theophylline 300 MG Extended Release Oral Capsule

INDICATIONS AND USAGE: Theophylline extended-release tablets are 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.

DOSAGE AND ADMINISTRATION Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg can be taken once a day in the morning or evening. It is recommended that Theophylline (Anhydrous) Extended-Release Tablets be taken with meals. Patients should be advised that if they choose to take Theophylline (Anhydrous) Extended-Release Tablets with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food. Theophylline (Anhydrous) Extended-Release Tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline. Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release theophylline product may be transferred to once-daily administration of 400 or 600 mg Theophylline (Anhydrous) Extended-Release Tablets on a mg-for-mg basis. It must be recognized that the peak and trough serum theophylline levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen. General Considerations 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/d in adults <60 years or 22 mg/kg/d 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 ). Healthcare providers should instruct patients and caregivers 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 (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. 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 admin. QD 300 mg/day If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ). admin. QD 2. After 3 days, if tolerated , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day admin. QD 400-600 mg/day admin. QD 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 admin. QD As with all theophylline products, doses greater than 600 mg should be titrated according to blood level (See Table VI ). 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 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 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 <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. 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 ). 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

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 <1 year, Elderly (>60 years) Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (≥102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants <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 healthcare professional 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 healthcare professional 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 ). 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 <1 year, Elderly (>60 years) Concurrent Diseases: Acute pulmonary edema, congestive heart failure, cor-pulmonale, fever (≥102° for 24 hours or more; or lesser temperature elevations for longer periods), reduced renal function in infants <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 healthcare professional 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 healthcare professional 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 ).

CONTRAINDICATIONS Theophylline (Anhydrous) Extended-Release Tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

CLINICAL PHARMACOLOGY: Mechanism of Action: Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Theophylline are not known with certainty, studies in animals suggest that bronchodilation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel. Serum Concentration-Effect Relationship: Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug's potential therapeutic benefit while minimizing the risk of serious adverse events. Pharmacokinetics: Overview: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory Tests ). Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states. ¶ Population Characteristics Total body clearance* mean (range)†† (mL/kg/min) Half-life mean (range)†† (hr) Age Premature neonates postnatal age 3-15 days 0.29 (0.09-0.49) 30 (17-43) postnatal age 25-57 days 0.64 (0.04-1.2) 20 (9.4-30.6) Term infants postnatal age 1-2 days NR† 25.7 (25-26.5) postnatal age 3-30 weeks NR† 11 (6-29) Children 1-4 years 1.7 (0.5-2.9) 3.4 (1.2-5.6) 4-12 years 1.6 (0.8-2.4) NR† 13-15 years 0.9 (0.48-1.3) NR† 6-17 years 1.4 (0.2-2.6) 3.7 (1.5-5.9) Adults (16-60 years) otherwise healthy non-smoking asthmatics 0.65 (0.27-1.03) 8.7 (6.1-12.8) Elderly (>60 years) non-smokers with normal cardiac, liver, and renal function 0.41 (0.21-0.61) 9.8 (1.6-18) Concurrent illness or altered physiological state Acute pulmonary edema 0.33** (0.07-2.45) 19** (3.1-82) COPD->60 years, stable non-smoker >1 year 0.54 (0.44-0.64) 11 (9.4-12.6) COPD with cor pulmonale 0.48 (0.08-0.88) NR† Cystic fibrosis (14-28 years) 1.25 (0.31-2.2) 6.0 (1.8-10.2) Fever associated with acute viral respiratory illness (children 9-15 years) NR† 7.0 (1.0-13) Liver disease - cirrhosis 0.31** (0.1-0.7) 32** (10-56) acute hepatitis 0.35 (0.25-0.45) 19.2 (16.6-21.8) cholestasis 0.65 (0.25-1.45) 14.4 (5.7-31.8) Pregnancy - 1st trimester NR† 8.5 (3.1-13.9) 2nd trimester NR† 8.8 (3.8-13.8) 3rd trimester NR† 13.0 (8.4-17.6) Sepsis with multi-organ failure 0.47 (0.19-1.9) 18.8 (6.3-24.1) Thyroid disease - hypothyroid 0.38 (0.13-0.57) 11.6 (8.2-25) hyperthyroid 0.8 (0.68-0.97) 4.5 (3.7-5.6) ¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. *Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. ††Reported range or estimated range (mean ± 2 SD) where actual range not reported. †NR = not reported or not reported in a comparable format. **Median NOTE: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline. Absorption: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single dose immediate release theophylline of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hour after the dose. Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms. Single-Dose Study: (450 mg) A single-dose, two-way crossover study was conducted in sixteen healthy male volunteers under fasting conditions with one 450 mg tablet being administered at 7 a.m. with a 6 oz. glass of water. No food or liquid (other than water) was allowed for 4 hours after which a standard lunch was served. Mean peak theophylline serum levels (C max ) was 6.69 mcg/mL and mean time of peak serum concentration (T max ) was 8.31 hours. (300 mg) A single-dose crossover study was conducted in twelve healthy male volunteers to compare pharmacokinetic parameters when theophylline extended-release tablets were administered with and without food. Subjects were fasted overnight and received a single 300 mg tablet early the following morning. When dosing was done under fed conditions, the subjects received a standard breakfast consisting of 2 fried eggs, 2 strips of bacon, 4 oz. hash brown potatoes, 1 slice of toast with a pat of butter, and 8 oz. whole milk 15 minutes pre-dosing. No food was allowed for five hours post-dosing, then a standard lunch was served; at ten hours post-dosing a standard supper was served. Mean peak theophylline serum levels for the two treatments were 3.7 mcg/mL (fasting) and 4.4 mcg/mL (with food). The time of peak serum level varied from subject to subject, occurring from 4 to 14 hours after dosing. However, 92% of the subjects had serum levels at least 75% of the maximum value at 4 to 8 hours after dosing, during each phase. Thus, blood samples taken 4 to 8 hours post-dosing should reference the peak serum level for most patients. The mean Tmax was 6.2 hours (fasting) and 8.7 hours (with food). The respective AUC (0-inf.) for these treatments were 73.3 mcg x hr/mL and 82.2 mcg x hr/mL, respectively. Multiple-Dose Study: (300 mg) A multiple-dose, steady-state study was conducted under fed conditions. Three high fat content meals were serve