Inititating Oral Therapy (Weinberger)

Weight-adjusted and maximal daily dose
Initial dose
  • ~10 mg/kg/d
  • Maximum 300 mg/d
If initial dose is tolerated, increase the dose no sooner than 3 days later to the 1st dose increase
1st dose increase
  • ~13 mg/kg/d
  • Maximum 450 mg/d
If the first dose increase is tolerated, increase the dose no sooner than 3 days later to the 2nd dose increase
2nd dose increase
  • ~16 mg/kg/d
  • Maximum 600 mg/d
  • Measure the peak serum concentration after at least 3 days at the highest tolerated dose
  • Adjust dose according to the peak serum concentration (see table below for when to draw and how to adjust)

Initial Dose Adjustment

Serum theophylline peak concentration (µg/mL)----
Adjustment to dose
Increase approximately 25%
10 to 15
Maintain dose if tolerated
15.1 to 19.9
Consider a reduction of approximately 10%
20 to 25
Withhold next dose, then resume treatment with next lower dose level
Withhold next 2 doses, then resume treatment with initial dose or lower dose
  • When to draw peak level varies with the form of theophylline used, see formulations section below

Monitoring and Target Serum Concentration

  • Efficacy and toxicity of theophylline are closely related to the peak serum concentration
  • After initial titration of the dose, check the serum concentration at the estimated peak (see tables below) every 12 months, unless a change in concomitant medications or health status (eg, pregnancy, symptoms of toxicity) dictates a shorter interval
Target peak serum concentration (µg/L)
  • Best documented to improve symptoms and reduce the need for rescue therapy for asthmatics on theophylline monotherapy
  • May be adequate for some patients, particularly if they are also receiving ICS
  • Bronchodilatory, antiinflammatory, and immunomodulatory effects of this drug are detectable at levels as low as 5 mg/L
  • Weinberger: recommend titrating dosage to a peak concentration of 10-15 with a formulation and dosing interval that will not result in large fluctuations between the peak and trough levels
  • Children: 5-10
  • Adults: 5-15
  • Whether this is a peak or trough is not specified
  • Trough of 10-15 may result in toxic peak levels

Theophylline Formulations

When to draw peak serum concentration
Variable depending on whether taken in the morning after an overnight fast, after breakfast, or in the evening
  • Incomplete absorption occurs when taken after an overnight fast
  • pH-dependent dissolution causes much more rapid (ie, dose-dumping) and complete absorption when taken after food or in the evening
Generic SR (slow release) tablets
3-7 h after morning dose when given q12 h
  • Scored tablets can be split without affecting absorption characteristics
  • Complete absorption occurs in the presence or absence of food
Generic SR (slow release) capsules
3-7 h after morning dose when given q12 h
  • Can be opened and sprinkled on a spoonful of soft food for children who cannot swallow the capsule
  • Contents must be swallowed without chewing
  • Complete absorption occurs in the presence or absence of food
8-12 h after qhs dose (next morning)
  • Incomplete absorption occurs when taken after overnight fast
  • More complete absorption occurs when taken after food or in the evening
  • Weinberger: recommend generic slow-release tablets or capsules for twice daily dosing, or Uniphyl taken with an evening meal for once daily dosing

Theophylline Adverse Effects

  • If a patient develops signs and symptoms of theophylline toxicity (eg, persistent, repetitive vomiting), a serum level should be measured and subsequent doses held

  • Adverse events observed at therapeuticserum levels:
    • Cardiovascular: Flutter, tachycardia
    • CNS: Headache, hyperactivity (children), insomnia, restlessness, seizures, tremor
    • Endocrine: Hypercalcemia (with concomitant hyperthyroid disease)
    • GI: Nausea, reflux or ulcer aggravation, vomiting
    • GU: Difficulty urinating (elderly males with prostatism)
    • Renal: diuresis (transient)
    • Theophylline may exacerbate disease in patients with existing tachyarrhythmias, hyperthyroidism, peptic ulcer disease, and seizure disorder
  • Theophylline clearance may be decreased in patients with acute pulmonary edema, CHF, cor pulmonale, fever, hepatic disease, acute hepatitis, cirrhosis, hypothyroidism, sepsis with multiorgan failure, and shock; clearance may also be decreased in neonates, infants <3 months of age with decreased renal function, children <1 year of age, the elderly >60 years of age, patients following cessation of smoking.

