Side Effects of Elixophyllin (theophylline)

Elixophyllin (theophylline) is a bronchodilator used to relieve and prevent airway narrowing (bronchospasm) in patients with asthma. 

Elixophyllin also can be used to treat patients with emphysema and chronic bronchitis when their symptoms are related to reversible airway narrowing. Elixophyllin can be administered together with other bronchodilators, such as albuterol for added bronchodilator effect. 

Asthma is a breathing problem caused by narrowing of the airways, the breathing passages that allow air to move in and out of the lungs. Airways can be narrowed due to accumulation of mucus, spasm of the muscles that surround these airways, or swelling of the lining of the airways. 

Airway narrowing leads to symptoms of shortness of breath, wheezing, cough, and congestion. The narrowed airways can open either spontaneously or with medications. 

Elixophyllin opens airways by relaxing the smooth muscles in the walls of the airways. Elixophyllin also can be helpful in patients with emphysema and chronic bronchitis when their symptoms are partially related to reversible airway narrowing. Elixophyllin also strengthens right heart function and diaphragm movement. 

Common side effects of Elixophyllin include:

• nausea,
• vomiting,
• diarrhea,
• headaches,
• irritability,
• flushing, and
• palpitations.

Serious side effects of Elixophyllin include:

• seizures and
• heart arrhythmias. 

Drug interactions of Elixophyllin include:

• ephedrine,
• allopurinol,
• cimetidine,
• ciprofloxacin,
• clarithromycin,
• itraconazole,
• ketoconazole,
• erythromycin,
• oral contraceptives,
• fluvoxamine, and
• propranolol.
  • These interactions can elevate Elixophyllin blood levels and cause:
    • nausea,
    • vomiting,
    • insomnia,
    • seizures,
    • agitation and
    • life-threatening heart rhythm abnormalities. 

St. John’s wort, rifampin, and carbamazepine decrease levels of Elixophyllin and potentially its effect by increasing its elimination. 

Elixophyllin may decrease levels and the effect of carbamazepine by increasing its elimination. 

There are no adequate studies of Elixophyllin in pregnant women. Elixophyllin is excreted in breast milk and may cause mild side effects such as irritability in the infant. Consult your doctor before breastfeeding. 

Common side effects are:

• nausea,
• vomiting,
• diarrhea,
• headaches,
• irritability,
• flushing and
• palpitations.

Other important and more serious side effects include seizures and heart arrhythmias. Theophylline should be used cautiously in patients with high blood pressure, peptic ulcer disease, seizure disorders, and serious heart disease, especially heart rhythm problems.

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.

The transient caffeine-like 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 agerelated maximum dose will significantly reduce the frequency of these transient adverse effects (see 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.*

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 steady-state 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 Table II and III are current as of February 9, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician 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*.

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

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.