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Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are < 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE). The transient caffeinelike adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., > 300 mg/day in adults and > 12 mg/kg/day in children beyond > 1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V). In a small percentage of patients ( < 3% of children and < 10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.
Other adverse reactions that have been reported at serum theophylline concentrations < 20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥ 15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations < 20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations < 20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations < 20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
TABLE IV. Manifestations of
theophylline toxicity. *
|Percentage of patients reported with sign or symptom|
(Large Single Ingestion)
(Multiple Excessive Doses)
(n = 157)
(n = 14)
(n = 92)
(n = 102)
|Other supraventricular tachycardias||2||21||12||14|
|Ventricular premature beats||3||21||10||19|
|Atrial fibrillation or flutter||1||NR**||12||NR**|
|Multifocal atrial tachycardia||0||NR**||2||NR**|
|Ventricular arrhythmias with hemodynamic instability||7||14||40||0|
|*These data are derived from two studies in patients with serum theophylline concentrations > 30 mcg/mL. In the first study (Study #1—Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2—Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations > 30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results.
**NR = Not reported in a comparable manner.
Read the Uniphyl (theophylline anhydrous tablet) Side Effects Center for a complete guide to possible side effects
Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steadystate theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., < 15% change in theophylline clearance).
The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.
TABLE II. Clinically significant
drug interactions with theophylline.*
|Drug||Type of Interaction||Effect**|
|Adenosine||Theophylline blocks adenosine receptors.||Higher doses of adenosine may be required to achieve desired effect.|
|Alcohol||A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.||30% 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 adose-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 increasesrelease 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 renal lithium clearance.||Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.|
|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 nondepolarizing 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 two weeks of concurrent PB.|
|Phenytoin||Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.||Serum theophylline and phenytoin concentrations decrease about 40%.|
|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|
|St. John's Wort (Hypericum Perforatum)||Decrease in theophylline plasma concentrations.||Higher doses of theophylline may be required to achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity.|
|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% increase|
|*Refer to PRECAUTIONS, Drug Interactions
for further information regarding table.
**Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
TABLE III. Drugs that have been
documented not to interact with theophylline or drugs that produce no
clinically significant interaction with theophylline. *
|albuterol, systemic and inhaled||mebendazole|
|ampicillin, with or without sulbactam||methylprednisolone|
|caffeine, dietary ingestion||nadolol|
|co-trimoxazole (trimethoprim and||nizatidine|
|hydrocortisone||sorbitol (purgative doses do not inhibit|
|*Refer to PRECAUTIONS: DRUG INTERACTIONS for information regarding table.|
The bioavailability of Uniphyl® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three singledose studies, subjects given Uniphyl (theophylline anhydrous tablet) 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics, Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.
The Effect of Other Drugs on Theophylline Serum Concentration Measurements
Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.
Read the Uniphyl Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/30/2009
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