Drug Interactions between Symbicort and theophylline

MONITOR: The concomitant use of theophylline and corticosteroids may theoretically increase the risk of hypokalemia due to additive potassium-lowering effects. Additionally, theophylline serum concentrations may be altered. The mechanism is unknown and data have been limited and conflicting; increased, decreased, and unchanged theophylline levels have all been reported.

MANAGEMENT: Monitoring for altered efficacy and safety of theophylline and altered serum potassium and theophylline concentrations is advisable when these drugs are coadministered. Patients should be advised to notify their physician if they experience signs of hypokalemia (e.g., weakness, lethargy, and muscle pains or cramps), worsening respiratory symptoms, or signs of theophylline toxicity (e.g., nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat).

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MONITOR: Concomitant use of beta-2 adrenergic agonists with theophylline may increase the risk and/or severity of hypokalemia and adverse cardiovascular effects such as palpitation, tachycardia, and blood pressure elevation. Adverse events, especially hypokalemia, may be more likely with systemic or nebulized formulations of beta-2 agonists or high dosages of theophylline. Beta-2 agonists can cause clinically significant but usually transient decreases in serum potassium concentrations, while hypokalemia associated with theophylline often occurs in toxicity. Serious events including rare cases of cardiorespiratory arrest and intestinal pseudo-obstruction have been reported in association with hypokalemia induced by these agents. Moreover, since QT prolongation is a possible side effect of beta-2 agonists, development of hypokalemia may potentiate the risk of torsade de pointes and other serious arrhythmias. Pharmacokinetically, some beta-2 agonists given systemically may decrease the plasma concentrations of theophylline. Albuterol, isoproterenol, and terbutaline have been specifically implicated, usually increasing theophylline clearance by approximately 10% to a third, although some studies with albuterol and terbutaline failed to demonstrate a significant effect on theophylline pharmacokinetics. The interaction also did not occur in studies with fenoterol, formoterol, and metaproterenol. A case report describes a significant increase in theophylline clearance during intravenous administration of albuterol in a 19-month-old child with severe asthma, who subsequently required a threefold increase in theophylline dosage. Theophylline clearance decreased by 50% upon discontinuation of albuterol. In another case, a greater than 4-fold increase in theophylline clearance was reported following the intravenous administration of isoproterenol and methylprednisolone in a critically patient receiving aminophylline and nebulized terbutaline.

MANAGEMENT: Although theophylline and beta-2 agonists are commonly used together to produce bronchodilation, it may be appropriate to monitor patient response as well as serum potassium level, blood pressure and heart rate during coadministration, especially if the beta-2 agonist is administered systemically or by nebulizer. Close monitoring is particularly important in patients with severe asthma, since the potential increases in blood pressure and heart rate may have more serious consequences in the presence of hypoxemia or hypercapnia due to increased myocardial oxygen consumption. Patients should be advised to notify their physician if they experience worsening of their respiratory condition or potential signs and symptoms of hypokalemia such as fatigue, weakness, myalgia, muscle cramps, numbness, tingling, abdominal pain, constipation, palpitation, and irregular heartbeat.

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Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.

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