THEO-24

Theophylline Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2, 6-dione, 3, 7-dihydro-1, 3-dimethyl-, and is represented by the following structural formula: The molecular formula of anhydrous theophylline is C 7 H 8 N 4 O 2 with a molecular weight of 180.17. Theo-24 is available as capsules intended for oral administration, containing 100 mg, 200 mg, 300 mg, or 400 mg of anhydrous theophylline per capsule, in an extended-release formulation which allows a 24-hour dosing interval for appropriate patients. Inactive ingredients are edible ink (which contains synthetic black iron oxide, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Yellow No. 6, D&C Yellow No. 10, FD&C Red No. 40), ethylcellulose, gelatin, pharmaceutical glaze, colloidal silicon dioxide, starch, sucrose, talc, titanium dioxide, and coloring agents: 100 mg - includes FD&C Yellow No. 6; 200 mg - FD&C Red No. 3 and D&C Yellow No. 10; 300 mg - FD&C Blue No. 1 and FD&C Red No. 40; 400 mg - FD&C Red No. 40 and D&C Red No. 28. Theo-24 Extended-release capsules meet Drug Release Test 6 as published in the current USP monograph for Theophylline Extended-release Capsules. This the structural formula for anhydrous theophylline.

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

General Considerations: Theo-24, like other extended-release theophylline products, is intended for patients with relatively continuous or recurring symptoms who have a need to maintain therapeutic serum levels of theophylline. It is not intended for patients experiencing an acute episode of bronchospasm (associated with asthma, chronic bronchitis, or emphysema). Such patients require rapid relief of symptoms and should be treated with an immediate-release or intravenous theophylline preparation (or other bronchodilators) and not with extended-release products. Patients who metabolize theophylline at a normal or slow rate are reasonable candidates for once-daily dosing with Theo-24. Patients who metabolize theophylline rapidly (e.g., the young, smokers, and some nonsmoking adults) and who have symptoms repeatedly at the end of a dosing interval, will require either increased doses given once a day or preferably, are likely to be better controlled by a schedule of twice-daily dosing. Those patients who require increased daily doses are more likely to experience relatively wide peak-trough differences and may be candidates for twice-a-day dosing with Theo-24. Patients should be instructed to take this medication each morning at approximately the same time and not to exceed the prescribed dose. Recent studies suggest that dosing of extended-release theophylline products at night (after the evening meal) results in serum concentrations of theophylline which are not identical to those recorded during waking hours and may be characterized by early trough and delayed peak levels. This appears to occur whether the drug is given as an immediate-release, extended-release, or intravenous product. To avoid this phenomenon when two doses per day are prescribed, it is recommended that the second dose be given 10 to 12 hours after the morning dose and before the evening meal. Food and posture, along with changes associated with circadian rhythm, may influence the rate of absorption and/or clearance rates of theophylline from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended that Theo-24 (when used as a once-a-day product) be administered at night. Patients who require a relatively high dose of theophylline (i.e., a dose equal to or greater than 900 mg or 13 mg/kg, whichever is less) should not take Theo-24 less than 1 hour before a high-fat-content meal since this may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state (see PRECAUTIONS, Drug/Food Interactions ). The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10 - 20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400 - 1600 mg/day in adults <60 years old and 10 - 36 mg/kg/day in children 1 - 9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/day in adults <60 years or 22 mg/kg/day in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10 - 20 mcg/mL in about 50% and 20 - 30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated , in small increments (See Table V). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION , Table VI). Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ). If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Table V. Dosing initiation and titration (as anhydrous theophylline).* * Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A reliably absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals. A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance . Titration Step Children <45 kg Children >45 kg and adults 1. Starting Dosage 12 - 14 mg/kg/day up to a maximum of 300 mg/day divided Q 24 hrs* 300 - 400 mg/day 1 divided Q 24 hrs* 2. After 3 days, if tolerated , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q 24 hrs* 400 - 600 mg/day 1 divided Q 24 hrs* 3. After 3 more days, if tolerated and if needed , increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided Q 24 hrs* As with all theophylline products, doses greater than 600 mg should be titrated according to blood level (see Table VI) 1 If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ). B. Patients with risk factors for impaired clearance, the elderly (>60 Years), and those in whom it is not feasible to monitor serum theophylline concentrations: In children 12-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. Table VI. Dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment * Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS ). <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment. 10 - 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.* If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. 15 - 19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. * 20 - 24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. 25 - 30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdosage treatment is indicated (see recommendations for chronic overdosage ). >30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage ). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

Theo-24 is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

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) * 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. 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

Drug/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 Table II is current as of June 2004. The listing of drugs in Table III is current as of January 2, 1996. New interactions are continuously being reported for theophylline, especially with new chemical entities. The healthcare professional 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 (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 (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 non-depolarizing 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 PB. 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 St. John's Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity. 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 hydrocortisone ofloxacin amoxicillin isoflurane omeprazole ampicillin, with or without isoniazid prednisone, prednisolone sulbactam isradipine ranitidine atenolol influenza vaccine rifabutin azithromycin ketoconazole roxithromycin caffeine, dietary ingestion lomefloxacin sorbitol cefaclor mebendazole (purgative doses do co-trimoxazole (trimethoprim medroxyprogesterone not inhibit theophylline and sulfamethoxazole) methylprednisolone absorption) diltiazem metronidazole sucralfate dirithromycin metoprolol terbutaline, systemic enflurane nadolol terfenadine famotidine nifedipine tetracycline felodipine nizatidine tocainide finasteride norfloxacin Drug/Food Interactions Taking Theo-24 ® less than one hour before a high-fat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon strips, 2 oz hashed brown potatoes, and 2 slices of buttered toast (about 985 calories, including approximately 71 g of fat) may result in a significant increase in peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state. In some cases (especially with doses of 900 mg or more taken less than one hour before a high-fat-content meal) serum theophylline levels may exceed the 20 mcg/mL level, above which theophylline toxicity is more likely to occur.

STORAGE Store below 77° F (25° C).