ELIXOPHYLLIN SR
Clinical safety rating
cautionComprehensive clinical and safety monograph for ELIXOPHYLLIN SR (ELIXOPHYLLIN SR).
Theophylline relaxes bronchial smooth muscle by inhibiting phosphodiesterase, increasing intracellular cAMP, and antagonizing adenosine receptors. It also has anti-inflammatory effects by reducing eosinophil infiltration and cytokine release.
| Metabolism | Hepatic via cytochrome P450 isoenzymes, primarily CYP1A2, with minor contributions from CYP2E1 and CYP3A4. |
| Excretion | Renal: approximately 90% of the dose is eliminated via hepatic metabolism (N-demethylation and hydroxylation), with about 10% excreted unchanged in urine. The primary metabolites are 1-methylxanthine, 1,3-dimethyluric acid, and 3-methylxanthine. Fecal excretion is negligible (<1%). |
| Half-life | Terminal elimination half-life: 7-9 hours in adults (nonsmokers). In smokers, hepatic clearance is increased, reducing half-life to 4-5 hours. In patients with hepatic cirrhosis, half-life may extend to 24 hours. In neonates, half-life is prolonged (20-30 hours). |
| Protein binding | Approximately 40% bound to albumin. Binding is reversible and concentration-independent. |
| Volume of Distribution | Apparent Vd: 0.3-0.7 L/kg. This reflects distribution throughout total body water, with slightly higher distribution in neonates (0.8-1.0 L/kg) due to lower protein binding. The Vd is relatively small, indicating limited tissue binding. |
| Bioavailability | Oral (sustained-release): 96-100% relative to oral immediate-release formulations. The sustained-release formulation yields lower peak concentrations but similar AUC. Food may increase peak concentration slightly (by about 10%) but does not affect overall bioavailability. |
| Onset of Action | Oral (sustained-release): 2-4 hours to reach therapeutic serum concentrations; peak effect at steady state (typically 2-3 days). Intravenous (aminophylline): within 30 minutes. Rectal: 1-2 hours. |
| Duration of Action | Sustained-release oral formulation: 12-14 hours. Provides stable serum levels with twice-daily dosing. Bronchodilation is maintained as long as serum concentrations remain within the therapeutic range (10-20 mcg/mL). |
| Molecular Weight | 180.17 |
300-600 mg orally every 12 hours; extended-release tablets. Adjust based on serum theophylline concentrations (target 5-15 mcg/mL).
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | No specific GFR-based dose reduction required; monitor serum levels closely. Theophylline clearance may be decreased in patients with impaired renal function, necessitating dose individualization. |
| Liver impairment | Child-Pugh A: reduce dose by 50%; Child-Pugh B: reduce dose by 50-75%; Child-Pugh C: reduce dose by 75% or avoid use. These recommendations are based on decreased clearance; monitor serum levels. |
| Pediatric use | Initial dose: 10-14 mg/kg/day orally divided every 12 hours; may increase gradually based on serum concentrations. Maximum: 16 mg/kg/day for children 1-9 years; 12 mg/kg/day for children 9-16 years. Use extended-release tablets only in children who can swallow tablets whole. |
| Geriatric use | Lower initial doses recommended (e.g., 300 mg/day) due to reduced clearance; monitor serum theophylline concentrations closely. Avoid in patients with significant cardiac or hepatic impairment. |
| 1st trimester | Theophylline crosses the placenta; limited human data show no consistent association with major malformations. Use only if clearly needed. |
| 2nd trimester | Monitor maternal serum levels close to therapeutic range (10-20 mcg/mL); avoid toxicity as fetal effects may occur. Dose adjustments may be needed due to physiological changes. |
| 3rd trimester | Neonatal toxicity (tachycardia, irritability, vomiting) may occur if maternal levels are high near term; avoid excessive dosing. Clearance decreases in late pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for ELIXOPHYLLIN SR (ELIXOPHYLLIN SR).
| Placental transfer | Theophylline crosses the placenta readily; cord blood levels are similar to maternal serum levels. Fetal concentrations approximate maternal levels. |
| Breastfeeding | Theophylline is excreted into breast milk (approximately 60-70% of maternal plasma levels). In therapeutic maternal doses, adverse effects in infants are rare but include irritability, insomnia, and, with high maternal levels, toxicity. Monitor infant for signs of caffeine-like effects. Use caution, especially in premature infants or those with impaired clearance. |
| Lactation Rating | L2 (Limited Data - Probably Compatible) |
| Teratogenic Risk | Theophylline crosses the placenta. First trimester: Limited data, but no major teratogenic effects reported in human studies; animal studies show no evidence of teratogenicity. Second and third trimesters: No known teratogenic risk; fetal serum levels approximate maternal levels. Use only if clearly needed. |
| Fetal Monitoring | Monitor maternal serum theophylline concentrations to maintain therapeutic range (10-20 mcg/mL). Assess maternal respiratory status and symptoms of toxicity (tachycardia, nausea, vomiting, seizures). Fetal monitoring includes assessment of fetal heart rate and growth via ultrasound; consider non-stress testing in third trimester if maternal condition warrants. |
| Fertility Effects | No documented effects on human fertility. Animal studies suggest no significant reproductive impairment at clinically relevant doses. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to theophylline or any component of the formulationPre-existing cardiac arrhythmias (e.g., tachyarrhythmias) unless controlledSeizure disorders (unless adequately controlled with anticonvulsants) - relative caution, but significant history may contraindicate
| Precautions | Consider dose adjustment in patients with hepatic impairment, cardiac dysfunction, or those on drugs that alter theophylline metabolism (e.g., cimetidine, fluoroquinolones, macrolides)., Monitor serum theophylline levels to avoid toxicity (therapeutic range: 10-20 mcg/mL)., Seizure, cardiac arrhythmias, and death can occur at high serum concentrations., Use with caution in patients with peptic ulcer disease, seizures, or hypothyroidism., Elderly patients and those with underlying cardiac disease are at increased risk of adverse effects. |
| Food/Dietary | Avoid large amounts of caffeine (coffee, tea, chocolate). Charcoal-grilled foods may decrease absorption. High-protein, low-carbohydrate diets may alter metabolism. |
| Clinical Pearls | Monitor serum theophylline levels (therapeutic range 10-20 mcg/mL). Sustained-release formulation allows twice-daily dosing. Use with caution in patients with hepatic impairment, heart failure, or fever, as clearance is reduced. Caffeine may increase toxicity. |
| Patient Advice | Swallow tablet whole; do not crush or chew. · Take doses 12 hours apart consistently with or without food. · Avoid caffeine-containing beverages and foods. · Report symptoms of toxicity: nausea, vomiting, insomnia, palpitations. · Do not change brand without consulting prescriber. |
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