ISOSORBIDE MONONITRATE- isosorbide mononitrate tablet, extended release
Golden State Medical Supply, Inc.
Isosorbide mononitrate tablets contain either 30 mg, 60 mg or 120 mg of isosorbide mononitrate in an extended-release formulation. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, lactose monohydrate and magnesium stearate.
The molecular formula of ISMN is C 6 H 9 NO 6 and the molecular weight is 191.14. The chemical name for ISMN is 1,4:3,6-dianhydro-,D-glucitol 5-nitrate; the compound has the following structural formula:
Isosorbide mononitrate is freely soluble in water, acetic acid, alcohol, acetone and ethyl acetate; soluble in ether and chloroform, slightly soluble in toluene; practically insoluble in aliphatic hydrocarbons.
Isosorbide mononitrate extended-release tablets, USP meets USP Dissolution Test 8.
Isosorbide mononitrate extended-release tablet are an oral extended-release formulation of ISMN, 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 ISMN 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 and 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, 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.
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.
After oral administration of ISMN as a solution or immediate-release tablets, maximum plasma concentrations of ISMN are achieved in 30 to 60 minutes, with an absolute bioavailability of approximately 100%. After intravenous administration, ISMN is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6 to 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 ISMN is approximately 5 hours.
The disposition of ISMN 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 ISMN 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 ISMN 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 ISMN 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 tablets, 60 mg and 120 mg (2 × 60 mg) 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 ISMN between elderly (≥65 years) and younger individuals (45 to 64 years) for the isosorbide mononitrate extended-release tablets 60 mg dose. The administration of isosorbide mononitrate extended-release tablets 120 mg (2 × 60 mg tablets every 24 hours for 7 days) produced a dose-proportional increase in C max and AUC, without changes in T max or the terminal half-life. The older group (65 to 74 years) showed 30% lower apparent oral clearance (Cl/F) following the higher dose, i.e., 120 mg, compared to the younger group (45 to 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 C max 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 ISMN between older (≥65 years) and younger individuals (45 to 64 years). The results of this study, however, should be viewed with caution due to the small number of subjects in each age subgroup and consequently the lack of sufficient statistical power.
The following table summarizes key pharmacokinetic parameters of ISMN after single- and multiple-dose administration of ISMN as an oral solution or isosorbide mononitrate extended-release tablets:
|SINGLE-DOSE STUDIES||MULTIPLE-DOSE STUDIES|
|PARAMETER||ISMN 60 mg||ISMN Extended-Release Tablets 60 mg||ISMN Extended-Release Tablets 60 mg||ISMN Extended-Release Tablets 120 mg|
|C max (ng/mL)||1242 to 1534||424 to 541||557 to 572||1151 to 1180|
|T max (hr)||0.6 to 0.7||3.1 to 4.5||2.9 to 4.2||3.1 to 3.2|
|AUC (ng∙hr/mL)||8189 to 8313||5990 to 7452||6625 to 7555||14241 to 16800|
|T ½ (hr)||4.8 to 5.1||6.3 to 6.6||6.2 to 6.3||6.2 to 6.4|
|Cl/F (mL/min)||120 to 122||151 to 187||132 to 151||119 to 140|
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.