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Elixophylline (Theophylline) - Warnings and Precautions



Concurrent Illness:

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

  •  Active peptic ulcer disease
  •  Seizure disorders
  •  Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive motoring of serum theophylline concentrations in patients with the following risk factors:


  •  Neonates (term and premature)
  •  Children <1 year
  •  Elderly (>60 years)

Concurrent Diseases

  •  Acute pulmonary edema
  •  Congestive heart failure
  •  Cor pulmonale
  •  Fever; ≥102°F for 24 hours or more; or lesser temperature elevations for longer periods
  •  Hypothyroidism
  •  Liver disease; cirrhosis, acute hepatitis
  •  Reduced renal function in infants <3 months of age
  •  Sepsis with multi-organ failure
  •  Shock

Cessation of Smoking

Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II).

When Signs or Symptoms of Theophylline Toxicity Are Present:

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI).

Dosage Increases:

Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests).

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).



Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient's clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations:

Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

  • When initiating therapy to guide final dosage adjustment after titration.
  • Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
  • Whenever signs or symptoms of theophylline toxicity are present.
  • Whenever there is a new illness, worsening of a chronic illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 1-2 hours after a dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than two hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests:

As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 μeq/l to 800 μeq/l), total cholesterol (from a mean of 140 vs 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

Information for Patients:

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Drug Interactions:

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*.
Drug Type of Interaction Effect**

* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.

** Average effect on steady state theophylline concentration or other clinical effect forpharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

AdenosineTheophylline blocksHigher doses of adenosine
adenosine receptors.may be required to achieve
desired effect.
AlcoholA single large dose of alcohol30% increase
(3 ml/kg of whiskey) decreases
theophylline clearance for up
to 24 hours
AllopurinolDecreases theophylline clearance25% increase at allopurinol
doses ≥600 mg/day.
Amino glutethimideIncreases theophylline clearance25% decrease
by induction of microsomal enzyme
CarbamazepineSimilar to aminoglutethimide30% decrease
CimetidineDecreases theophylline clearance70% increase
by inhibiting cytochrome P450 1A2.
CiprofloxacinSimilar to cimetidine.40% increase
ClarithromycinSimilar to erythromycin.25% increase
DiazepamBenzodiazepines increase CNSLarger diazepam doses
concentrations of adenosine, a potentmay be required to
CNS depressant, while theophyllineproduce desired level of
blocks adenosine receptors.sedation. Discontinuation
of theophylline without
reduction of diazepam
dose may result in
respiratory depression.
DisulfiramDecreases theophylline clearance50% increase
by inhibiting hydroxylation and
EnoxacinSimilar to cimetidine.300% increase
EphedrineSynergistic CNS effects.Increased frequency of
nausea, nervousness,
and insomnia.
ErythromycinErythromycin metabolite decreases35% increase.
theophylline clearance by inhibitingErythromycin steady-state
cytochrome P450 3A3serum concentrations
decrease by a similar amount.
EstrogenEstrogen containing oral contraceptives decrease theophylline30% increase
clearance in a dose-dependent fashion.
The effect of progesterone on theophylline
clearance is unknown.
FlurazepamSimilar to diazepam.Similar to diazepam.
FluvoxamineSimilar to cimetidine.Similar to cimetidine.
HalothaneHalothane sensitizes theIncreased risk of ventricular
myocardium to catecholamines,arrhythmias
theophylline increases release of
endogenous catecholamines.
Interferon, humanDecreases theophylline clearance.100% increase
recombinant alpha-A
Isoproterenol (IV)Increases theophylline clearance.20% decrease
KetaminePharmacologicMay lower theophylline
seizure threshold.
LithiumTheophylline increases renalLithium dose required to
lithium clearance.achieve a therapeutic
serum concentration
increased an average of
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 antagonizeLarger dose of pancuronium may be required to
non-depolarizing neuromuscular
blocking effects; possibly due toachieve neuromuscular
phosphodiesterase inhibition.blockade.
PentoxifyllineDecreases theophylline clearance.30% increase
Phenobarbital (PB)Similar to aminoglutethimide.25% decrease after two
weeks of concurrent PB.
PhenytoinPhenytoin increases theophyllineSerum theophylline and
clearance by increasing microsomalphenytoin concentrations
enzyme activity. Theophylline decreases phenytoin absorption.decrease about 40%.
PropafenoneDecreases theophylline clearance40% increase. Beta-2
and pharmacologic interaction.blocking effect may
decrease efficacy of theophylline.
PropranololSimilar to cimetidine and100% increase. Beta-2
pharmacologic interaction.blocking effect may
decrease efficacy
of theophylline.
RifampinIncreases theophylline clearance20-40% decrease
by increasing cytochrome P450 1A2
and 3A3 activity.
SulfinpyrazoneIncreases theophylline clearance by20% decrease
increasing demethylation and hydroxyllation.
Decreases renal clearance of
TacrineSimilar to cimetidine, also increases90% increase
renal clearance of theophylline.
ThiabendazoleDecreases theophylline clearance.190% increase
TiclopidineDecreases theophylline clearance.60% increase
TroleandomycinSimilar to erythromycin.33-100% increase depending
on troleandomycin dose.
VerapamilSimilar to disulfiram.20% increase
Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

   systemic and inhaledmebendazole
   with or without sulbactammetronidazole
   dietary ingestionnizatidine
   (trimethoprim andomeprazole
   sulfamethoxazole)prednisone, prednisolone
felodipine   (purgative doses do not
finasteride   inhibit theophylline
hydrocortisone   absorption)
isoniazid terbutaline,systemic
influenza vaccinetetracycline

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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75mg/kg). Results are pending.

Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose.

In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.


CATEGORY C: There are no adequate and well controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents (e.g., rabbits). Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m2 basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

Nursing Mothers:

Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline per day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

Pediatric Use:

Theophylline is safe and effective for the approved indications in pediatric patients (See INDICATIONS AND USAGE). The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V). Due to the immaturity of theophylline metabolic pathways in infants under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group.

Geriatric Use:

Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline dose. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum daily dose of theophylline in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady state serum theophylline concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION). Theophylline doses greater than 400 mg/d should be prescribed with caution in elderly patients.

Page last updated: 2006-10-16

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