TABLE 1 summarizes key pharmacokinetic parameters of isosorbide mononitrate after single- and multiple-dose administration of isosorbide mononitrate as an oral solution or isosorbide mononitrate extended release tablets:

Food Effects: The influence of food on the bioavailability of isosorbide mononitrate after single-dose administration of isosorbide mononitrate extended release tablets 60 mg was evaluated in three different studies involving either a "light" breakfast or a high-calorie, high-fat breakfast. Results of these studies indicate that concomitant food intake may decrease the rate (increase in T_max) but not the extent (AUC) of absorption of isosorbide mononitrate.

CLINICAL STUDIES

Immediate Release Tablets

Controlled trials of single doses of isosorbide mononitrate tablets have demonstrated that antianginal activity is present about 1 hour after dosing, with peak effect seen from 1-4 hours after dosing.

In placebo-controlled trials lasting 2-3 weeks, isosorbide mononitrate tablets were administered twice daily, in asymmetric regimens (with interdosing intervals of 7 and 17 hours) designed to avoid tolerance. One trial tested doses of 10 mg and 20 mg; one trial tested doses of 20 mg, 40 mg, and 60 mg; and three trials tested only doses of 20 mg. In each trial, the subjects were persons with known chronic stable angina, and the primary measure of efficacy was exercise tolerance on a standardized treadmill test. After initial dosing and for at least three weeks, exercise tolerance in patients treated with isosorbide mononitrate 20 mg tablets was significantly greater than that seen in patients treated with placebo, although there was some attenuation of effect with time. Treatment with isosorbide mononitrate tablets was superior to placebo for at least 12 hours after the first dose (i.e., 5 hours after the second dose) of each day. Significant tolerance and rebound phenomena were not observed.

The 10-mg dose was not unequivocally superior to placebo, while the effect of the 40-mg dose was similar to that of the 20-mg dose. The 60-mg dose appeared to be less effective, and it was associated with a rebound phenomenon (early-morning worsening).

Extended Release Tablets

Controlled trials with isosorbide mononitrate extended release tablets have demonstrated antianginal activity following acute and chronic dosing. Administration of isosorbide mononitrate extended release tablets once daily, taken early in the morning on arising, provided at least 12 hours of antianginal activity.

In a placebo control parallel study, 30, 60, 120, and 240 mg of isosorbide mononitrate extended release tablets were administered once daily for up to 6 weeks. Prior to randomization, all patients completed a 1- to 3-week single-blind placebo phase to demonstrate nitrate responsiveness and total exercise treadmill time reproducibility. Exercise tolerance tests using the Bruce Protocol were conducted prior to and at 4 and 12 hours after the morning dose on days 1, 7, 14, 28, and 42 of the double-blind period. Isosorbide mononitrate extended release tablets 30 and 60 mg (only doses evaluated acutely) demonstrated a significant increase from baseline in total treadmill time relative to placebo at 4 and 12 hours after the administration of the first dose. At day 42, the 120 and 240 mg dose of isosorbide mononitrate extended release tablets demonstrated a significant increase in total treadmill time at 4 and 12 hours post dosing, but by day 42 the 30 and 60 mg doses no longer were differentiable from placebo. Throughout chronic dosing rebound was not observed in any isosorbide mononitrate extended release tablets treatment group.

Bookmark this page: