SOMOPHYLLIN
Clinical safety rating
cautionComprehensive clinical and safety monograph for SOMOPHYLLIN (SOMOPHYLLIN).
Theophylline is a methylxanthine that relaxes bronchial smooth muscle by inhibiting phosphodiesterase, increasing cAMP levels, and antagonizing adenosine receptors. It also has anti-inflammatory and immunomodulatory effects.
| Metabolism | Primarily hepatic via cytochrome P450 enzymes, mainly CYP1A2, with minor contributions from CYP2E1 and CYP3A4. Metabolized to 3-methylxanthine, 1,3-dimethyluric acid, and 1-methyluric acid. |
| Excretion | Theophylline is primarily eliminated by hepatic metabolism (>90%), with only about 10-15% excreted unchanged in urine. Renal excretion of the parent drug is minor; however, metabolites are excreted renally. Biliary/fecal excretion accounts for less than 1%. |
| Half-life | The terminal elimination half-life of theophylline is approximately 8 hours in healthy non-smoking adults (range 3-12 hours). It is prolonged in patients with hepatic cirrhosis (up to 30 hours), heart failure (up to 30 hours), and in neonates (20-30 hours). Smoking (including marijuana) decreases half-life to 4-5 hours. Half-life is shorter in children (3-5 hours). Clinical context: Due to narrow therapeutic index, half-life variability necessitates therapeutic drug monitoring. |
| Protein binding | Theophylline is approximately 40% bound to plasma proteins, primarily albumin. Protein binding is decreased in neonates, patients with hepatic disease, and in the presence of unbound fatty acids. |
| Volume of Distribution | The apparent volume of distribution (Vd) of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg). This approximates total body water. Vd is increased in premature infants (0.6-0.8 L/kg) and patients with hepatic disease. Clinical meaning: Vd is used to calculate loading dose. |
| Bioavailability | Oral immediate-release: 96-100% (rapidly and completely absorbed). Oral sustained-release: 80-100% depending on formulation. Rectal enema: 80-100%. Rectal suppository: 70-90%. IV: 100%. |
| Onset of Action | Intravenous (IV) bolus: Onset of bronchodilation occurs within 5-15 minutes. IV infusion: steady state achieved in about 4 half-lives. Oral immediate-release: onset within 30-60 minutes. Oral sustained-release: onset delayed, typically 2-4 hours. Rectal (enema/suppository): onset within 30-60 minutes. |
| Duration of Action | IV bolus: Duration of bronchodilation is 4-6 hours. Oral immediate-release: 4-6 hours. Oral sustained-release: 8-12 hours for twice-daily formulations, up to 24 hours for once-daily formulations. Clinical note: sustained-release forms designed to maintain therapeutic concentrations with fewer side effects. |
| Molecular Weight | 180.16 |
Oral: 200–400 mg every 6 hours; IV: 6 mg/kg loading dose over 30 minutes, then 0.4–0.6 mg/kg/h continuous infusion.
| Dosage form | ENEMA |
| Renal impairment | No adjustment necessary in renal impairment as theophylline is primarily hepatically metabolized. However, in severe renal failure (CrCl <10 mL/min), consider reducing dose by 25%. |
| Liver impairment | Child-Pugh Class A: reduce dose by 25%; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: reduce dose by 75% or avoid use. |
| Pediatric use | Loading dose: 6 mg/kg IV; maintenance: <1 year: (0.2 x age in weeks) + 5 mg/kg/day divided q4-6h; 1-9 years: 20-24 mg/kg/day divided q4-6h; >9 years: 16 mg/kg/day divided q4-6h. |
| Geriatric use | Elderly patients >60 years: reduce maintenance dose by 25-50% due to decreased clearance; monitor serum levels closely; target 5-15 mg/L. |
| 1st trimester | Avoid. Theophylline is not recommended in the first trimester due to potential teratogenic effects, though human data are limited. Use only if clearly needed. |
| 2nd trimester | Use with caution. Theophylline crosses the placenta and may cause neonatal tachycardia, irritability, and jitteriness. Monitor maternal serum levels and adjust dose to the lowest effective. |
| 3rd trimester | Use with caution. Near term, theophylline may accumulate in the fetus and cause neonatal withdrawal symptoms (e.g., irritability). Monitor closely and consider dose reduction. |
Clinical note
Comprehensive clinical and safety monograph for SOMOPHYLLIN (SOMOPHYLLIN).
| Placental transfer | Extensive. Theophylline freely crosses the placenta, achieving fetal serum concentrations similar to maternal levels. |
| Breastfeeding | Theophylline is excreted into breast milk in small amounts (about 1% of maternal dose). In infants, levels are low but may cause irritability or poor feeding. Monitor infant for signs of toxicity. Use lowest effective maternal dose and consider timing feeds to avoid peak milk levels. |
| Lactation Rating | L2 (Limited data - probably compatible) |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: No well-controlled studies; potential risk of minor malformations based on animal data. Second and third trimesters: No evidence of major teratogenicity; risk of fetal tachycardia and irritability due to transplacental passage; avoid high doses near term. |
| Fetal Monitoring | Maternal: Serum theophylline levels (target 5-15 mcg/mL), heart rate, respiratory status, signs of toxicity (nausea, tachycardia, arrhythmias). Fetal: Heart rate monitoring during labor; consider ultrasound for growth if high doses used. |
| Fertility Effects | No known adverse effects on human fertility. Animal studies show no impairment of fertility at therapeutic doses. |
■ FDA Black Box Warning
None. However, close monitoring of serum theophylline levels is required due to narrow therapeutic index.
| Serious Effects |
Hypersensitivity to theophylline or any componentActive seizure disorder (unless controlled with anticonvulsants and benefit outweighs risk)Uncontrolled cardiac arrhythmias (e.g., tachyarrhythmias)Hyperthyroidism (untreated or poorly controlled, as metabolism is altered)
| Precautions | Serum levels must be monitored to avoid toxicity (target 5-15 mcg/mL). Use with caution in patients with cardiac disease, seizure disorders, hepatic impairment, and elderly. Drug interactions (e.g., cimetidine, fluoroquinolones, macrolides) can increase levels. Smoking induces metabolism leading to decreased efficacy. |
| Food/Dietary | Avoid large amounts of caffeine-containing foods and beverages (coffee, tea, cola, chocolate) as they may increase central nervous system stimulation. Charcoal-broiled foods and high-protein/low-carbohydrate diets may increase clearance of theophylline, potentially reducing efficacy. |
| Clinical Pearls | SOMOPHYLLIN (theophylline) is a narrow therapeutic index drug; monitor serum levels (therapeutic range 5-15 μg/mL for asthma). Use with caution in patients with hepatic impairment, congestive heart failure, or elderly due to reduced clearance. Cigarette smoking and charcoal-broiled foods increase clearance, requiring dose adjustment. Concurrent use with cimetidine, fluoroquinolones, or macrolides can increase levels and toxicity. |
| Patient Advice | Take exactly as prescribed; do not change dose without consulting your doctor. · Avoid smoking and charcoal-grilled foods as they can affect drug levels. · Avoid caffeine-containing beverages and foods (coffee, tea, cola, chocolate) as they may increase side effects. · Report symptoms of toxicity: persistent nausea, vomiting, insomnia, palpitations, or seizures. · Missed dose: take as soon as remembered unless close to next dose; do not double dose. |
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