The apparent low adverse effect profile of the new drug zafirlukast has made it an attractive choice in the treatment of asthma. We present the first case (to our knowledge) of a potentially serious drug-drug interaction between zafirlukast and theophylline. A 15-year-old white girl with asthma had been taking theophylline (Slo-bid, Rhone-Poulenc Rorer Pharmaceuticals Inc, Collegeville, Pa) (300 mg twice daily), with drug levels of approximately 61 µmol/L (11.0 µg/mL) for several years. Recently, her serum theophylline levels had increased to the toxic range (133.2 µmol/L [24 µg/mL]) shortly after the addition of zafirlukast (Accolate, Zeneca Pharmaceuticals, Wilmington, Del) to her regimen. Attempts were made to stop and then restart the theophylline therapy at progressively lower doses; however, with each attempt, the patient's reaction to the drug became more toxic, with serum theophylline levels ranging between 99.9 and 149.9 µmol/L (18 and 27 µg/mL). So this potential drug-drug interaction could be investigated, the patient stopped taking both drugs for 1 week. Then, she again started taking theophylline (75 mg twice daily), and over 2 days reached a steady state serum theophylline level of 12.8 to 14.4 µmol/L (2.3-2.6 µg/mL). On the third day, zafirlukast (20 mg twice daily) was reintroduced to the regimen, and the theophylline therapy was continued. By the fifth day, a dramatic 7-fold increase was seen in the serum theophylline level (101.6 µmol/L [18.3 µg/mL]). The areas under the curve for theophylline alone and theophylline with zafirlukast were 29.3 and 197 (mg·h)/L, respectively. One explanation for the noted increase in the theophylline level is that metabolism occurs mainly by cytochrome P450 (CYP 1A2), an enzyme that is known to be inhibited with high concentrations of zafirlukast. Although the current metabolism of the 2 drugs in combination is poorly understood, the potential for serious interactions seems to exist in the rapidly growing population of persons with asthma, for whom they may be prescribed. The noted increase in the theophylline level after zafirlukast administration is in contrast to the original reports by the manufacturer. Therefore, we recommend that physicians evaluate serum theophylline levels closely when prescribing the 2 drugs in combination.
Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more
Subscribe for full-text access to content from 1998 forward and a host of useful features
Activate your current subscription (AMA members and current subscribers)
Purchase Online Access to this article for 24 hours
Theophylline concentration vs time in relation to the administration of zafirlukast. To convert values to micromoles per liter, multiply by 5.55.
Thank you for submitting a comment on this article. It will be reviewed by JAMA Internal Medicine editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 14
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
The Rational Clinical Examination
Cross-Reactivity With Other -Lactam Antibiotics
All results at
and access these and other features:
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.