Prescription Drugs

DESCRIPTION Slo-Phyllin® Tablets (theophylline tablets, USP) are scored, dye-free tablets providing 100 mg or 200 mg of theophylline, anhydrous, USP. Slo-Phyllin® 80mg Syrup (theophylline, anhydrous) is a nonalcoholic sugar-free solution containing per 15 mL theophylline, anhydrous, USP. 80 mg with sodium benzoate, NF, 18 mg and methylparaben, NF, 3 mg added as preservatives. Both tablets and syrup are intended for oral administration. Theophylline is a bronchodilator structurally classified as a xanthine derivative. Theophylline is a 1H-Purine-2,6-dione,3,7-dihydro,1,3-dimethyl-. The molecular formula of theophylline, anhydrous is C7H8N4O2 with a molecular weight of 180.17. Theophylline is a white odorless crystalline powder having a bitter taste. Inactive Ingredients (theophylline, anhydrous) Syrup: Citric acid, FD&C Red No. 40, flavors, glycerin, methylparaben, propylene glycol, saccharin sodium, sodium benzoate, sorbitol, purified water. Tablets 100 mg: Lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate; Tablets 200 mg: Magnesium stearate, microcrystalline cellulose, sodium starch glycolate.

INDICATIONS For relief and/or prevention of symptoms of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. DOSAGE AND ADMINISTRATION Effective use of theophylline (i.e.,the concentration of drug in the serum associated with optimal benefit and minimal risk of toxicity) is considered to occur when the theophylline concentration is maintained from 10 to 20 pg/mL. The early studies from which these levels were derived were carried out in patients immediately or shortly after recovery from acute exacerbations of their disease (some hospitalized with status asthmaticus). Although the 20 µg/mL level remains appropriate as a critical value (above which toxicity is more likely to occur) for safety purposes, additional data are now available which indicate that the serum theophylline concentrations required to produce maximum physiologic benefit may, in fact, fluctuate with the degree of bronchospasm present and are variable. Therefore, the physician should individualize the range appropriate to the patients requirements, based on both symptomatic response and improvement in pulmonary function. It should be stressed that serum theophylline concentrations maintained at the upper level of the 10 to 20 pg/mL range may be associated with potential toxicity when factors known to reduce theophylline clearance are operative (see WARNINGS). If it is not possible to obtain serum level determinations, restriction of the daily dose (in otherwise healthy adults) to not greater than 13 mg/kg/day to a maximum of 900 mg of anhydrous theophylline in divided doses will result in relatively few patients exceeding serum levels of 20 pg/mL and the resultant greater risk of toxicity. Caution should be exercised for younger children who cannot complain of minor side effects. Older adults, those with cor pulmonale, congestive heart failure, and/or liver disease may have unusually low dosage requirements and thus may experience toxicity at the maximal dosage recommended below. Theophylline does not distribute into fatty tissue. Dosage should be calculated on the basis of lean (ideal) body weight where mg/kg doses are presented. Frequency of Dosing When immediate-release products with rapid absorption are used, dosing to maintain serum levels generally requires administration every 6 hours. This is particularly true in children, but dosing intervals up to 8 hours may be satisfactory in adults since they eliminate the drug at a slower rate. Some children, and adults requiring higher than average doses (those having rapid rates of clearance, e.g., half-lives of under 6 hours) may benefit and be more effectively controlled during chronic therapy when given products with extended-release characteristics, since these provide longer dosing intervals and/or less fluctuation in serum concentration between dosing. Dosage guidelines are approximations only and the wide range of theophylline clearance between individuals (particularly those with concomitant disease) make indiscriminate usage hazardous. Dosage Guidelines I. Acute Symptoms of Asthma or Bronchospasm Requiring Rapid Attainment of Theophylline Serum Levels NOTE: Status asthmaticus should be considered a medical emergency and is defined as that degree of bronchospasm which is not rapidly responsive to usual doses of conventional bronchodilators. Optimal therapy for such patients frequently requires both additional medication, parenterally administered, and close monitoring, preferably in an intensive care setting. A. Patients not currently receiving theophylline products: Theophylline Dosage Oral Loading Maintenance Children age 1 to under 9 years 5 mg/kg 4 mg/kg q 6 hours Children age 9 to under 16 years; and smokers 5 mg/kg 3 mg/kg q 6 hours Otherwise healthy nonsmoking adults 5 mg/kg 3 mg/kg q 8 hours Older patients and patients with cor pulmonale 5 mg/kg 2 mg/kg q 8 hours Patients with congestive heart failure 5 mg/kg 1-2 mg/kg q 12 hours B. Patients currently receiving theophylline products: Determine, where possible, the time, amount, dosage form, and route of administration of the last dose the patient received. The loading dose for theophylline is based on the principle that each 0.5 mg/kg of theophylline administered as a loading dose will result in a 1.0 µg/mL increase in serum theophylline concentration. Ideally, the loading dose should be deferred if a serum theophylline concentration can be obtained rapidly. If this is not possible, the clinician must exercise judgment in selecting a dose based on the potential for benefit and risk. When there is sufficient respiratory distress to warrant a small risk, then 2.5 mg/kg of theophylline administered in rapidly absorbed form is likely to increase serum concentration by approximately 5 pg/mL. If the patient is not experiencing theophylline toxicity, this is unlikely to result in dangerous adverse effects. Subsequent to the decision regarding use of a loading dose for this group of patients, the maintenance dosage recommendations are the same as those described above. II. Chronic Therapy Theophylline is a treatment for relief and/or prevention of symptoms from asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. A dosage form that allows small incremental doses is desirable for initiating therapy. A liquid preparation should be considered for children to permit easier and more accurate dosage adjustment. Slow clinical titration is generally preferred to assure acceptance and safety of the medication, and to allow the patient to develop tolerance to transient caffeine-like side effects. Initial Dose 16 mg/kg/24 hours or 400 mg/24 hours (whichever is less) of anhydrous theophylline in divided doses at 6-or 8-hour intervals. Increasing Dose The above dosage may be increased in approximately 25 percent increments at 3-day intervals so long as the drug is tolerated, until clinical response is satisfactory or the maximum dose indicated in section III (below) is reached. The serum concentration may be checked at these intervals, but at a minimum should be determined at the end of this adjustment period. It is important that no patient be maintained on any dosage that is not tolerated. When instructing patients to increase dosage according to the schedule above, they should be told not to take a subsequent dose if apparent side effects occur and to resume therapy at a lower dose once adverse effects have disappeared. III. Maximum Dose of Theophylline Where the Serum Concentration is Not Measured WARNING: DO NOT ATFEMPT TO MAINTAIN ANY DOSE THAT IS NOT TOLERATED. Not to exceed the following (or 900 mg, whichever is less): Age 1 to under 9 years 24 mg/kg/day Age 9 to under 12 years 20 mg/kg/day Age 12 to under 16 years 18 mg/kg/day Age 16 years or older 13 mg/kg/day IV. Measurement of Serum Theophylline Concentrations During Chronic Therapy If the above maximum doses are to be maintained or exceeded, serum theophylline measurement is essential (see PRECAUTIONS: Laboratory Tests for guidance). V. Final Adjustment of Dosage Dosage adjustment after serum theophylline measurement If serum theophylline is: Directions: Within desired range Maintain dosage if tolerated. Too high 20 to 25 µg/mL Decrease doses by about 10% and recheck serum level after 3 days. 25 to 30 pg/mL Skip the next dose and decrease subsequent doses by about 25%. Recheck serum level after 3 days. Over 30 pg/mL Skip next 2 doses and decrease subsequent doses by 50%. Recheck serum level after 3 days. Too low Increase dosage by 25% at 3- day intervals until either the desired serum concentration and/ or clinical response is achieved. The total daily dose may need to be administered at more frequent intervals if symptoms occur repeatedly at the end of a dosing interval. The serum concentration may be rechecked at appropriate intervals, but at least at the end of any adjustment period. When the patient's condition is otherwise clinically stable and none of the recognized factors that alter elimination are present, measurement of serum levels need be repeated only every 6 to 12 months. HOW SUPPLIED Strength Size NDC Color Markings 100 mg tablets Bottles of 100 0075-0351-68 White Rhone-Poulenc Rorer Logo and 351 200 mg tablets Bottles of 100 0075-0352-68 White Rhone-Poulenc Rorer Logo and 352 80 mg/15 mL nonalcoholic syrup 16 FL OZ 0075-3650-16 Pink STORAGE CONDITIONS: Store at room temperature. Protect from excessive heat, light and moisture. Caution: Federal law prohibits dispensing without prescription. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN

