature away from moisture and heat. · Keep regular appointments for blood level monitoring. |
Loading safety data…