What is 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:

Serious side effects of Elixophyllin include:

Drug interactions of Elixophyllin include:

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

What are the important side effects of Elixophyllin (theophylline)?

Common side effects are:

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.

Elixophyllin (theophylline) side effects list for healthcare professionals

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.*

Sign/SymptomPercentage of patients reported with sign or symptom
Acute Overdose
(Large Single Inges tion)
Chronic Overdos age
(Multiple Exces sive Doses )
Study 1
(n=157)
Study 2
(n=14)
Study 1
(n=92)
Study 2
(n=102)
AsymptomaticNR**0NR**6
Gastrointestinal
  Vomiting73933061
  Abdominal PainNR**21NR**12
  DiarrheaNR**0NR**14
  HematemesisNR**0NR**2
Metabolic/Other
  Hypokalemia85794443
  Hyperglycemia98NR**18NR**
  Acid/base disturbance342195
  RhabdomyolysisNR**7NR**0
Cardiovascular
  Sinus tachycardia1008610062
  Other supraventricular tachycardias2211214
  Ventricular premature beats3211019
  Atrial fibrillation or flutter1NR**12NR**
  Multifocal atrial tachycardia0NR**2NR**
  Ventricular arrhythmias with hemodynamic instability714400
  Hypotension/shockNR**21NR**8
Neurologic
  NervousnessNR**64NR**21
  Tremors38291614
  DisorientationNR**7NR**11
  Seizures514145
  Death321104
*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 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.

What drugs interact with Elixophyllin (theophylline)?

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*.

DrugType of InteractionEffect**
AdenosineTheophylline blocks adenosine receptors.Higher doses of adenosine may be required to achieve desired effect.
AlcoholA single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.30% increase
AllopurinolDecreases theophylline clearance at allopurinol doses ≥ 600 mg/day.25% increase
Amino glutethimideIncreases theophylline clearance by induction of microsomal enzyme activity.25% decrease
CarbamazepineSimilar to aminoglutethimide.30% decrease
CimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2.70% increase
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
Diazepam DisulfiramBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Decreases theophylline clearance by inhibiting hydroxylation and demethylation.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. 50% increase
EnoxacinSimilar to cimetidine.300% increase
EphedrineSynergistic CNS effectsIncreased frequency of nausea, nervousness, and insomnia.
ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.30% increase
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidineSimilar to cimetidine
HalothaneHalothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-ADecreases theophylline clearance.100% increase
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline seizure threshold.
LithiumTheophylline increases renal lithium clearance.Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
LorazepamSimilar to diazepam.Similar to diazepam.
Methotrexate (MTX)Decreases theophylline clearance.20% increase after low dose MTX, higher dose MTX may have a greater effect.
MexiletineSimilar to disulfiram.80% increase
MidazolamSimilar to diazepam.Similar to diazepam.
MoricizineIncreases theophylline clearance.25% decrease
PancuroniumTheophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.Larger dose of pancuronium may be required to achieve neuromuscular blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two weeks of concurrent PB.
PhenytoinPhenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.Serum theophylline and phenytoin concentrations decrease about 40%.
PropafenoneDecreases theophylline clearance and pharmacologic interaction.40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
PropranololSimilar to cimetidine and pharmacologic interaction.100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
RifampinIncreases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.20-40% decrease
SulfinpyrazoneIncreases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearanc of theophylline.20% decrease e
T acrineSimilar to cimetidine, also increases renal clearance of theophylline.90% increase
ThiabendazoleDecreases theophylline clearance.190% increase
T iclo pidineDecreases theophylline clearance.60% increase
TroleandomyciniSimilar to erythromycin.33-100% increase depending on troleandomycin dose.
VerapamilSimilar to disulfiram.20% increase
*Refer to product labeling for more information.
**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 inhaledfelodipinefinasteridenizatidine
norfloxacin
amoxicillinhydrocortisoneofloxacin
ampicillin, with or withoutisoflurane isoniazidomeprazole prednisone,
sulbactam atenololisradipineprednisolone ranitidine
azithromycininfluenza vaccinerifabutin
caffeine, dietary ingestionketoconazo lelomefloxacinroxithromycin sorbitol (purgative doses do not inhibit theophylline absorption)
cefaclormebendazole
co-trimoxazole (trimethoprim and sulfamethoxazole)medroxyprogesterone
methylprednisolone
diltiazemmetronidazolesucralfate
dirithromycinmetoprololterbutaline, systemic
enfluranenadololterfenadine
famotidinenifedipinetetracycline tocainide
*Refer to product labeling for more information.

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.

Summary

Elixophyllin (theophylline) is a bronchodilator used to relieve and prevent airway narrowing (bronchospasm) in patients with asthma. Common side effects of Elixophyllin include nausea, vomiting, diarrhea, headaches, irritability, flushing, and palpitations. Serious side effects of Elixophyllin include seizures and heart arrhythmias. 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.

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Medically Reviewed on 5/13/2020
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