PATIENT INFORMATION The physician should reinforce the importance of taking only the prescribed dose at the prescribed time intervals.

OVERDOSE Management It is suggested that the management principles (consistent with the clinical status of the patient when first seen) outlined below be instituted and that simultaneous contact with a Regional Poison Control Center be established. In this way both updated information and individualization regarding required therapy may be provided. 1. When potential oral overdose is established and seizure has not occurred: If patient is alert and seen soon after ingestion, induction of emesis may be of value. Gastric lavage has been demonstrated to be of no value in influencing outcome in patients who present more than 1 hour after ingestion. Administer a cathartic. Sorbitol Solution is reported to be of value. Administer repeated doses of activated charcoal and monitor theophylline serum levels. Prophylactic administration of phenobarbital has been shown to increase the seizure threshold in laboratory animals, and administration of this drug may be of value. 2. If patient presents with a seizure: Establish an airway. Administer oxygen. Treat the seizure with intravenous diazepam 0.1 to 0.3 mg/kg up to 10 mg. If seizures cannot be controlled, the use of general anesthesia should be considered. Monitor vital signs, maintain blood pressure and provide adequate hydration. 3. If postseizure coma is present: Maintain airway and oxygenation. Follow above recommendations to prevent absorption of drug, but intubation and lavage will have to be performed instead of inducing emesis and the cathartic and charcoal will need to be introduced via a large-bore gastric lavage tube. Continue to provide full supportive care and adequate hydration until the drug is metabolized. In general, drug metabolism is sufficiently rapid so as not to warrant dialysis. If repeated oral activated charcoal is ineffective (as noted by stable or rising serum levels), charcoal hemoperfusion may be indicated. CONTRAINDICATIONS Slo-Phyllin (theophylline, anhydrous) Tablets and Syrup are contraindicated in individuals who have shown hypersensitivity to any of the components of this product or to xanthine derivatives. It is also contraindicated in patients with active peptic ulcer disease, and in individuals with underlying seizure disorders (unless receiving appropriate anticonvulsant medication).

WARNINGS 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. Decreased clearance of theophylline may be associated with either influenza immunization or active influenza, and with other viral infections. 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. PRECAUTIONS General 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. Laboratory Tests 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. Drug Interactions 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. Carcinogenesis, Mutagenesis, and Impairment of Fertility 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. Pregnancy 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. Nursing Mothers 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. Pediatric Use 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 Premature Infants: 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.