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Theolair

SIDE EFFECTS

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). 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 age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V). 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.*

  Percentage of Patients Reported With Sign or Symptom
Acute Overdose
(Large Single Ingestion)
Chronic Overdosage
(Multiple Excessive Doses)
Sign/Symptom Study 1
(n=157)
Study 2
(n=14)
Study 1
(n=92)
Study 2
(n=102)
Asymptomatic NR** 0 NR** 6
Gastrointestinal
  Vomiting 73 93 30 61
  Abdominal Pain NR** 21 NR** 12
  Diarrhea NR** 0 NR** 14
  Hematemesis NR** 0 NR** 2
Metabolic/Other
  Hypokalemia 85 79 44 43
  Hyperglycemia 98 NR** 18 NR**
  Acid/base disturbance 34 21 9 5
  Rhabdomyolysis NR** 7 NR** 0
Cardiovascular
  Sinus tachycardia 100 86 100 62
  Other supraventricular tachycardias 2 21 12 14
  Ventricular premature beats 3 21 10 19
  Atrial fibrillation or flutter 1 NR** 12 NR**
  Multifocal atrial tachycardia 0 NR** 2 NR**
  Ventricular arrhythmias with hemodynamic instability 7 14 40 0
  Hypotension/shock NR** 21 NR** 8
Neurologic
  Nervousness NR** 64 NR** 21
  Tremors 38 29 16 14
  Disorientation NR** 7 NR** 11
  Seizures 5 14 14 5
Death 3 21 10 4
* 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.

Read the Theolair (theophylline) Side Effects Center for a complete guide to possible side effects

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 June, 1996. 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**
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
Amino-glutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P-450 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 P-450 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 unkown. 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 (IV) 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 Decreases theophylline clearance. (MTX) higher dose MTX may have a greater effect. 20% increase after low dose MTX,
Mexiletine Similar to disulfiram. 80% increase
Midazolam Similar to diazepam. Similar to diazepam.
Moricizine Increases theophylline clearance. 25% decrease
Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; due to phosphodiesterase inhibition. Larger dose of pancuronium possibly 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 PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Serum theophylline and phenytoin concentrations decrease about Theophylline decreases phenytoin 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. beta2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. beta2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P-450 1A2 and 3A3 activity. 20-40% decrease
Sulfinpyrazone Increases theophylline clearance by in-creasing 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
* 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.

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 inhaled mebendazole
amoxicillin medroxyprogesterone
ampicillin, with or without sulbactam methylprednisolone
atenolol metronidazole
azithromycin metoprolol
caffeine, dietary ingestion nadolol
cefaclor nifedipine
co-trimoxazole (trimethoprim and sulfamethoxazole) nizatidine
norfloxacin
diltiazem ofloxacin
dirithromycin omeprazole
enflurane prednisone, prednisolone
famotidine ranitidine
felodipine rifabutin
finasteride roxithromycin
hydrocortisone sorbitol (purgative doses do not inhibittheophylline absorption)
isoflurane
isoniazid sucralfate
isradipine terbutaline, systemic
influenza vaccine terfenadine
ketoconazole tetracycline
lomefloxacin tocainide
* Refer to PRECAUTIONS: DRUG INTERACTIONS for information regarding table.

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.

Read the Theolair Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 4/7/2009
This monograph has been modified to include the generic and brand name in many instances.

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