Theophylline:Tips for Safe and Effective Use

December 31, 2006

Theophylline has numerouswell-documented and clinicallysignificant drug interactions.Several diseases alsoaffect theophylline clearance.Here, I provide examples of drug anddisease interactions that are most relevantto office practice.

Theophylline has numerouswell-documented and clinicallysignificant drug interactions.Several diseases alsoaffect theophylline clearance.Here, I provide examples of drug anddisease interactions that are most relevantto office practice.During the past decade, the useof theophylline has declined becauseof concerns about serious adverseeffects.1-6 In addition, safer and moreefficacious therapies for asthma7 andchronic obstructive pulmonary disease(COPD)8,9 have become available.However, millions of patientscontinue to take theophylline as maintenancetherapy--among them, thosewith COPD who use this drug as a"step 3" agent after inhaled bronchodilators,including long- and short-actingβ2-agonists and anticholinergics.8,9Although long-acting inhaled β2-agonistsare the agents of choice for nocturnalasthma not controlled by inhaledcorticosteroids and environmentalmeasures, an evening dose oftheophylline is an effective alternative.10 In addition to its other pharmacologicproperties, theophylline hasmild anti-inflammatory effects.11MAINTAININGTHERAPEUTIC SERUMCONCENTRATIONSBecause of the potential toxicityof this drug, appropriate initial andmaintenance dosages--as well asserum theophylline concentration(STC) monitoring--are essential.7,11Table 1 lists factors that must be addressedto ensure the safe use oftheophylline. When the NIH Guidelinesfor the Diagnosis and Managementof Asthma were originally publishedin 1991 (and updated in 1997),the therapeutic range for STC was es-tablished as 5 to 15 μg/mL in patientswith asthma. 7 There is no advantageto pushing the steady-state STC higherthan 15 μg/mL (a range of 10 to 20μg/mL was formerly recommended),but there is potential danger in doingso if a factor that increases STC, suchas a drug, is added.In patients with COPD, a steadystateSTC range of 5 to 15 μg/mL isalso appropriate. Some experts recommenda range of 8 to 12 μg/mL.9Start with a low dose. If a higherdose is indicated, increase slowly andmonitor the STC. The initial doses listedin the updated FDA guidelines12(which are also given in the productliterature for theophylline products)usually result in an STC in the therapeuticrange, assuming drug interactionsand other factors that affecttheophylline levels are appropriatelymanaged.THEOPHYLLINE-DRUGINTERACTIONSTable 2 provides examples ofdrugs that may increase STC; Table 3lists drugs that may cause a declinein STC. Table 4 summarizes the ef-fects of theophylline on other drugs.Careful attention to these interactionsand appropriate management of themcan help reduce risk of serious toxicityor subtherapeutic effect.Knowledge of the time courseof interactions is important. For example,most studies have shown thata 5-day or shorter course of erythromycinproduces no interaction,whereas a 7- to 10-day course has amarked effect. On the other hand,cimetidine reduces theophyllineclearance within 1 day.Adjust the theophylline dosagewhen starting and discontinuinginteracting drugs, and monitor theSTC. However, it is far preferableto circumvent an interaction; for example,if an H2-blocker is indicated,select one other than cimetidine.Although theophylline interactswith numerous drugs, not all wellknowninhibitors of drug metabolismaffect theophylline, which ismetabolized by cytochrome P-450isozymes CYP1A2, CYP2E1, andCYP3A3.11 If new drugs are releasedon the market that are known inhibitorsof these isozymes, it can beanticipated--pending the results ofcontrolled trials--that these agentsmay interact with theophylline.EFFECT OF DISEASE ONTHEOPHYLLINECONCENTRATIONAlthough it is perhaps easier toremember theophylline-drug interactions,it is no less important to considerthe effect of disease on dosing requirements.The literature gives ample evidencethat failure to do so may provecatastrophic.13 Although much of thedata regarding the effects of liver dis-ease and heart failure were publishedin the mid to late 1970s, evidence publishedin the late 1990s clearly showsthat the dangers associated with thesediseases and theophylline are stillsometimes overlooked.6 Table 5 listsdiseases that may increase STC as wellas those that may reduce it.OTHER FACTORSTO CONSIDERTo prescribe theophylline safely,the patient's age, ideal body weight,diet, and smoking history must betaken into account. For example,young children metabolize theophyllinefaster than adults and generallyrequire higher mg/kg doses.11 Cigarettesmoking usually shortens theelimination half-life in adults to valuessimilar to those in children; however,within 1 week of smoking cessation,theophylline elimination is slowed bymore than 30%.11,14 "Dose dumping,"or rapid absorption, may occur whensome--but not all--sustained-releaseproducts are taken with a high-fatmeal.11

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