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warnings
WARNINGS 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 monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature), children less than 1 year, elderly (greter than 60 years). Concurrent Diseases Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (greater than or equal to 102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants less than 3 months of age, sepsis with multi-organ failure, and 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 cortico-steroids 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).
ADVERSE REACTIONS Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are less than 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., greater than 300 mg/day in adults and greater than 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 (less than 3% of children and less than 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 to 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 less than 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 greater than or equal to 15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations less than 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 less than 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 less than 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 Asymotomatic Gastointestinal Study 1 Study 2 (n= 157) (n= 14) NR† 0 Study 1 Study 2 (n=92) (n=102) NR† 6 Vomiting Abdominal Pain Diarrhea Hematemesis 73 93 NR† 21 NR† 0 NR† 0 30 61 NR† 12 NR† 14 NR† 2 Metabolic/Other Hypokalemia Hyperglycemia Acid/base disturbance Rhabdomyolysis 85 79 98 NR† 34 21 NR† 7 44 43 18 NR† 9 5 NR† 0 Cardiovascular Sinus tachycardia Other supraventricular tachycardias Ventricular premature beats Atrial fibrillation or flutter Multifocal atrial tachycardia Ventricular arrhythmias hemodynamic instability Hypotension/shock 100 86 2 21 3 21 1 NR† 0 NR† 7 14 NR† 21 100 62 12 14 10 19 12 NR† 2 NR† 40 0 NR† 8 Neurologic Nervousness Tremors Disorientation Seizures Death NR† 64 38 29 NR† 7 5 14 3 21 NR† 21 16 14 NR† 11 14 5 10 4 * These data are derived from two studies in patients with serum theophylline concentrations greater than 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 greater than 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.
adverse reactions
ADVERSE REACTIONS Oral administration of choline at high doses up to 15 grams daily is generally well tolerated. The most common adverse reactions of higher doses — from 15 to 30 grams daily — are nausea, abdominal cramps, and diarrhea. Some patients may experience these symptoms at lower doses. The total combined amount of amino acids in each Sentra AM capsule does not exceed 400 mg.