Clinically Significant Drug Interactions

Type of interaction
Effect on theophylline serum concentrations or pharmacologic effect
Theophylline blocks adenosine receptors
Higher doses of adenosine may be required to achieve desired anti-arrhythmic effect
A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours
33% increase
Decreases theophylline clearance at allopurinol doses ≥600 mg/day
25% increase
Increases theophylline clearance by induction of microsomal enzyme activity
25% decrease
Similar to aminoglutethimide
30% decrease
Decreases theophylline clearance by inhibiting cytochrome P450 1A2
70% increase
Similar to cimetidine
40% increase
Similar to erythromycin
25% increase
Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors
Larger diazepam doses may be required to produce desired level of sedation
Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression
Decreases theophylline clearance by inhibiting hydroxylation and demethylation
50% increase
Similar to cimetidine
300% increase
Synergistic CNS effects
Increased frequency of nausea, nervousness, and insomnia
Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3
35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount
Estrogen-containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown
30% increase
Similar to diazepam
Similar to diazepam
Similar to cimetidine
Similar to cimetidine
Halothane sensitizes the myocardium to catecholamines; theophylline increases release of endogenous catecholamines
Increased risk of ventricular arrhythmias
Interferon, human recombinant alpha-A
Decreases theophylline clearance
100% increase
Isoproterenol (IV)
Increases theophylline clearance
20% decrease
May lower theophylline seizure threshold
Theophylline increases lithium renal clearance
Lithium dose required to achieve a therapeutic serum concentration increased an average of 60 percent
Similar to diazepam
Similar to diazepam
Methotrexate (MTX)
Decreases theophylline clearance
20% increase after low-dose MTX, higher dose MTX may have a greater effect
Similar to disulfiram
80% increase
Similar to diazepam
Similar to diazepam
Increases theophylline clearance
25% decrease
Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition
Larger dose of pancuronium may be required to achieve neuromuscular blockade
Decreases theophylline clearance
30% increase
Phenobarbital (PB)
Similar to aminoglutethimide
25% decrease after more than two weeks of concurrent PB
Phenytoin increases theophylline clearance by increasing microsomal enzyme activity
Serum theophylline and phenytoin concentrations decrease about 40 percent
Theophylline decreases phenytoin absorption
Decreases theophylline clearance and pharmacologic interaction
40% increase. Beta-2-blocking effect may decrease efficacy of theophylline
Similar to cimetidine and pharmacologic interaction
100% increase. Beta-2-blocking effect may decrease efficacy of theophylline
Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity
20-40% decrease
Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline
20% decrease
Similar to cimetidine, also increases renal clearance of theophylline
90% increase
Decreases theophylline clearance
190% increase
Decreases theophylline clearance
60% increase
Similar to erythromycin
33-100% increase depending on troleandomycin dose
Similar to disulfiram
20 percent increase
Mechanism not studied; theophylline decreases either bioavailability or clearance of zafirlukast. Zafirlukast has no effect on theophylline clearance
Zafirlukast blood levels decrease an average of 40 percent, which is likely to render it ineffective
Zileuton inhibits cytochrome P-450 1A2 and, thus, decreases theophylline clearance
100% increase


Drugs that have been documented NOT to interact with theophylline or NOT to have clinically important interactions with theophylline
  • Albuterol
  • Amoxicillin, Ampicillin, with or without sulbactam
  • Atenolol
  • Azithromycin
  • Caffeine (dietary ingestion)
  • Cefaclor
  • Co-trimoxazole (trimethoprim and sulfamethoxazole)
  • Diltiazem
  • Dirithromycin
  • Enflurane
  • Famotidine
  • Felodipine
  • Fluoxetine
  • Finasteride
  • Hydrocortisone
  • Isoflurane
  • Isoniazid
  • Isradipine
  • Influenza vaccine
  • Ketoconazole
  • Lomefloxacin
  • Mebendazole
  • Medroxyprogesterone
  • Methylprednisolone
  • Metronidazole
  • Metoprolol
  • Nadolol
  • Nifedipine
  • Nizatidine
  • Norfloxacin
  • Ofloxacin
  • Omeprazole
  • Paroxetine
  • Prednisone, prednisolone
  • Ranitidine
  • Rifabutin
  • Roxithryomycin
  • Sertraline
  • Sorbitol (purgative doses do not inhibit theophylline absorption)
  • Sucralfate
  • Terbutaline, systemic
  • Terfenadine
  • Tetracycline
  • Tocainide