THEOPHYL-225
Clinical safety rating
cautionComprehensive clinical and safety monograph for THEOPHYL-225 (THEOPHYL-225).
Theophylline is a methylxanthine that inhibits phosphodiesterase, leading to increased intracellular cAMP levels, and antagonizes adenosine receptors (A1, A2). This results in bronchodilation, reduced airway inflammation, and enhanced diaphragmatic contractility.
| Metabolism | Primarily hepatic via CYP1A2 and to a lesser extent CYP2E1, CYP3A4; exhibits nonlinear pharmacokinetics at high concentrations. |
| Excretion | Renal: 10% unchanged; hepatic metabolism (CYP1A2, CYP3A4) accounts for ~90% of elimination, with metabolites (e.g., 3-methylxanthine, 1,3-dimethyluric acid) excreted renally. |
| Half-life | Terminal half-life: 3–12 hours (adults); shorter (1–5 hours) in children and smokers; prolonged in hepatic cirrhosis, heart failure, or elderly. Steady-state achieved in 1–2 days. |
| Protein binding | Approximately 40% bound to albumin (primarily); binding is concentration-independent. |
| Volume of Distribution | 0.3–0.7 L/kg; distributes freely into tissues and breast milk; Vd reflects moderate tissue penetration and rapid equilibration. |
| Bioavailability | Oral: 100% (complete absorption); bioavailability not significantly affected by food. Rectal: ~80% (variable due to absorption site). |
| Onset of Action | Oral: 30–60 minutes (immediate-release); 1–3 hours (extended-release). IV: 15–30 minutes. Rectal: 30–60 minutes. |
| Duration of Action | Immediate-release: 4–6 hours. Extended-release: 8–12 hours (or 12–24 hours for once-daily formulations). Duration correlates with half-life and formulation. |
| Molecular Weight | 180.164 |
225 mg orally every 6 hours; adjust based on serum theophylline levels to maintain therapeutic range 10-20 mcg/mL.
| Dosage form | ELIXIR |
| Renal impairment | No specific GFR-based adjustment required; monitor serum theophylline levels as renal impairment may affect clearance. |
| Liver impairment | Child-Pugh A: reduce dose by 50%; Child-Pugh B: reduce dose by 50-75%; Child-Pugh C: reduce dose by 75-90% or consider alternative. Frequent serum level monitoring is mandatory. |
| Pediatric use | Initial: 5 mg/kg orally every 6 hours; titrate based on serum levels. Usual maintenance: 10-20 mg/kg/day divided every 6 hours. Not recommended under 1 year without specialist advice. |
| Geriatric use | Start at lower dose (e.g., 112.5 mg every 6 hours) due to decreased clearance; titrate slowly with close serum level monitoring. Target lower end of therapeutic range (8-12 mcg/mL) if tolerated. |
| 1st trimester | Limited human data; animal studies show increased risk of congenital defects at high doses. Use only if clearly needed. |
| 2nd trimester | Monitor maternal serum levels closely; adjust dose to avoid toxicity. Associated with preterm labor and low birth weight. |
| 3rd trimester | Risk of neonatal irritability, jitteriness, and apnea if maternal levels high. Use lowest effective dose. |
Clinical note
Comprehensive clinical and safety monograph for THEOPHYL-225 (THEOPHYL-225).
| Placental transfer | Crosses placenta; fetal levels similar to maternal. Detected in amniotic fluid. |
| Breastfeeding | Enters breast milk in small amounts; infant serum levels ~10% of maternal. May cause irritability or insomnia in infant. Use caution, monitor infant for adverse effects. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Theophylline crosses the placenta. First trimester: No clear association with major malformations in human studies, but limited data. Second/third trimester: Risk of fetal tachycardia, jitteriness, and irritability at high maternal serum levels (toxicity). May cause transient neonatal withdrawal symptoms (apnea, vomiting) if used near term. |
| Fetal Monitoring | Monitor maternal serum theophylline levels (target 5-12 mcg/mL), heart rate, and signs of toxicity (nausea, palpitations, seizures). Fetal monitoring: assess heart rate for tachycardia, especially at higher maternal levels. Consider ultrasound for fetal growth if used long-term. |
| Fertility Effects | No significant adverse effects on fertility in human studies. Animal studies show no impairment at clinically relevant doses. |
■ FDA Black Box Warning
No FDA black box warning.
| Common Effects | Limited data available |
| Serious Effects |
Hypersensitivity to theophylline or xanthinesActive seizure disorder (uncontrolled)Severe hypotension
| Precautions | Narrow therapeutic index; serum levels must be monitored (target 5-15 mcg/mL), Risk of seizure and cardiac arrhythmias at toxic levels, Increased seizure risk in patients with preexisting seizure disorders, Use with caution in liver impairment, congestive heart failure, and elderly, May cause tachycardia, palpitations, and exacerbation of arrhythmias |
| Food/Dietary | Avoid excessive caffeine from coffee, tea, cola, and chocolate which can increase side effects. High-protein, low-carbohydrate diets may increase theophylline clearance. Charcoal-broiled foods and cruciferous vegetables (e.g., broccoli, cabbage) may induce metabolism and lower levels. |
| Clinical Pearls | Theophylline has a narrow therapeutic index; target serum concentration is 5-15 mcg/mL. Monitor levels due to variable clearance. CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine) and inducers (e.g., rifampin, smoking) significantly alter levels. Use with caution in hepatic impairment, heart failure, and elderly. Slow IV infusion over 20-30 minutes for loading dose to avoid hypotension and arrhythmias. Caffeine and theobromine (chocolate) can increase toxicity risk. |
| Patient Advice | Take the medication exactly as prescribed; do not change dose without consulting your doctor. · Avoid smoking and limit caffeine intake (coffee, tea, cola, chocolate) as they can affect drug levels. · Report symptoms of toxicity immediately: nausea, vomiting, diarrhea, restlessness, insomnia, rapid heartbeat, or seizures. · Do not crush or chew sustained-release tablets; swallow whole. · Keep all appointments for blood tests to monitor theophylline levels. · Inform your doctor of all medications you are taking, especially antibiotics, seizure medicines, and heart medications. |
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