Inititating Oral Therapy (Weinberger)


Weight-adjusted and maximal daily dose
Comments
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
<10
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
>25
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)
Comments
10-20
  • Best documented to improve symptoms and reduce the need for rescue therapy for asthmatics on theophylline monotherapy
5-10
  • 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
10-15
  • 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
Lexicomp:
  • 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

Formulation
When to draw peak serum concentration
Comments
Theo-24
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
Uniphyl
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

Drug
Type of interaction
Effect on theophylline serum concentrations or pharmacologic effect
Adenosine
Theophylline blocks adenosine receptors
Higher doses of adenosine may be required to achieve desired anti-arrhythmic effect
Alcohol
A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours
33% increase
Allopurinol
Decreases theophylline clearance at allopurinol doses ≥600 mg/day
25% increase
Aminoglutethimide
Increases theophylline clearance by induction of microsomal enzyme activity
25% decrease
Carbamazepine
Similar to aminoglutethimide
30% decrease
Cimetidine
Decreases theophylline clearance by inhibiting cytochrome P450 1A2
70% increase
Ciprofloxacin
Similar to cimetidine
40% increase
Clarithromycin
Similar to erythromycin
25% increase
Diazepam
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
Disulfiram
Decreases theophylline clearance by inhibiting hydroxylation and demethylation
50% increase
Enoxacin
Similar to cimetidine
300% increase
Ephedrine
Synergistic CNS effects
Increased frequency of nausea, nervousness, and insomnia
Erythromycin
Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3
35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount
Estrogen
Estrogen-containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown
30% increase
Flurazepam
Similar to diazepam
Similar to diazepam
Fluvoxamine
Similar to cimetidine
Similar to cimetidine
Halothane
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
Ketamine
Pharmacologic
May lower theophylline seizure threshold
Lithium
Theophylline increases lithium renal clearance
Lithium dose required to achieve a therapeutic serum concentration increased an average of 60 percent
Lorazepam
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
Mexiletine
Similar to disulfiram
80% increase
Midazolam
Similar to diazepam
Similar to diazepam
Moricizine
Increases theophylline clearance
25% decrease
Pancuronium
Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition
Larger dose of pancuronium may be required to achieve neuromuscular blockade
Pentoxifylline
Decreases theophylline clearance
30% increase
Phenobarbital (PB)
Similar to aminoglutethimide
25% decrease after more than two weeks of concurrent PB
Phenytoin
Phenytoin increases theophylline clearance by increasing microsomal enzyme activity
Serum theophylline and phenytoin concentrations decrease about 40 percent
Theophylline decreases phenytoin absorption
Propafenone
Decreases theophylline clearance and pharmacologic interaction
40% increase. Beta-2-blocking effect may decrease efficacy of theophylline
Propranolol
Similar to cimetidine and pharmacologic interaction
100% increase. Beta-2-blocking effect may decrease efficacy of theophylline
Rifampin
Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity
20-40% decrease
Sulfinpyrazone
Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline
20% decrease
Tacrine
Similar to cimetidine, also increases renal clearance of theophylline
90% increase
Thiabendazole
Decreases theophylline clearance
190% increase
Ticlopidine
Decreases theophylline clearance
60% increase
Troleandomycin
Similar to erythromycin
33-100% increase depending on troleandomycin dose
Verapamil
Similar to disulfiram
20 percent increase
Zafirlukast
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
Zileuton inhibits cytochrome P-450 1A2 and, thus, decreases theophylline clearance
100% increase

Theo_drug_interactions.png

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

References