Theophylline

Approved Indications:

• Chronic Asthma: Maintenance therapy for mild to moderate persistent asthma not adequately controlled with inhaled corticosteroids.
• Chronic Obstructive Pulmonary Disease (COPD): Adjunctive treatment in stable COPD to improve airflow and reduce symptoms.
• Apnea of Prematurity (especially theophylline derivatives like aminophylline): Treatment and prevention of apnea episodes in neonates.

Clinically Accepted Off-Label Uses:

• Obstructive Sleep Apnea (OSA): As adjunctive therapy in select cases.
• Bronchospasm from Heart Failure: Occasionally used in pulmonary edema-related wheezing.
• Post-extubation Respiratory Failure in premature infants.
• Refractory Status Asthmaticus (IV form as last-line therapy).

Route of Administration: Oral (tablet, capsule, syrup), Intravenous (IV injection/infusion), Rectal (less common)

Adults:

• Asthma/COPD (Oral): 300–600 mg/day in divided doses.
• Start with 200–300 mg/day; titrate based on serum levels.
• Max: 900–1000 mg/day in divided doses depending on formulation.
• IV Loading Dose: 4.6 mg/kg (ideal body weight) over 30 minutes, followed by maintenance infusion.

Pediatrics:

• Children (1–9 years): 16 mg/kg/day (max 400 mg/day); may increase to 24 mg/kg/day under monitoring.
• Neonates (Apnea of Prematurity):
• Loading: 4–6 mg/kg IV or orally
• Maintenance: 2 mg/kg every 12 hours or continuous infusion

Elderly:

• Start at lower end of dosage range (e.g., 200 mg/day)
• Monitor closely due to reduced clearance.

Renal/Hepatic Impairment:

• Hepatic Impairment: Dose reduction required.
• Renal Impairment: Caution with metabolites accumulation; monitor levels.

Monitoring:

• Therapeutic range: 10–20 mcg/mL
• Monitor serum levels regularly, especially during dose adjustments.

Theophylline is a methylxanthine derivative that acts primarily by inhibiting phosphodiesterase (PDE) enzymes, particularly PDE III and PDE IV, leading to increased intracellular cyclic AMP (cAMP). This results in bronchodilation, reduced inflammatory mediator release, and improved diaphragmatic contractility. Theophylline also antagonizes adenosine receptors in the CNS and airways, contributing to bronchodilation and respiratory stimulation. Its immunomodulatory and mild anti-inflammatory effects further enhance its utility in chronic respiratory diseases.

• Absorption: Rapid and nearly complete oral absorption (bioavailability ~90–100%)
• Distribution: Widely distributed; volume of distribution ~0.5 L/kg
• Protein Binding: ~40%
• Metabolism: Hepatic via CYP1A2, CYP2E1, and CYP3A4 pathways
• Active Metabolites: 1-methyluric acid, 3-methylxanthine
• Elimination Half-life:
• Adults: 7–9 hours
• Neonates: Up to 24–36 hours (immature hepatic metabolism)
• Smokers: Shortened (4–5 hours)
• Excretion: Mainly renal as metabolites (~90%); unchanged drug <10%

• Pregnancy: Not assigned a formal FDA category (former Category C). Use only if potential benefit justifies potential fetal risk. Theophylline crosses the placenta.
• Lactation: Excreted in breast milk. May cause irritability or feeding problems in the infant. Monitor infants for signs of toxicity.

• Primary Class: Methylxanthine Bronchodilator
• Subclass: Non-selective Phosphodiesterase Inhibitor
• Related Compounds: Caffeine, Aminophylline (a salt of Theophylline)

• Known hypersensitivity to Theophylline or other xanthine derivatives
• Active peptic ulcer disease
• Uncontrolled seizure disorders
• Recent myocardial infarction (IV form, relative contraindication)
• Tachyarrhythmias (e.g., atrial fibrillation)

• Narrow Therapeutic Index: Requires close monitoring of serum levels.
• Seizure Risk: May lower seizure threshold, especially at toxic levels.
• Cardiovascular Caution: Use cautiously in patients with arrhythmias or heart failure.
• Drug Interactions: Many CYP inhibitors/inducers alter clearance.
• Smoking & Diet Impact: Tobacco and high-protein diets increase clearance.
• Monitoring: Regular blood levels, liver function tests in long-term use.

Common (dose-dependent):

• Gastrointestinal: Nausea, vomiting, diarrhea
• CNS: Headache, insomnia, irritability, restlessness
• Cardiac: Tachycardia, palpitations

Serious:

• Seizures (especially at >20 mcg/mL)
• Ventricular arrhythmias
• Hypotension (IV overdose)
• Hepatotoxicity (rare)

Rare:

• Rhabdomyolysis
• Allergic rash
• Hyperglycemia or hypokalemia

Major Interactions:

• CYP1A2 Inhibitors (e.g., ciprofloxacin, fluvoxamine, cimetidine): Increase Theophylline levels → toxicity.
• CYP Inducers (e.g., phenytoin, rifampicin, smoking): Decrease levels → reduced efficacy.
• Macrolides (e.g., erythromycin): May increase serum concentration.
• Fluoroquinolones (e.g., ciprofloxacin): Potent CYP1A2 inhibition → toxicity risk.

Food/Alcohol:

• High-fat meals can delay absorption of extended-release forms.
• Alcohol may increase CNS side effects.

• Global Initiative for Asthma (GINA) Guidelines: Theophylline no longer recommended as a first-line controller therapy due to safety concerns and superior alternatives.
• FDA Alerts: Continued monitoring advised due to high inter-individual variability in metabolism and risk of toxicity.
• EMA Recommendations: Emphasis on therapeutic drug monitoring and individualized dosing.

• Oral Tablets/Capsules:
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• IV Solution:
• Store at 2°C to 8°C (refrigerated)
• Do not freeze; protect from excessive heat
• Handling: Shake liquid formulations well before use; avoid prolonged exposure to air.