THEO-24
Clinical safety rating: caution
Comprehensive clinical and safety monograph for THEO-24 (THEO-24).
Theophylline, a xanthine derivative, acts as a non-selective phosphodiesterase (PDE) inhibitor (primarily PDE3 and PDE4), increasing intracellular cAMP and cGMP in airway smooth muscle and inflammatory cells. It also antagonizes adenosine receptors (A1, A2), stimulates endogenous catecholamine release, and may enhance histone deacetylase activity, reducing inflammation.
| Metabolism | Primarily hepatic via cytochrome P450 CYP1A2, with minor contributions from CYP2E1 and CYP3A4. Metabolized to 1,3-dimethyluric acid, 3-methylxanthine, and 1-methyluric acid. Saturable metabolism leads to non-linear pharmacokinetics at high doses. |
| Excretion | Approximately 90% of theophylline is eliminated hepatically via metabolism (principally CYP1A2 and CYP3A4), with less than 10% excreted unchanged in urine. Renal excretion of unchanged drug is minimal (about 5%) in adults. Biliary/fecal excretion accounts for less than 1%. |
| Half-life | Terminal elimination half-life is approximately 3–8 hours in adults (non-smokers), 4–5 hours in smokers (due to enzyme induction), and highly variable in neonates (24–36 hours) and children (1–9 hours). Half-life is prolonged in cirrhosis (up to 30 hours), heart failure, and with concomitant medications (e.g., cimetidine, erythromycin). |
| Protein binding | Approximately 53–65% bound to albumin in plasma. Binding is saturable and decreases at high concentrations, leading to increased free fraction. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 0.3–0.7 L/kg (average 0.45 L/kg), indicating distribution into total body water. Vd is larger in neonates and smaller in obese individuals. It does not correlate with therapeutic effect; therapeutic range is based on serum concentration. |
| Bioavailability | Oral bioavailability is nearly 100% for theophylline base (rapid absorption). For THEO-24 sustained-release capsules, bioavailability is 100% relative to immediate-release, though absorption is slower and pH-dependent. Food may slightly decrease rate but not extent of absorption. |
| Onset of Action | For oral immediate-release theophylline, onset of action is 30–60 minutes. For sustained-release formulations such as THEO-24, onset is 1–2 hours. Peak effect for bronchodilation occurs at the time of peak serum concentration (Cmax). |
| Duration of Action | Duration depends on formulation. For THEO-24 (once-daily sustained-release), duration is approximately 12–24 hours, with steady-state maintained over 24 hours when dosed appropriately. Clinical effect (bronchodilation) persists as long as serum levels remain within the therapeutic range (10–20 mcg/mL). |
300-600 mg orally once daily, extended-release capsule; individualize based on serum theophylline concentration targeting 5-15 mcg/mL.
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | No specific GFR-based dose adjustment recommended; monitor serum theophylline levels and adjust dose accordingly due to potential accumulation in renal impairment. |
| Liver impairment | For Child-Pugh class A: reduce dose by 50%; Child-Pugh class B: reduce dose by 50% and monitor levels; Child-Pugh class C: avoid use or use extreme caution with 25% of normal dose and frequent monitoring. |
| Pediatric use | Initial dose: 10-14 mg/kg/day orally in divided doses every 12 hours (extended-release); maximum 300 mg/day for children <1 year; adjust based on serum theophylline levels. |
| Geriatric use | Start at lower end of dosing range (300 mg once daily) with cautious titration; monitor serum theophylline levels closely due to decreased clearance and increased risk of toxicity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for THEO-24 (THEO-24).
| Breastfeeding | Theophylline is excreted into breast milk; M/P ratio approximately 0.7. Infant serum levels can reach therapeutic or toxic ranges. Potential for irritability and insomnia in breastfed infants. Use with caution; monitor infant for signs of theophylline toxicity. |
| Teratogenic Risk | Theophylline (THEO-24) is pregnancy category C. First trimester: Limited data suggest no increased risk of major malformations; however, rare associations with cardiac defects reported. Second and third trimesters: Possible fetal tachycardia, irritability, and jitteriness at birth due to placental transfer; no known teratogenicity. |
■ FDA Black Box Warning
None
| Serious Effects |
["Hypersensitivity to theophylline or any component of the formulation.","Seizure disorders (relative contraindication; may lower seizure threshold).","Active peptic ulcer disease (relative).","Uncontrolled cardiac arrhythmias (relative)."]
| Precautions | ["Narrow therapeutic index; serum concentrations should be monitored (therapeutic range 10-20 mcg/mL for asthma/COPD).","Toxicity risk increased with doses > 400 mg/day or serum levels > 20 mcg/mL; symptoms include nausea, vomiting, diarrhea, headache, insomnia, irritability, and at higher levels, tachycardia, seizures, and cardiac arrest.","Risk of status epilepticus and fatal outcome with seizures.","Use caution in patients with peptic ulcer disease, hyperthyroidism, seizure disorders, hepatic or renal impairment, or cardiac disease (e.g., arrhythmias, congestive heart failure).","Interactions with drugs that inhibit CYP1A2 (e.g., cimetidine, ciprofloxacin, fluvoxamine, macrolides) increase toxicity.","Interactions with drugs that induce CYP1A2 (e.g., rifampin, phenobarbital, carbamazepine, smoking) decrease efficacy.","Elderly, acutely ill, or patients with cor pulmonale have reduced clearance.","Hypersensitivity to theophylline or other xanthines.","Pregnancy category C (risks not ruled out)."] |
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| Fetal Monitoring | Monitor maternal serum theophylline levels (target 5-15 mcg/mL). Fetal heart rate monitoring for tachycardia. Assess for maternal adverse effects (nausea, vomiting, arrhythmias). In neonates, monitor for withdrawal or toxicity if used near term. |
| Fertility Effects | No established effects on fertility in humans. Animal studies not suggestive of impaired fertility. |