Isorsorbide Mononitrate Extended-release

ISORSORBIDE MONONITRATE EXTENDED-RELEASE- isosorbide mononitrate tablet, coated
Actavis Elizabeth LLC

DESCRIPTION

Isosorbide mononitrate, an organic nitrate and the major biologically active metabolite of isosorbide dinitrate, is a vasodilator with effects on both arteries and veins.

Isosorbide mononitrate extended-release tablets for oral administration contain 30 mg or 60 mg of isosorbide mononitrate in an extended-release formulation. The inactive ingredients are carnauba wax, colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maltodextrin, polyethylene glycol, stearic acid, titanium dioxide, and triacetin. The 60 mg tablet also contains synthetic red iron oxide and synthetic yellow iron oxide. The chemical name for isosorbide mononitrate is 1,4:3,6-dianhydro-D-glucitol 5-nitrate; the compound has the following structural formula:

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Isosorbide mononitrate is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of about 90°C, and an optical rotation of +144° (2% in water, 20°C).

Isosorbide mononitrate is freely soluble in water, ethanol, methanol, chloroform, ethyl acetate, and dichloromethane.

CLINICAL PHARMACOLOGY

Mechanism Of Action:This product is an oral extended-release formulation of isosorbide mononitrate, the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate.

The principal pharmacological action of isosorbide mononitrate and all organic nitrates in general is relaxation of vascular smooth muscle, producing dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood, decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, and systolic arterial pressure and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Pharmacodynamics: Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored. Isosorbide mononitrate extended-release tablets during long-term use over 42 days dosed at 120 mg once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing but its effects (although better than placebo) are less than or at best equal to the effects of the first dose of 60 mg.

Pharmacokinetics And Metabolism: After oral administration of isosorbide mononitrate as a solution or immediate-release tablets, maximum plasma concentrations of isosorbide mononitrate are achieved in 30 to 60 minutes, with an absolute bioavailability of approximately 100%. After intravenous administration, isosorbide mononitrate is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6-0.7 L/kg. Isosorbide mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide mononitrate is cleared by denitration to isosorbide and glucuronidation as the mononitrate, with 96% of the administered dose excreted in the urine within 5 days and only about 1% eliminated in the feces. At least six different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least five metabolites. The metabolites are not pharmacologically active. Renal clearance accounts for only about 4% of total body clearance. The mean plasma elimination half-life of isosorbide mononitrate is approximately 5 hours.

The disposition of isosorbide mononitrate in patients with various degrees of renal insufficiency, liver cirrhosis, or cardiac dysfunction was evaluated and found to be similar to that observed in healthy subjects. The elimination half-life of isosorbide mononitrate was not prolonged, and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing.

The pharmacokinetics and/or bioavailability of isosorbide mononitrate extended-release tablets have been studied in both normal volunteers and patients following single- and multiple-dose administration. Data from these studies suggest that the pharmacokinetics of isosorbide mononitrate administered as isosorbide mononitrate extended-release tablets are similar between normal healthy volunteers and patients with angina pectoris. In single- and multiple-dose studies, the pharmacokinetics of isosorbide mononitrate were dose proportional between 30 mg and 240 mg.

In a multiple-dose study, the effect of age on the pharmacokinetic profile of isosorbide mononitrate extended-release 60 mg and 120 mg (2 x 60 mg) tablets was evaluated in subjects

≥ 45 years. The results of that study indicate that there are no significant differences in any of the pharmacokinetic variables of isosorbide mononitrate between elderly (≥ 65 years) and younger individuals (45-64 years) for the isosorbide mononitrate extended release 60 mg dose. The administration of isosorbide mononitrate extended release tablets 120 mg (2 x 60 mg tablets every 24 hours for 7 days) produced a dose-proportional increase in Cmax and AUC, without changes in Tmax or the terminal half-life. The older group (65-74 years) showed 30% lower apparent oral clearance (Cl/F) following the higher dose, ie, 120 mg, compared to the younger group (45-64 years); Cl/F was not different between the two groups following the 60 mg regimen. While Cl/F was independent of dose in the younger group, the older group showed slightly lower Cl/F following the 120 mg regimen compared to the 60 mg regimen. Differences between the two age groups, however, were not statistically significant. In the same study, females showed a slight (15%) reduction in clearance when the dose was increased. Females showed higher AUCs and Cmax compared to males, but these differences were accounted for by differences in body weight between the two groups. When the data were analyzed using age as a variable, the results indicated that there were no significant differences in any of the pharmacokinetic variables of isosorbide mononitrate between older (≥ 65 years) and younger individuals (45-64 years). The results of this study, however, should be viewed with caution due to the small numbers of subjects in each age subgroup and consequently the lack of sufficient statistical power.

The following table 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:

SINGLE-DOSE STUDIES MULTIPLE-DOSE STUDIES
PARAMETER ISOSORBIDE
MONONITRATE
60 mg
ISOSORBIDE MONONITRATE
EXTENDED-RELEASE
60 mg
ISOSORBIDE MONONITRATE
EXTENDED-RELEASE
60 mg
ISOSORBIDE MONONITRATE
EXTENDED-RELEASE
120 mg
Cmax (ng/mL) 1242-1534 424-541 557-572 1151-1180
Tmax (hr) 0.6-0.7 3.1-4.5 2.9-4.2 3.1-3.2
AUC (ng•hr/mL 8189-8313 5990-7452 6625-7555 14241-16800
t½ (hr) 4.8-5.1 6.3-6.6 6.2-6.3 6.2-6.4
Cl/F (mL/min) 120-122 151-187 132-151 119-140

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 Tmax ) but not the extent (AUC) of absorption of isosorbide mononitrate.

CLINICAL TRIALS :

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 treatment group.

Pooled data from two other trials, comparing isosorbide mononitrate extended-release tablets 60 mg once daily, isosorbide dinitrate 30 mg QID, and placebo QID in patients with chronic stable angina using a randomized, double-blind, three-way crossover design found statistically significant increases in exercise tolerance times for isosorbide mononitrate extended-release tablets compared to placebo at hours 4, 8, and 12 and to isosorbide dinitrate at hour 4. The increases in exercise tolerance on day 14, although statistically significant compared to placebo, were about half of that seen on day 1 of the trial.

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