"The U.S. Food and Drug Administration is alerting hospitals, health care professionals, and patients of a voluntary recall of all non-expired drug products produced and distributed for sterile use by Abrams Royal Compounding Pharmacy in Dallas, T"...
(Generic versions may still be available.)
Serum levels above 20 pg/mL are rarely found after appropriate administration of the recommended doses. However, in individuals in whom theophylline plasma clearance is reduced for any reason, even conventional doses may result in increased serum levels and potential toxicity. Reduced theophylline clearance has been documented in the following readily identifiable groups: 1) patients with impaired liver function; 2) patients over 55 years of age, particularly males and those with chronic lung disease; 3) those with cardiac failure from any cause; 4) patients with sustained high fever; 5) neonates and infants under 1 year of age; and 6) those patients taking certain drugs (see DRUG INTERACTIONS). Frequently, such patients have markedly prolonged theophylline serum levels following discontinuation of the drug.
It is important to consider reduction of dosage and measurement of serum theophylline levels in the above individuals.
Reduction of dosage and laboratory monitoring is especially appropriate in the above individuals.
Serious side effects such as ventricular arrhythmias, convulsions, or even death may appear as the first sign of toxicity without any previous warning. Less serious signs of theophylline toxicity (i.e.,nausea and restlessness) may occur frequently when initiating therapy, but are usually transient; when such signs are persistent during maintenance therapy, they are often associated with serum concentrations above 20 pg/mL. Stated differently, serious toxicity is not reliably preceded by less severe side effects. A serum concentration measurement is the only reliable method of identifying a potential for life-threatening toxicity.
Many patients who require theophylline exhibit tachycardia due to their underlying disease process, so the cause/effect relationship to elevated serum theophylline concentrations may not be appreciated. Theophylline products may cause or worsen arrhythmias and any significant change in rate and/or rhythm warrants monitoring and further investigation.
Studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The significance of these findings when applied to humans is currently unknown.
On the average, theophylline half-life is shorter in cigarette and marijuana smokers than in nonsmokers, but smokers can have half-lives as long as nonsmokers.
Theophylline should not be administered concurrently with other xanthine preparations. Use with caution in patients with hypoxemia, hypertension, or with a history of peptic ulcer. Theophylline may occasionally act as a local irritant to the GI tract, although GI symptoms are more commonly centrally mediated and associated with serum drug concentrations over 20 pg/mL.
Xanthines can potentiate hypokalemia resulting from beta 2 agonist therapy, steroids, diuretics, other xanthines and hypoxia. Particular caution is advised in severe asthma. It is recommended that serum potassium levels be monitored in such situations.
Information for Patients
See PATIENT INFORMATION section.
Serum levels should be monitored periodically to determine the theophylline level associated with observed clinical response and to identify the potential for toxicity. For such measurements, the serum sample should be obtained at the time of peak concentration, 1 to 2 hours after administration for immediate-release products. It is important that the patient has not missed or taken additional doses during the previous 48 hours and that dosing intervals have been reasonably equally spaced. DOSAGE ADJUSTMENT BASED ON SERUM THEOPHYLLINE MEASUREMENTS WHEN THESE INSTRUCTIONS HAVE NOT BEEN FOLLOWED MAY RESULT IN RECOMMENDATIONS THAT PRESENT RISK OF TOXICITY TO THE PATIENT.
See DRUG INTERACTIONS section.
Drug/ Laboratory Test Interactions
Currently available analytical methods, including high pressure liquid chromatography and immunoassay techniques, for measuring serum theophylline levels are specific. Metabolites and other drugs generally do not affect the results. Other new analytic methods are also now in use. The physician should be aware of the laboratory method used and whether other drugs will interfere with the assay for theophylline.
Long-term carcinogenicity studies have not been performed with theophylline. Chromosome-breaking activity was detected in human cell cultures at concentrations of theophylline up to 50 times the therapeutic serum concentration in humans. Theophylline was not mutagenic in the dominant lethal assay in male mice given theophylline intraperitoneally in doses up to 30 times the maximum daily human oral dose. Studies to determine the effect on fertility have not been performed with theophylline.
Category C - Reproduction studies performed in mice and rats at oral doses from 7 to 17 times the human dose (maximum human dose for adults assumed to be 13 mg/kg/day) have indicated that theophylline may cause malformations, but these effects only occurred at or near doses that were toxic to the maternal animals. There are no adequate and well-controlled studies in pregnant women. It is not known whether theophylline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Theophylline is distributed into breast milk and may cause irritability or other signs of toxicity in nursing infants. Because of the potential for serious adverse reactions in nursing infants from theophylline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Sufficient numbers of infants under the age of 1 year have not been studied in clinical trials to support use in this age group; however, there is evidence recorded that the use of dosage recommendations for older infants and young pediatric patients (16 mg/kg/24 hours) may result in the development of toxic serum levels. Such findings very probably reflect differences in the metabolic handling of the drug related to absent or undeveloped enzyme systems. Consequently, prescribers of the drug for this age group should carefully consider the associated benefits and risks. If used, the maintenance dose must be conservative and in accord with the following guidelines:
Initial Maintenance Dosage of Theophylline, Anhydrous
Up to 24 days postnatal age - 1.0 mg/kg q12h
Beyond 24 days postnatal age - 1.5 mg/kg ql2h
Infants 6 to 52 weeks:
[(0.2x age in weeks) + 5.0] x kg body wt = 24 hour dose in mg.
Up to 26 weeks, divide into q8h dosing intervals.
From 26-52 weeks, divide into q6h dosing intervals.
Final Dosage should be guided by serum concentration after a steady state (no further accumulation of drug) has been achieved.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
Additional Slo-phyllin Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.