Intravenous theophylline is indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.
Contraindications
Aminophylline is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product including ethylenediamine.
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 infusion rate 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 monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature) Children <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor pulmonale Fever; ≥102° 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), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately.
Dosage Increases Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is <10 mcg/mL. 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 infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION , TABLE VI ).
Interactions
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 Tables II and III are current as of September 1, 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 for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. 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 a dose-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 increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (I.V.) 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 Phenobarbital.
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 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 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. albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide The Effect of Other Drugs on Theophylline Serum Concent
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Pregnancy and breastfeeding
Pregnancy: Category C: There are no adequate and well controlled studies in pregnant women. Additionally, there are no teratogenicity studies in nonrodents (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/m 2 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/m 2 basis.
At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.
Adverse reactions
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 ).
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).
Products containing aminophylline may rarely produce severe allergic reactions of the skin, including exfoliative dermatitis, after systemic administration in a patient who has been previously sensitized by topical application of a substance containing ethylenediamine. In such patients skin patch tests are positive for ethylenediamine, a component of aminophylline, and negative for theophylline. Pharmacists and other individuals who experience repeated skin exposure while physically handling aminophylline may develop a contact dermatitis due to the ethylenediamine component.
Table IV. Manifestations of Theophylline Toxicity* Percentage of Patients Reported With Sign or Symptom * 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.
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