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 ). 

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 (Anhydrous) Extended-Release Tablets administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Theophylline (Anhydrous) Extended-Release Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the   
pharmacokinetic parameters were AUC=241.9 ± 83.0 mcg hr/mL, C max =9.3 ± 2.0 mcg/mL, T max =12.8 ± 4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7 ± 83.0 mcg hr/mL, C max =9.2 ± 2.0 mcg/mL, T max =12.5 ± 4.2 hours.

A study in which Theophylline (Anhydrous) Extended-Release 400 mg Tablets were administered to 17 fed adult asthmatics produced similar theophylline level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.

A single-dose study in 15 normal fasting male volunteers whose theophylline inherent mean elimination half-life was verified by a liquid theophylline product to be 6.9±2.5 (SD) hours were administered two or three Theophylline (Anhydrous) Extended Release 400 mg Tablets. The relative bioavailability of Theophylline (Anhydrous) Extended-Release Tablets given in the fasting state in comparison to an immediate-release product was 59%. Peak serum theophylline levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Theophylline (Anhydrous) Extended-Release Tablets was 17.2±5.8 (SD) hours.

Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Theophylline (Anhydrous) Extended-Release Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Theophylline (Anhydrous) Extended-Release Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C max and C min values obtained in this study were as follows:

Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, C max =8.4±2.6 mcg/mL, T max =17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, C max =5.5±1.5 mcg/mL, T max =6.5±2.1 hours.

Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Theophylline (Anhydrous) Extended-Release 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Theophylline (Anhydrous) Extended-Release Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, C max =10.9±1.7 mcg/mL, T max =11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, C max =6.7±1.7 mcg/mL, T max =7.3±2.2 hours.

Thus, administration of single Theophylline (Anhydrous) Extended-Release doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of theophylline with Theophylline (Anhydrous) Extended-Release Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Theophylline (Anhydrous) Extended-Release Tablet. A single-dose study in 24 subjects with an established theophylline clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Theophylline (Anhydrous) Extended-Release Tablet and one and one-half 400 mg Theophylline (Anhydrous) Extended-Release Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Theophylline (Anhydrous) Extended-Release Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, C max =10.58±2.21 mcg/mL and T max =9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, C max =10.39±1.91 mcg/mL and T max =9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, C max = 7.37±1.83 mcg/mL and T max =8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, C max =7.66±2.09 mcg/mL and T max =9.67±4.89 hours.

In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.

In another study, the bioavailability of the 600 mg Theophylline (Anhydrous) Extended-Release Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Theophylline (Anhydrous) Extended-Release Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, C max =10.6±1.3 mcg/mL and T max =12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, C max =9.7±1.4 mcg/mL and T max =13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of Theophylline (Anhydrous) Extended-Release Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Theophylline (Anhydrous) Extended-Release 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release theophylline product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).

The pharmacokinetic parameters for Theophylline (Anhydrous) Extended-Release 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, C max =12.1±3.8 mcg/mL, C min =4.50±3.6, T max =8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, C max =11.0±4.1 mcg/mL, C min =7.28±3.5, T max =6.9±3.4 hours. The mean percent fluctuation [(C max -C min /C min )x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg Theophylline (Anhydrous) Extended-Release Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Theophylline (Anhydrous) Extended-Release Tablets. All subjects had previously established theophylline clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Theophylline (Anhydrous) Extended-Release Tablet regimens. Steady-state results were:

The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.

Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Theophylline (Anhydrous) Extended-Release Tablets whether dosed in the morning or evening.